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0e62b82f017a0682b72160f2502977f0

The results indicate that bombesin and acetylcholine are the main intramural neural regulators of gastrin and somatostatin secretion .

Inhibition of neurally mediated gastrin secretion by bombesin antiserum. In vitro studies on the vascularly perfused rat stomach have shown that gastrin secretion is regulated by intramural cholinergic and noncholinergic neurons. We have postulated that bombesin (gastrin-releasing peptide), a known gastrin stimulant present in antral mucosal nerve fibers, is the most likely candidate for noncholinergic transmitter. bombesin antiserum (final dilution, 1:150) but not control serum added to the vascular perfusate inhibited the gastrin response to 1,1-dimethyl-4-phenylpiperazinium by 59 +/- 17% (P less than 0.01) and to electrical field stimulation by 60 +/- 16% (P less than 0.01), and its effect was additive to that of 10(-7) M atropine (75-94%), thus accounting for the greater part of neurally induced gastrin secretion. The effects of atropine and bombesin antiserum on somatostatin secretion were consistent also with blockade of cholinergic and noncholinergic neurons, respectively. The results indicate that bombesin and acetylcholine are the main intramural neural regulators of gastrin and somatostatin secretion . Acetylcholine acts predominantly to decrease the paracrine secretion of somatostatin, thereby eliminating the continuous restraint of somatostatin on gastrin secretion and enabling bombesin to exert its potent stimulatory effect on gastrin secretion.

https://pubmed.ncbi.nlm.nih.gov/2858981/

024d9fa53cb36e2f053a42cd0283b6ff

Synergistic effects were seen between zeaxanthin and resveratrol or meclofenamic acid .

Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. Although the exact pathogenesis of age-related macular degeneration (AMD) is not clear, most studies indicate a role for retinal pigment epithelial (RPE) cell damage and death caused by oxidative stress. The purpose of this study was to examine the potential protective effects of lutein, zeaxanthin, meclofenamic acid, and resveratrol on the acrolein-induced oxidative stress in human RPE cells. ### methods Cultured human RPE R-50 cells were treated with acrolein at different concentrations and treatment times. The protective effects of lutein (100 microM), zeaxanthin (100 microM), meclofenamic acid (30 microM), and resveratrol (10 microM) were investigated by pretreatment with the above agents before toxicant exposure in acute toxicity models and cotreatment with the toxicant in chronic toxicity models. The synergistic effects of acrolein and hydrogen peroxide exposure were also studied. Fluorescent latex beads were used to assess the phagocytic function of the cells. ### results Acrolein inhibited the phagocytic function of human RPE R-50 cells, and the inhibitory effects were time dependent. Pretreatment with lutein, zeaxanthin, meclofenamic acid, or resveratrol alleviated the inhibition of phagocytosis in the acute acrolein and combined acrolein/hydrogen peroxide toxicity models. Synergistic effects were seen between zeaxanthin and resveratrol or meclofenamic acid . Cotreatment with lutein, zeaxanthin, meclofenamic acid, or resveratrol showed a protective effect against the damage caused by 7-day acrolein exposure followed by hydrogen peroxide treatment. ### conclusions Our results indicated an inhibitory effect of compounds found in cigarette smoke on human RPE phagocytosis, and lutein, zeaxanthin, meclofenamic acid, and resveratrol each offered protection against this inhibition. Therefore, red wine polyphenol, resveratrol, might ameliorate acrolein-induced or age-related RPE degeneration, such as AMD.

https://pubmed.ncbi.nlm.nih.gov/20565308/

cf1168701bbaab2b930ece01ee27c709

Among the non-faecalis organisms , penicillin resistance was significantly more frequent among isolates from patients given penicillin than from patients not given this antibiotic , and clindamycin resistance was significantly more frequent among isolates from patients given lincomycin and clindamycin than from patients not given these antibiotics .

Antibiotic susceptibilities of streptococci from the mouth and blood of patients treated with penicillin or lincomycin and clindamycin. Patients undergoing dental extractions were non-randomly allocated to three groups, one of which received no antibiotic, one benzylpenicillin followed by oral penicillin for 5 days, and the third intramuscular lincomycin followed by oral clindamycin. Dental extraction was performed at the beginning of the course of chemotherapy. Streptococci were isolated from the extracted teeth, from blood cultures collected before and immediately after dental extraction, and from sutures removed from the gums 5-7 days after the operation. The species of these organisms was determined, and their susceptibilities to penicillin, clindamycin, cephaloridine, erythromycin and tetracycline were assessed. The majority of streptococci isolated from teeth belonged to the species Streptococcus sanguis, S. mitior, S. mutans and S. milleri. Occasional isolates of each of these organisms collected before the antibiotic could take effect were resistant to penicillin. Three of these species, but not S. mutans, were the commonest streptococci to be isolated from the blood after dental extraction. Penicillin completely suppressed dental bacteriaemia under the conditions of our investigation, and lincomycin reduced the incidence by about 60 per cent. The commonest streptococci from sutures were also S. sanguis, S. mitior, S. mutans and S. milleri. S. faecalis was also isolated, but only in patients who had received antibiotics. Among the non-faecalis organisms , penicillin resistance was significantly more frequent among isolates from patients given penicillin than from patients not given this antibiotic , and clindamycin resistance was significantly more frequent among isolates from patients given lincomycin and clindamycin than from patients not given these antibiotics .

https://pubmed.ncbi.nlm.nih.gov/1050385/

39fc1b8fd6fc73d93cc01a141dfaf692

Fifthteen patients were included : 12 underwent erlotinib treatment and 3 a crizotinib treatment .

[Patient's beliefs about oral targeted therapies and impact on drug adherence in lung cancer: A pilot prospective study]. Oral targeted therapies are a new option for lung cancer treatment. However, patient's belief about these drugs - which may interact with adherence - is poorly known in this setting. ### method Our study is a pilot prospective unicentric study. Inclusion criteria were: to have been diagnosed with a lung cancer; and to be prescribed with an oral targeted therapy in second line or more. The main objective was to assess patient's specific (SB) and general beliefs (GB) about these drugs according to the Beliefs about Medicines Questionnaire (BMQ). The declared adherence was assessed with the Morisky's test. All included patients underwent a semi-structured interview with a psychologist. ### results Fifthteen patients were included : 12 underwent erlotinib treatment and 3 a crizotinib treatment . The mean score (±standard deviation) at BMQ was 54/85 (±6) overall; 34/50 (±5) for specific belief and 19/35 (±3) for general belief about drugs. During interview, 47% believed in efficacy of targeted oral therapy; 93% reported concerns about their drug; 80% considered that the information given by the physician about the drug was comprehensive; but 40% still required additional information about it. The mean score at Morisky's test was 3/4 (±2) and 53% reported to have forgotten at least once their antineoplastic drug. No correlation was found between belief and adherence. ### conclusion Belief about t anti-cancer targeted oral therapy is relatively fair but adherence is moderate in this pilot study. Interview shows the need for additional information about the prescribed drug.

https://pubmed.ncbi.nlm.nih.gov/26210879/

2b9d190145ddd4a628f05555cb7921d3

The combination of trastuzumab with paclitaxel ( Taxol ) is well approved .

Immunotherapy: new options in breast cancer treatment. Immunotherapy is a promising new approach in breast cancer treatment, complementing surgery, chemotherapy, radiation and antihormonal therapy. Primarily, two treatment options are available which are supported by a rapidly growing body of clinical evidence. These are active specific immunotherapy with Theratope and passive immunotherapy targeting the HER-2 receptor with trastuzumab (Herceptin). trastuzumab has a proven efficacy as monotherapy as well as in combination with chemotherapeutic agents in HER-2-overexpressing metastatic breast cancer. trastuzumab is generally well tolerated although cardiotoxicity has been observed, especially when in combination with doxorubicin (Adriamycin), where this can be a serious concern. Therefore, less cardiotoxic combinations with docetaxel (Taxotere), vinorelbine (Navelbine) and epirubicin (Pharmorubicin) or cyclophosphamide (Endoxana) have been tested. The combination of trastuzumab with paclitaxel ( Taxol ) is well approved . The use of trastuzumab in adjuvant and preoperative therapy is currently being examined in controlled trials. After a brief outline of immunotherapy with Theratope and trastuzumab, this article reviews recent and ongoing clinical studies conducted with trastuzumab.

https://pubmed.ncbi.nlm.nih.gov/12820782/

94681c8fb169a65440199170cf112a55

Intensive regimen of combined immunosuppressive therapy ( high-dose corticosteroids , oral cyclosporin and intravenous cyclophosphamide ( IVCY , 900 - 1000 mg/m(2 ) in every other week ) ) improved the survival rate of anti-MDA5-positive patients .

[Anti-MDA5 (melanoma differentiation-associated gene 5) antibody and dermatomyositis with rapidly progressive interstitial pneumonia]. Anti-MDA5 antibody is one of the dermatomyositis-specific autoantibodies and anti-MDA5-potsitive patients show characteristic clinical features, such as hypomyositis, high prevalence of acute/subacute interstitial pneumonia (A/SIP) with poor prognosis, hyperferritinemia and elevated hepatobiliary enzyme. We found that serum IL-6, IL-18, M-CSF and IL-10 were significantly higher and serum IL-12 and IL-22 were significantly lower in anti-MDA5-positive patients than in anti-MDA5-negative patients before treatment. Taking together these serological findings, we hypothesized that monocyte and macrophage activation may underlie in the pathophysiology of anti-MDA5-positive patients. They rarely survive after they become to need oxygenation, and so need to be treated as soon as possible once the diagnosis has been made. Intensive regimen of combined immunosuppressive therapy ( high-dose corticosteroids , oral cyclosporin and intravenous cyclophosphamide ( IVCY , 900 - 1000 mg/m(2 ) in every other week ) ) improved the survival rate of anti-MDA5-positive patients . Especially, the serum ferritin levels tended to go down about 14 days after IVCY, suggesting that IVCY might be a key drug in the treatment of anti-MDA5-positive A/SIP patients.

https://pubmed.ncbi.nlm.nih.gov/23629426/

386773ec27190e0288d3c849b56376e8

Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib , hsa-miR-135a-3p for JNJ-707 and hsa-miR-185 - 3p for Panobinostat .

MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. In this way they might influence whether a cell is sensitive or resistant to a certain drug. So far, only a limited number of relatively small scale studies comprising few cell lines and/or drugs have been performed. To obtain a broader view on miRNAs and their association with drug response, we investigated the expression levels of 411 miRNAs in relation to drug sensitivity in 36 breast cancer cell lines. For this purpose IC50 values of a drug screen involving 34 drugs were associated with miRNA expression data of the same breast cancer cell lines. Since molecular subtype of the breast cancer cell lines is considered a confounding factor in drug association studies, multivariate analysis taking subtype into account was performed on significant miRNA-drug associations which retained 13 associations. These associations consisted of 11 different miRNAs and eight different drugs (among which paclitaxel, docetaxel and veliparib). The taxanes, paclitaxel and docetaxel, were the only drugs having miRNAs in common: hsa-miR-187-5p and hsa-miR-106a-3p indicative of drug resistance while paclitaxel sensitivity alone associated with hsa-miR-556-5p. tivantinib was associated with hsa-let-7d-5p and hsa-miR-18a-5p for sensitivity and hsa-miR-637 for resistance. Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib , hsa-miR-135a-3p for JNJ-707 and hsa-miR-185 - 3p for Panobinostat . Drug resistance was associated with hsa-miR-182-5p for veliparib and hsa-miR-629-5p for Tipifarnib. Pathway analysis for significant miRNAs was performed to reveal biological roles, aiding to find a potential mechanistic link for the observed associations with drug response. By doing so hsa-miR-187-5p was linked to the cell cycle G2-M checkpoint in line with this checkpoint being the target of taxanes. In conclusion, our study shows that miRNAs could potentially serve as biomarkers for intrinsic drug resistance and that pathway analyses can provide additional information in this context.

https://pubmed.ncbi.nlm.nih.gov/31063487/

4606c1b0568cd281128a16c2bbeef511

No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported .

Interstitial pneumonia suspected during regorafenib administration and exacerbated by subsequent therapy with lenvatinib for unresectable hepatocellular carcinoma. Recently, three tyrosine kinase inhibitors (TKIs) have become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a case of a 59-year-old man with interstitial pneumonia that was suspected during regorafenib administration and was exacerbated by subsequent lenvatinib treatment for advanced HCC. After sorafenib was discontinued due to progressive HCC, regorafenib treatment was started. Progressive HCC was again noted and reticular shadows were suspected in both lower lung fields at 2 months after starting regorafenib administration. Subsequent treatment with lenvatinib obtained a partial response for HCC, but the reticular shadows became marked and dyspnea on effort emerged, followed by hypoxemia and an increased Krebs von den Lungen-6 (KL-6) value. Because we suspected acute interstitial pneumonia, due to these TKIs, intravenous pulse steroid therapy was started immediately after discontinuing lenvatinib. Within 1 week after starting steroid therapy, the patient's respiratory condition and hypoxemia gradually began improving. No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported . This case emphasizes that it is necessary to observe the patient's respiratory condition and to perform imaging examinations to monitor for adverse events during TKI treatment.

https://pubmed.ncbi.nlm.nih.gov/31020569/

859d945a579d4986f9e78e5574061f18

Treatment of articular manifestations of Lyme borreliosis is based on doxycycline , ceftriaxone , or amoxicillin for 28 days .

Lyme borreliosis and other tick-borne diseases. Guidelines from the French scientific societies (II). Biological diagnosis, treatment, persistent symptoms after documented or suspected Lyme borreliosis. The serodiagnosis of Lyme borreliosis is based on a two-tier strategy: a screening test using an immunoenzymatic technique (ELISA), followed if positive by a confirmatory test with a western blot technique for its better specificity. Lyme serology has poor sensitivity (30-40%) for erythema migrans and should not be performed. The seroconversion occurs after approximately 6 weeks, with IgG detection (sensitivity and specificity both>90%). Serological follow-up is not recommended as therapeutic success is defined by clinical criteria only. For neuroborreliosis, it is recommended to simultaneously perform ELISA tests in samples of blood and cerebrospinal fluid to test for intrathecal synthesis of Lyme antibodies. Given the continuum between early localized and disseminated borreliosis, and the efficacy of doxycycline for the treatment of neuroborreliosis, doxycycline is preferred as the first-line regimen of erythema migrans (duration, 14 days; alternative: amoxicillin) and neuroborreliosis (duration, 14 days if early, 21 days if late; alternative: ceftriaxone). Treatment of articular manifestations of Lyme borreliosis is based on doxycycline , ceftriaxone , or amoxicillin for 28 days . Patients with persistent symptoms after appropriate treatment of Lyme borreliosis should not be prescribed repeated or prolonged antibacterial treatment. Some patients present with persistent and pleomorphic symptoms after documented or suspected Lyme borreliosis. Another condition is eventually diagnosed in 80% of them.

https://pubmed.ncbi.nlm.nih.gov/31155367/

efa4b08c5bbcc2355040e7796d79ceea

Serious adverse events were reported by 24 ( 34 % ) of 71 patients receiving olaparib and abiraterone ( seven of which were related to treatment ) and 13 ( 18 % ) of 71 patients receiving placebo and abiraterone ( one of which was related to treatment ) .

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. ### methods We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. ### findings Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 ( 34 % ) of 71 patients receiving olaparib and abiraterone ( seven of which were related to treatment ) and 13 ( 18 % ) of 71 patients receiving placebo and abiraterone ( one of which was related to treatment ) . One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. ### interpretation olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. ### funding AstraZeneca.

https://pubmed.ncbi.nlm.nih.gov/29880291/

7c77850fbf02b6b1536f130d367ec91e

In autoperfused hindquarters , the pressor-response curve to noradrenaline was dose-dependently shifted to the left by propranolol and to the right by labetalol or prazosin .

Blood pressure lowering action and alpha-adrenolytic effect of adimolol in rats. Adimolol is a new antihypertensive agent with strong nonselective beta- and moderate alpha-adrenolytic properties. In order to elucidate whether the alpha-adrenoceptor blockade by adimolol may contribute to the blood pressure lowering action of the compound, we tested 1) the effect on heart rate and blood pressure in conscious spontaneously hypertensive rats after oral administration and 2) the influence on the pressor effect of intra-arterially injected noradrenaline in autoperfused rat hindquarters after i.v. administration. Adimolol was compared with propranolol, labetalol, prazosin and combinations of propranolol plus low-dose prazosin. In conscious spontaneously hypertensive rats, labetalol, propranolol plus low-dose prazosin and adimolol lowered blood pressure considerably in parallel with heart rate. propranolol alone acutely lowered heart rate, but not blood pressure. Low-dose prazosin alone lowered blood pressure and heart rate only moderately. In autoperfused hindquarters , the pressor-response curve to noradrenaline was dose-dependently shifted to the left by propranolol and to the right by labetalol or prazosin . The leftward shift by propranolol could be antagonized dose-dependently by addition of low doses of prazosin. Adimolol, at doses of 0.1, 10 and 20 mg/kg, did not significantly influence the pressor-response curve to noradrenaline in this model, whereas a slight but significant shift to the left was observed with 1 mg/kg. In summary, the cardiovascular effects of adimolol in rats cannot completely be explained by beta-adrenoceptor blockade. They can be mimicked by the concomitant administration of a beta-adrenoceptor blocking and an alpha-adrenoceptor blocking agent. We conclude that the alpha-adrenolytic activity of adimolol can be demonstrated in vivo and may contribute to the blood pressure lowering action of the compound in rats.

https://pubmed.ncbi.nlm.nih.gov/2576194/

15c493f5c41258d28222b26c07daf4de

Expert opinion : Rivastigmine , a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase , is effective for dementia , whereas the use of Donepezil is still in the realm of investigation .

Pharmacotherapies for Parkinson's disease symptoms related to cholinergic degeneration. Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion : Rivastigmine , a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase , is effective for dementia , whereas the use of Donepezil is still in the realm of investigation . Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.

https://pubmed.ncbi.nlm.nih.gov/27785919/

d505ef0fff3fd78f3452d6b88fde849a

Chemotherapy with methotrexate , cyclophosphamide , vincristine , doxorubicin , etoposide , and dexamethasone was effective , and the patient has been free from the disease for 1 year since completion of consolidation treatment with autologous peripheral blood stem cell transplantation .

[Burkitt's lymphoma occurring as a primary lymphomatous effusion]. A 39-year-old man was admitted with massive ascites. Specimens of ascitic fluid contained numerous cells with a FAB-L3 appearance, and small noncleaved cell lymphoma morphology. These cells expressed CD10, CD19, CD20, CD38, CD45, HLA-DR, and IgM antigens, and were positive for IgM and c-myc protein in cytoplasmic immunostaining tests. Clonal rearrangements of IgH and c-myc genes were detected by Southern blot analysis. No mass lesions were found by physical examination, and systemic computed photography did not reveal enlargement of lymph nodes, spleen, or liver. Bone marrow aspiration showed no infiltration of malignant cells. Ga scintigraphy indicated hot lesions only in the abdomen. These findings suggested that Burkitt's lymphoma had developed in the peritoneal cavity as a primary lymphomatous effusion. Chemotherapy with methotrexate , cyclophosphamide , vincristine , doxorubicin , etoposide , and dexamethasone was effective , and the patient has been free from the disease for 1 year since completion of consolidation treatment with autologous peripheral blood stem cell transplantation .

https://pubmed.ncbi.nlm.nih.gov/10846464/

815dc3835a7afa5fb197dd55ae65116e

We have examined whether the DNA-damaging agents etoposide ( VP-16 ) and doxorubicin can affect IL-8 , VEGF , and HIF-1 expressions in human melanoma cancer cells .

A(2B) and A(3) adenosine receptors modulate vascular endothelial growth factor and interleukin-8 expression in human melanoma cells treated with etoposide and doxorubicin. Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often have abnormal growth factor and cytokine profiles. Thus, serum levels of interleukin-8 (IL-8) are elevated in patients with malignant melanoma. In addition to IL-8, aggressive melanoma cells secrete, through its transcriptional regulator hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), which promotes angiogenesis and metastasis of human cancerous cells. Whether these responses are related to adenosine, a ubiquitous mediator expressed at high concentrations in cancer and implicated in numerous inflammatory processes, is not known and is the focus of this study. We have examined whether the DNA-damaging agents etoposide ( VP-16 ) and doxorubicin can affect IL-8 , VEGF , and HIF-1 expressions in human melanoma cancer cells . In particular, we have investigated whether these responses are related to the modulation of the adenosine receptor subtypes, namely, A(1), A(2A), A(2B), and A(3). We have demonstrated that A(2B) receptor blockade can impair IL-8 production, whereas blocking A(3) receptors, it is possible to further decrease VEGF secretion in melanoma cells treated with VP-16 and doxorubicin. This understanding may present the possibility of using adenosine antagonists to reduce chemotherapy-induced inflammatory cytokine production and to improve the ability of chemotherapeutic drugs to block angiogenesis. Consequently, we conclude that adenosine receptor modulation may be useful for refining the use of chemotherapeutic drugs to treat human cancer more effectively.

https://pubmed.ncbi.nlm.nih.gov/19794965/

fff0835233d3ddbb7dcf88fe31cc57ee

The effect of combined therapy with tamsulosin hydrochloride and meloxicam in patients with benign prostatic hyperplasia symptoms and impact on nocturia and sleep quality .

The effect of combined therapy with tamsulosin hydrochloride and meloxicam in patients with benign prostatic hyperplasia symptoms and impact on nocturia and sleep quality . We aimed to compare the effect and feasibility of a combined therapy with tamsulosin hydrochloride plus meloxicam, and tamsulosin hydrochloride alone in patients with benign prostate hyperplasia symptoms and impact on nocturia and sleep quality. ### Materials And Methods Four hundred male patients were included in this study between 2008 and 2011. Patients were randomly divided into two groups: one received tamsulosin hydrochloride 0.4 mg (Group 1, 200 patients) and the other tamsulosin hydrochloride 0.4 mg plus meloxicam 15 mg (Group 2, 200 patients) prospectively. Patients were evaluated for benign prostate hyperplasia (BPH) symptoms according to the American Urological Association clinical guidelines and sleep quality according to Pittsburgh Sleep Quality Index (PSQI). Patients were reevaluated after three months of treatment. The International Prostatic Symptom Score (IPSS), IPSS-Quality of Life (IPSS-QoL), maximal urinary flow rates (Qmax), average urinary flow rates (AFR), post void residual urine volumes (PVR), nocturia and Pittsburgh Sleep Quality Score (PSQS) were recorded at baseline and after three months. ### results Mean age was 63.3 ± 6.6 and 61.4 ± 7.5 years in groups 1 and 2, respectively (p = 0.245). There were no statistically significant differences between both groups. Also, baseline prostate specific antigen (PSA), prostate volume, creatinine, International Prostatic Symptom Score (IPSS), IPSS-Quality of Life (IPSS-QoL), maximal urinary flow rates (Qmax), average urinary flow rates (AFR), post void residual urine volumes (PVR), nocturia and Pittsburgh Sleep Quality Score (PSQS) were similar in both groups. In addition, the total IPSS, IPSS-QoL, PVR, nocturia, and PSQS were significantly lower in Group 2 compared with Group 1 after treatment (p < 0.05). Qmax and AFR were higher significantly in Group 2 compared with Group 1 after treatment (p < 0.05). ### conclusions Cyclooxygenase (COX)-2 inhibitors in combination with an alpha blocker may decrease benign prostatic hyperplasia symptoms and increase sleep quality without serious side effects.

https://pubmed.ncbi.nlm.nih.gov/24267123/

92b0668dfd2cd4b06c20baf98572f867

We investigated two human ( RD2 and TE 671 ) cell lines by cultivating them with doxorubicin , cisplatinum , and etoposide .

Induction of drug resistance in human rhabdomyosarcoma cell lines is associated with increased maturation: possible explanation for differentiation in recurrences? In rhabdomyosarcoma (RMS) of childhood and adolescence very little is known about interactions of cytotoxic drugs and tumor cells. In recurrent RMS the tumor cells are often more mature than in the primary tumor. The biological properties of these cells are still a subject of controversy. We investigated two human ( RD2 and TE 671 ) cell lines by cultivating them with doxorubicin , cisplatinum , and etoposide . Degree of differentiation and proliferation rate were estimated morphologically and by means of immunohistochemistry and a monolayer proliferation assay. Both morphological and immunohistochemical maturation was measurable in most resistant cell lines. An increase in myosin expression was most marked in the etoposide- and doxorubicin-resistant RD cell lines. The proliferation rate was decreased in almost all resistant cell lines. Nevertheless, the resistant cell lines tolerated high-dose levels of cytotoxic drugs at a higher proliferation rate than parental cell lines cultivated under similar conditions. The maturation seen in some recurrent tumors of RMS can be simulated in vitro by cultivating cell lines with cytotoxic drugs at sublethal doses. Interestingly, the resistance-associated induced maturation was not accompanied by p170 expression. After comparing these in vitro results with the maturation seen in RMS specimens after chemotherapy, we conclude that chemotherapy-induced differentiation in vivo might be a morphological sign of chemoresistance.

https://pubmed.ncbi.nlm.nih.gov/12007020/

fdbfe393e896f570074585fcec3e2409

Retrospective study on antihyperlipidemic efficacy and safety of simvastatin , ezetimibe and their combination in Korean adults .

Retrospective study on antihyperlipidemic efficacy and safety of simvastatin , ezetimibe and their combination in Korean adults . Antihyperlipidemic agents such as 3-hydroxymethyglutaryl-coenzyme A reductase inhibitors and cholesterol transporter inhibitors are used in coronary heart disease. However, controversy remains over the pharmacologic effects and safety of these drugs, especially when used in combination therapies. This retrospective study evaluated the therapeutic effect and safety of simvastatin 20 mg and ezetimibe 10 mg combination therapy compared to simvastatin 20 mg or ezetimibe 10 mg monotherapy in Korean patients according to gender, age, baseline low-density lipoprotein cholesterol, and cardiovascular risk factors. We observed significant differences among patient subgroups. simvastatin and ezetimibe monotherapies and combination therapy reduced low-density lipoprotein cholesterol levels by 27.6%, 10.1%, and 36.8% (p < 0.001) and total cholesterol levels by 17.5%, 9.2%, and 25.3% (p < 0.001), respectively. Both monotherapy and combination therapy groups had similar incidences of all types of adverse events. However, one case of rhabdomyolysis was observed in the combination therapy group. These results suggest that, compared to monotherapy, combination therapy has an additive effect that is not influenced by risk factors. Despite the low incidence of adverse events, caution is required when using these drugs, especially in the context of musculoskeletal side effects.

https://pubmed.ncbi.nlm.nih.gov/21910055/

622f8e3f26b52587b2eda3e55333e6f1

The primary melanoma was surgically resected , and combination hepatic arterial infusion ( HAI ) therapy using dacarbazine , nimustine , vincristine ( DAV ) , and cisplatin was applied to the metastatic focus .

Combination hepatic arterial infusion therapy is effective for ocular melanoma metastasis to the liver. Regional treatments including chemotherapy have been applied to patients with malignant melanoma metastasis to the liver in clinical trials, but with limited efficacy. To improve efficacy, combination therapy may be beneficial. We had a case of multiple liver metastasis from right ocular malignant melanoma. The primary melanoma was surgically resected , and combination hepatic arterial infusion ( HAI ) therapy using dacarbazine , nimustine , vincristine ( DAV ) , and cisplatin was applied to the metastatic focus . After HAI, marked regression of the liver metastatic focus was observed. Unfortunately, the patient passed away due to involvement of thrombotic thrombocytopenic purpura 9 months after the initial consultation, however, aggravation of the liver metastatic focus was not observed. Combination HAI therapy may have a potent therapeutic effect on malignant melanoma metastasis to the liver, and our regimen using DAV and CDDP may be beneficial to the improvement of prognosis without serious side effects.

https://pubmed.ncbi.nlm.nih.gov/16273253/

d30d8e197ed62a5846fa39352fea2768

These results were similar to those of previously reported salvage therapies for relapsed AML including intensive chemotherapy consisting of intermediate-dose Ara-C and sequential mitoxantrone with or without etoposide ( MC/MEC ) , which we previously adopted .

[Comparison of low-dose cytosine arabinoside and aclarubicin in combination with granulocyte colony-stimulating factor to intermediate-dose cytosine arabinoside and mitoxantrone with or without etoposide in the treatment of relapsed acute myeloid leukemia]. We used a new chemotherapy regimen for the treatment of 18 consecutive patients with relapsed AML. The regimen consisted of low-dose cytosine arabinoside (Ara-C), low-dose aclarubicin and concurrent use of G-CSF (CAG regimen). Fifteen out of 18 patients (83%) achieved complete remission (CR). Median CR duration and median survival were 6 months and 15 months, respectively. These results were similar to those of previously reported salvage therapies for relapsed AML including intensive chemotherapy consisting of intermediate-dose Ara-C and sequential mitoxantrone with or without etoposide ( MC/MEC ) , which we previously adopted . Myelosuppression and non-hematological toxicities were apparently lower and less frequent compared to MC/MEC. The CAG regimen seems promising for the treatment of relapsed AML with its low toxicity contributing to a high quality of life for the patient.

https://pubmed.ncbi.nlm.nih.gov/7540220/

ebad3a925e573f30f197694c7209639f

Sensitivity of the test samples to the anti-cancer drugs cisplatin ( CDDP ) , doxorubicin ( DXR ) and etoposide ( VP-16 ) was examined using the MTT¿3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl [2H]-tetrazolium bromide ¿ assay .

Expression of multidrug-resistance-associated protein (MRP) and chemosensitivity in human gastric cancer. Evidence has accumulated that, in addition to the MDR1 gene-coded P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) also mediates the multidrug resistance (MDR) of various human tumors. In the case of gastric cancer, there is little or no involvement of P-glycoprotein, and the mechanisms of MDR remain to be understood. To search for a possible relationship between expression of MRP and sensitivity to anti-cancer agents in gastric cancer, 4 gastric cancer cell lines, 43 human gastric carcinomas and 17 adjacent normal gastric tissue samples were analyzed. Expression of MRP mRNA was evaluated using reverse transcription PCR (RT-PCR) and Southern hybridization. Sensitivity of the test samples to the anti-cancer drugs cisplatin ( CDDP ) , doxorubicin ( DXR ) and etoposide ( VP-16 ) was examined using the MTT¿3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl [2H]-tetrazolium bromide ¿ assay . Immunohistochemical staining with the use of the MRP antibody (MRPr1) was done to confirm the findings regarding the expression of mRNA levels. The MRP expression evaluated with RT-PCR and Southern hybridization as well as with immunohistochemical staining revealed that 23 of 43 gastric-cancer tissues (53.5%), 15 of 17 normal gastric tissues (88%) and 3 of 4 gastric-cancer cell lines (75%) were positive. The MTT assay showed that DXR was significantly more sensitive (p < 0.01) in gastric carcinoma tissues lacking MRP expression than in those with positive expression. The same tendency was seen with the other agents used. Of the cell lines, one which showed no MRP expression also had a higher sensitivity to CDDP, DXR and VP-16 than the other positive cases. These results show that MRP expression is involved in MDR of human gastric cancer and is inversely related to the chemosensitivity of tumor cells against some anticancer drugs.

https://pubmed.ncbi.nlm.nih.gov/8903480/

87e13e6988ace8256ef6c96df9bd8310

In this phase I study , we combined cyclophosphamide , alvocidib and rituximab ( CAR ) in a schema designed to mitigate tumor lysis syndrome ( TLS ) seen previously with alvocidib .

Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia. Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study , we combined cyclophosphamide , alvocidib and rituximab ( CAR ) in a schema designed to mitigate tumor lysis syndrome ( TLS ) seen previously with alvocidib . Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.

https://pubmed.ncbi.nlm.nih.gov/23867058/

e08870403d68a688ed8b3eb1241f2f6d

Newer-generation recombinant tissue-type plasminogen activators , such as desmoteplase and tenecteplase , will also help extend the time window .

[Current and future aspects of intravenous thrombolysis for acute stroke]. Intravenous thrombolysis using alteplase was approved for clinical use for acute ischemic stroke treatment in Japan in 2005, on the basis of the results of a domestic clinical trial, Japan alteplase Clinical Trial. This therapeutic strategy has become the standard strategy during the following 8 years. However, this therapy still has room for improvement. One of the important drawbacks of intravenous thrombolysis is the limited therapeutic time window. On the basis of the results of the European Cooperative Acute Stroke Study III and the pooled analysis, the current time window is within 4.5 h of stroke onset. The window may be extended to 6 h or longer, probably by appropriate determination of the eligibility of a patient for receiving therapy by using penumbral imaging techniques, such as diffusion-weighted imaging (DWI)/perfusion-weighted imaging mismatch and DWI/magnetic resonance imaging mismatch. Newer-generation recombinant tissue-type plasminogen activators , such as desmoteplase and tenecteplase , will also help extend the time window . Patients with wake-up and unclear-onset strokes are generally ineligible for thrombolysis; therefore, the optimal therapeutic strategy for such patients should be established. Another important drawback is acute stroke therapy paralleling or following intravenous thrombolysis. Mechanical recanalization by endovascular therapy, antithrombotic therapy, neuroprotective therapy (e.g., using intravenous free radical scavenger), and sonothrombolysis are promising candidates for combined use with intravenous thrombolysis.

https://pubmed.ncbi.nlm.nih.gov/23832978/

672452da6ce653fb21320042736dbde0

Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide ( 200 mg/m(2 ) per day ) , doxorubicin ( 12.5 mg/m(2 ) per day ) , and etoposide ( 60 mg/m(2 ) per day ) ( CDE ) by continuous intravenous infusion for 4 days ( 96 hours ) every 3 weeks for a maximum of 8 cycles .

Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493). Preclinical and clinical evidence suggest a potential advantage for infusional therapy in lymphoma. Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide ( 200 mg/m(2 ) per day ) , doxorubicin ( 12.5 mg/m(2 ) per day ) , and etoposide ( 60 mg/m(2 ) per day ) ( CDE ) by continuous intravenous infusion for 4 days ( 96 hours ) every 3 weeks for a maximum of 8 cycles . By the age-adjusted International Prognostic Index (IPI), 42% were at high risk and 58% were at high-intermediate risk. Complete response (CR) occurred in 30 (48%) patients (95% confidence interval [CI], 35%, 64%), and partial response occurred in 16 (26%) patients, yielding an overall response rate of 74% (95% CI, 62%, 84%). Failure-free survival (FFS) rates at 1 and 2 years were 55% (95% CI, 43%, 67%) and 50% (95% CI, 38%, 62%), respectively. When comparing the outcome for 62 patients receiving infusional CDE with historical data derived from 927 IPI-matched lymphoma patients using a Cox proportional hazards model, there was a nonsignificant trend favoring CDE in FFS (P =.12) and overall survival (P =.09). Severe or life-threatening toxicity included neutropenia (68%), anemia (57%), thrombocytopenia (44%), and infection (24%). Two patients (3%) died of treatment-related infectious complications. The primary end point of improving 1-year FFS from 55% to 70% was not achieved with infusional CDE given as initial therapy in patients with poor-risk intermediate-grade lymphoma. It is unlikely that infusional therapy as used in this study produces a 25% or greater relative improvement in FFS compared with standard therapy.

https://pubmed.ncbi.nlm.nih.gov/12176882/

4f68a01aceb6dbfae710114c2757110d

Preinjection of blocking doses of unlabeled epibatidine , (-)-nicotine , lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus , but not in cerebellum , whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR ( e.g. , mecamylamine , scopolamine , N-methylspiperone and ketanserin ) had no effect on [18F]FPH accumulation in any of the brain regions examined .

Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors. Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent 18F-labeled analog of epibatidine, (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human brain. ### methods Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [18F]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs with known pharmacological action before [18F]FPH was injected. The effect of the drugs on [18F]FPH accumulation was evaluated. ### results [18F]FPH was rapidly incorporated into the mouse brain; peak activity (2.4% of the injected dose) was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 min. Highest concentrations of 18F occurred at 15 min in areas known to contain high densities of nAChR ¿e.g., thalamus [9.7% of injected dose per gram tissue (ID/g¿] and superior colliculus (8.3% ID/g)]. Accumulation of the 18F tracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0, 5.6, 4.2 and 5.6% ID/g, respectively) and low in the cerebellum (2.8% ID/g). The distribution of [18F]FPH in the mouse brain matched that of other in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3H](-)-nicotine and [3H]cytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine , (-)-nicotine , lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus , but not in cerebellum , whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR ( e.g. , mecamylamine , scopolamine , N-methylspiperone and ketanserin ) had no effect on [18F]FPH accumulation in any of the brain regions examined . ### conclusion Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.

https://pubmed.ncbi.nlm.nih.gov/9255161/

fc51943869ba80c534c3a9735da9494e

The combination carboplatin 35 mg/m2 , etoposide 50 mg/m2 , and ifosfamide 1,200 mg/m2 was administered intravenously daily for 3 consecutive days .

Carboplatin, etoposide, and ifosfamide as second-line treatment for ovarian cancer. A total of 25 patients with epithelial ovarian cancer were treated with second-line carboplatin, etoposide, and ifosfamide (ICE) following failure of first-line cisplatin-based combination chemotherapy. The combination carboplatin 35 mg/m2 , etoposide 50 mg/m2 , and ifosfamide 1,200 mg/m2 was administered intravenously daily for 3 consecutive days . Response was seen in 13 patients (52%) with 7 complete responses (28%) and 6 partial responses (24%). Median duration of response was 9+ months (range: 4-17+ months). Response rate to second-line ICE relates directly to prior response to first-line cisplatin-based chemotherapy: 12 patients (67%) responded to second-line ICE who responded to first-line cisplatin-based chemotherapy, while only 1 patient (14%) responded who progressed on first-line cisplatin-based chemotherapy. Median survival was 18+ months (range: 2-31+ months). There were six episodes (4%) of grade 4 neutropenia, seven episodes (4%) of grade 4 thrombocytopenia and no grade 3 or 4 nonhematologic toxicity. ICE has moderate activity with minimal toxicity as second-line treatment of advanced epithelial ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/8048396/

12a4c168d9a7ea026a7670baf0c300e0

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells .

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells . tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

https://pubmed.ncbi.nlm.nih.gov/28415819/

35f8267ec936fcf39e0b686b22908b3a

Eighty-three patients were in the control group who have performed a surgical intervention with pre-operative 120-hour antibiotic prophylaxis by Claforan ( cefotaxime ) combining with Metrogel ( metronidazole ) .

Antibacterial Prophylaxis in Emergency Surgery of Abdominal Infection. The results of antibiotic prophylaxis in 148 patients with destructive acute surgical sicknesses of abdominal cavity being urgently operated in the Republican hospital of Baku city from 2011 to 2016 were analyzed. Sixty-five patients were in the basic group which had got as preoperative antibiotic prophylaxis 120-hour course of amoxiclav (amoxicillin in combination with clavulanic acid). Eighty-three patients were in the control group who have performed a surgical intervention with pre-operative 120-hour antibiotic prophylaxis by Claforan ( cefotaxime ) combining with Metrogel ( metronidazole ) . it was showed that applying antibiotic prophylaxis using amoxiclav positively lowered the frequency of as postoperative purulent-septic complications as recurring operations to 8.1%.

https://pubmed.ncbi.nlm.nih.gov/30828552/

a1696a8b7ddd5677c27fdea2510cac89

The regimen was CD DP 40 mg/m2 day 1 and 6 , 5-FU 600 mg/m2 day 2 and 4 , leucovorin 20 mg/m2 day 2 and 4 , etoposide 60 mg/m2 day 3 and 5 , and doxorubicin 20 mg/m2 day 7 , with repetition every 28 days .

[Etoposide, doxorubicin, cisplatin and 5-FU (EAP-F) therapy of advanced gastric cancer--its antitumor effect and evaluation of quality of life]. Fourteen patients with advanced gastric cancer were treated with EAP-F therapy. The regimen was CD DP 40 mg/m2 day 1 and 6 , 5-FU 600 mg/m2 day 2 and 4 , leucovorin 20 mg/m2 day 2 and 4 , etoposide 60 mg/m2 day 3 and 5 , and doxorubicin 20 mg/m2 day 7 , with repetition every 28 days . Thirteen patients were evaluable; one patient was CR, four were PR, five were NC and three were PD. The response rate was 38.5% and median survival was 7 months. Hematologic toxicities were moderate to severe but tolerable, gastrointestinal toxicities were mild and renal toxicity was absent. Quality of life (QOL) of the patients was evaluated by means of symptom-free ratio (duration of symptom-free to survival time) and outpatient ratio (duration at home in relation to survival time). Patients with lymph node metastasis showed a higher symptom-free ratio and outpatient ratio than those with liver metastasis or peritoneal dissemination. All high-QOL patients were chemotherapy responders. In conclusion, EAP-F therapy is effective for advanced gastric cancer and its side effects are tolerable. CR or PR is necessary to achieve a high QOL.

https://pubmed.ncbi.nlm.nih.gov/8379671/

8baac7e5456a6ad064382efcdc6c224a

A German Hodgkin 's lymphoma ( HL ) study group designed the BEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisolone ) regimen .

Multicentre phase II study of the baseline BEACOPP regimen for patients with advanced-stage Hodgkin's lymphoma. A German Hodgkin 's lymphoma ( HL ) study group designed the BEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisolone ) regimen . In the BEACOPP regimen, treatment intervals were shortened and the dose-intensity was increased compared with those in the ABVD regimen (doxorubicin, bleomycin, vinblastine and darcarbacine), resulting in a long-term disease-free survival rate of approximately 75-80%. In the present study, we evaluated the safety and efficacy of the BEACOPP regimen. Between April 2001 and February 2004, 20 patients with HL of stage IIB or higher who had received no previous treatment were enrolled. The patients were aged 17-69 years (median 22 years). The histologic types were mixed cellularity in four cases and nodular sclerosis in 16 cases. The stages were stage IIB in four cases, stage III in 12 cases, and stage IV in four cases. Nineteen (95%) of the 20 patients achieved complete remission. The 3-year survival rate was 100% and the 3-year progression-free survival rate was 89.7%. Adverse drug reactions were grade 4 neutropenia in 12 patients, grade 3-4 thrombocytopenia in seven patients, and grade 3 or higher non-hematologic toxicities in two patients (stomatitis in one patient and ALT/AST elevation in one patient). The BEACOPP regimen for advanced-stage HL showed an excellent complete remission rate and high efficacy even in stage III/IV patients. However, a long-term risk of the BEACOPP regimen is the development of secondary leukemia or myelodysplastic syndrome. Therefore, long-term follow-up of these patients, including monitoring for toxicities, is necessary.

https://pubmed.ncbi.nlm.nih.gov/17065005/

3ce3c390490d351b517a25102e52bd40

High-risk node-negative or low-risk node-positive breast cancer patients received AC given : ( arm I ) concurrently ( AC ) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously ( IV ) every 3 weeks for six cycles ; or ( arm II ) in sequence ( A C ) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles .

Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). ### Patients And Methods High-risk node-negative or low-risk node-positive breast cancer patients received AC given : ( arm I ) concurrently ( AC ) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously ( IV ) every 3 weeks for six cycles ; or ( arm II ) in sequence ( A C ) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles . Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. ### results Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar. ### conclusion The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

https://pubmed.ncbi.nlm.nih.gov/17308269/

7c6e57e9403313b30190f927bebc1b20

The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide : 500 mg/m2 , doxorubicin : 30 mg/m2 , and vincristine : 1 mg/m2 ( day 1 ) and cisplatin : 50 mg/m2 ( day 8) and etoposide : 75 mg/m2 ( days 8 and 9 ) .

Dose-intensive weekly alternating chemotherapy for patients with small cell lung cancer: randomized trial, can it improve survival of patients with good prognostic factors? We conducted a randomized trial of dose-intensive weekly alternating chemotherapy (CAV/PE-W) and standard alternating chemotherapy (CAV/PE) in small cell lung cancer (SCLC) patients with good prognostic factors. A total of 76 patients with SCLC was randomized. The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide : 500 mg/m2 , doxorubicin : 30 mg/m2 , and vincristine : 1 mg/m2 ( day 1 ) and cisplatin : 50 mg/m2 ( day 8) and etoposide : 75 mg/m2 ( days 8 and 9 ) . The CAV/PE consisted of 2 alternating cycles of cyclophosphamide: 800 mg/m2, doxorubicin: 50 mg/m2, and vincristine: 1.4 mg/m2 (day 1), cisplatin: 100 mg/m2 (day 22) and etoposide: 100 mg/m2 (days 22, 23 and 24). Eligibility criteria were no prior therapy, no active concomitant malignancy, ECOG PS of 0 or 1, age < or =75, adequate hematologic functions and no brain metastasis. The complete response (CR) rate for CAV/PE-W (14/38, 36.8%) was significantly higher than that for CAV/PE (6/38, 15.8%, chi2; p=0. 032). However, the response rate in patients on CAV/PE-W (36/38, 94. 7%) was not significantly higher than the rate for CAV/PE (31/38, 81. 6%, chi2; p=0.076). Progression-free survival for patients on CAV/PE-W was significantly longer than that of patients on CAV/PE (41.4 weeks vs. 21.3 weeks, log-rank; p=0.0007, generalized Wilcoxon; p=0.0034) as was overall median survival (67.0 weeks vs. 51.2 weeks, log-rank; p=0.028). Actual dose-intensity of CAV/PE-W was 1.74 times that of CAV/PE. Hematological toxicities were equally frequent and G-CSF contributes to treatment efficacy by allowing administration of dose-intensive chemotherapy. The CAV/PE-W achieved a higher CR rate and longer survival, than the CAV/PE.

https://pubmed.ncbi.nlm.nih.gov/10671676/

804db6df1fe6220163926d911218acbe

Cyclophosphamide , methotrexate , 5-fluorouracil , and folinic acid ( CMFF ) as first line chemotherapy for treatment of advanced breast cancer .

Cyclophosphamide , methotrexate , 5-fluorouracil , and folinic acid ( CMFF ) as first line chemotherapy for treatment of advanced breast cancer . In order to evaluate the maximum tolerable dose of a combination chemotherapy consisting of cyclophosphamide, methotrexate, 5-fluorouracil, and folinate (CMFF), 30 female patients with histopathologically confirmed, previously untreated advanced breast cancer were entered into this pilot study. Chemotherapy consisted of fixed doses for methotrexate (40 mg/m2 i.v. on day 1), 5-fluorouracil (500 mg/m2 i.v. on day 2 to 4) and folinic acid (2 x 200 mg/m2 i.v., 0 + 2 h on day 2 to 4). The dose of cyclophosphamide was escalated stepwise, starting with 200 mg/m2 i.v. on day 2 to 4, to 240 mg/m2, 290 mg/m2, 360 mg/m2 and 400 mg/m2, respectively, for each subsequent five patients. Treatment was repeated every four weeks. A total of 92 treatment cycles was given. Myelosuppression was the dose-limiting toxicity: leukopenia WHO grade III or IV was observed after a total of 28 cycles and anemia of equal intensity after 1 cycle. No thrombocytopenia WHO grade III or IV was recorded. Myelotoxicity increased with higher doses of cyclophosphamide. Among non-hematologic toxicities, alopecia was reported in two-thirds of the patients. Nausea and vomiting was noted in 25% of treatment cycles, but in one cycle only WHO grade III was recorded. No other toxicities exceeding WHO grade II occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/7556280/

56fc8b6a971baec8e8e6232a1d49c4db

High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia .

High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia . The aim of the study was to compare the efficacy of high-dose rosuvastatin, low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega-3 fatty acids with regard to the lipid profile in patients with mixed hyperlipidemia. The primary endpoint was changes in non-high density lipoprotein-cholesterol (non-HDL-C) levels. Study participants were randomly allocated to receive rosuvastatin 40 mg (n = 30, R group), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, RF group) or rosuvastatin 10 mg plus n-3 fatty acids 2 g (n = 30, RN group). Non-HDL-C levels were reduced in all groups: in R group by 54%, in RF group by 42% and in RN group by 42%. Significant reductions in total cholesterol (TC), low density lipoprotein (LDL)-C and triglyceride levels were observed in all groups. The reductions in total and LDL-C were greatest in the R group while a more pronounced reduction of triglycerides in the RF group compared with that in the R and the RN group was observed. HDL-C levels were significantly increased only in the RF group. In conclusion, high doses of rosuvastatin and small doses of rosuvastatin plus either fenofibrate or n-3 fatty acids exhibit favorable effects on both LDL-C and non-HDL-C levels. However, rosuvastatin monotherapy more potently reduces these parameters. The combination of rosuvastatin plus fenofibrate leads to a greater decrease in triglyceride levels and a greater increase in HDL-C levels compared with the other two treatments. While awaiting the results of ongoing trials high doses of rosuvastatin may represent the treatment of choice in individuals with mixed dyslipidemia.

https://pubmed.ncbi.nlm.nih.gov/21327725/

17cb9a6a848c31e4bcf08252e3b4f2a4

Patients were divided randomly into 3 groups ( Group A : 0.5 % bupivacaine 5 mL , n = 12 ; Group B : 0.5 % bupivacaine 4.5 mL + 20 mg of triamcinolone 0.5 mL , n = 10 ; and Group C : 0.5 % bupivacaine 4 mL + 40 mg of triamcinolone 1 mL , n = 10 ) .

Effects of stellate ganglion block on breast cancer-related lymphedema: comparison of various injectates. To determine the effects of SGB in BCRL patients and the efficacy of corticosteroids in SGB. ### Study Design A double-blinded, randomized, controlled trial. ### setting A single academic hospital, outpatient setting. ### methods In total, 32 patients with BCRL were recruited. Patients were divided randomly into 3 groups ( Group A : 0.5 % bupivacaine 5 mL , n = 12 ; Group B : 0.5 % bupivacaine 4.5 mL + 20 mg of triamcinolone 0.5 mL , n = 10 ; and Group C : 0.5 % bupivacaine 4 mL + 40 mg of triamcinolone 1 mL , n = 10 ) . All patients received 3 consecutive SGBs, every 2 weeks. The primary outcomes were changes in forearm and upper arm circumference. Circumference was measured at baseline, 2 weeks (before the second injection), 4 weeks (before the third injection), and 8 weeks (one month follow-up after 3 consecutive SGBs). Moreover, subjective data were collected using EORTC C-30 at baseline and 8 weeks. ### results After 3 consecutive SGBs, forearm and upper arm circumferences were decreased significantly from baseline in all groups (P < 0.05/3). The upper arm circumference of group C was reduced significantly more than that of group A (P < 0.05/3). The subjective data by EORTC-C30 at baseline and one month after 3 consecutive SGBs revealed no statistically significant difference. ### limitations Relatively few patients were enrolled. We did not compare SGB with any other BCRL treatment, such as complex decongestive therapy. ### conclusions This study suggests that SGB may be an effective treatment for BCRL. Furthermore, it appears that corticosteroids could have an additive effect in SGB.

https://pubmed.ncbi.nlm.nih.gov/25675063/

997c056fe37bad3e5f2f38a1ca36251f

Irinotecan and etoposide were combined using the ( d x 5)2 i.v . schedule for both drugs , in which irinotecan was given 2 h before or 2 h after the administration of etoposide .

Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma. irinotecan [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothec in] administered i.v. in two courses, each course consisting of administration every day for 5 days [(dx5)2] on days 1-5 and 8-12, has demonstrated significant activity against advanced human tumor xenografts derived from colon adenocarcinomas and several childhood cancers. To build on this therapy, we have evaluated the combination of irinotecan given on this schedule with 5-fluorouracil given on days 1, 7, and 14 with or without leucovorin [(dx5)3 i.v.] against colon tumors, or combined with etoposide administered (dx5)2 i.v. either 2 h before or 2 h after irinotecan for treatment of colon tumors and rhabdomyosarcomas. A combination of 5-fluorouracil at 75% and irinotecan at 50% of their respective maximum tolerated doses when administered as single agents on this schedule gave acceptable toxicity. Against colon adenocarcinoma xenografts, 5-fluorouracil did not enhance the response rate compared with that obtained with the optimum dose of irinotecan given as a single agent. Against GC3/TK- xenografts, which lack thymidine kinase and cannot salvage thymidine to circumvent the inhibition of thymidylate synthase, the addition of leucovorin to the combination increased the complete response rate from 10 to >90%, whereas the response rates for the optimal doses of irinotecan or 5-fluorouracil, as single agents, were 30 and <10%, respectively. etoposide d x 5 i.v. for two or three courses or (d x 5)3 p.o. did not cause objective regression of any colon tumors. In contrast, three of five rhabdomyosarcoma lines demonstrated a high frequency of partial regressions or complete regressions when treated (d x 5)1 i.v. Repetitive courses [e.g., (d x 5)2 or (d x 5)3] i.v. or p.o. or by 4-h infusion d x3 i.v. were either equally effective or less effective. Irinotecan and etoposide were combined using the ( d x 5)2 i.v . schedule for both drugs , in which irinotecan was given 2 h before or 2 h after the administration of etoposide . Each drug could be combined at only 38% of its respective maximum tolerated dose when administered as a single agent, indicating greater than additive toxicity. Toxicity was similar irrespective of the sequence of administration and was manifested by loss of weight (73% of the initial weight, nadir day 7), myelosuppression, and prolonged thrombocytopenia. The responses of colon carcinomas to the combination given in either sequence were similar to that achieved with irinotecan given alone at the same dose as used in the combination. Similarly, when etoposide was given before irinotecan, the responses of rhabdomyosarcomas were similar to those for irinotecan. However, in experiments in which etoposide was administered 2 h after each dose of irinotecan, there was significant antagonism of the antitumor activity of irinotecan.

https://pubmed.ncbi.nlm.nih.gov/9816097/

621f146564276541685c53b25bb29395

Combination of sofosbuvir , pegylated-interferon and ribavirin for treatment of hepatitis C virus genotype 1 infection : a systematic review and meta-analysis .

Combination of sofosbuvir , pegylated-interferon and ribavirin for treatment of hepatitis C virus genotype 1 infection : a systematic review and meta-analysis . Hepatitis C virus (HCV) infection is an important cause of chronic liver disease which has been affected 3% of world's population. Some studies have shown that adding sofosbuvir (SOF), an HCV polymerase inhibitor to the conventional therapy of Pegylated-interferon (PegIFN) plus ribavirin (RBV) can increase the rate of sustained virologic response (SVR) among HCV-infected patients. This study was conducted to determine the effect of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection using systematic review with meta-analysis. ### methods In this study, electronic databases including PubMed, Scopus, Science Direct, and Web of Science were comprehensively searched using appropriate strategies containing all related keywords of "hepatitis C", "PegIFN", "RBV" and "SOF". Studies assessed the efficacy of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection were included in the meta-analysis. ### results After screening of 757 records, we included five articles with total sample size of 411 to the meta-analysis. Based on the fixed-effect model (χ ### conclusions Combination therapy with PegIFN and RBV plus SOF results in high treatment response in patients with HCV genotype 1 infection.

https://pubmed.ncbi.nlm.nih.gov/28427463/

0918877efd6947ff1d51584709e4a6d1

Immunosuppressive protocol : preoperative : Cyclosporin + Azathioprine .

[Predictive variables of early mortality after orthotopic heart transplant in adults]. The purpose of the study was to analyze some variables of donors, recipients and surgical procedures in order to discover factors that could predict mortality during the early stage (< 30 days) of orthotopic heart transplants. ### Material And Method 125 consecutive orthotopic heart transplants in adults were analyzed. The average age was 51 +/- 11 (range: 12-67), 109 (87%) were men, 16 were women (13%). Two groups were compared: 15 patients who died within 30 days after heart transplant and 110 who survived during that period. Immunosuppressive protocol : preoperative : Cyclosporin + Azathioprine . Intraoperative: methylprednisolone Postoperative: methylprednisolone (first 24 h), antilymphocyte monoclonal antibodies (7-10 days after heart transplant) + cyclosporin + azathioprine + Corticoids. The following parameters of the recipient were analyzed: sex, age, weight, size, thoracic perimeter, pretransplant cardiopathy, previous thoracic operations, functional stage or need for catecholamines during the days prior to the transplant, pulmonary artery pressure and resistance, history of systemic arterial hypertension, elevation of creatinine, blood type, urgent transplant indication, receptor/donor weight relationship. The following parameters of donors and operation were analyzed: sex, age, weight, thoracic perimeter, period in intensive care unit, dose of dopamine and dobutamine, blood type, origin of the organ, cause of death, ischaemia time, cardiopulmonary by-pass time and cardioplegia type. ### results The rate of early mortality was 12%. The univariate analysis showed differences in: prior cardiovascular surgery, receptor blood type, need for urgent transplantation, pulmonary artery resistance > 2.5 Wood Units, cardiopulmonary by-pass time, weight relationship between receptor and donor. The death cause of the donor proved significant. On multivariate analysis, the following parameters independently predicted early mortality: history of operation with extracorporeal circulation, high pulmonary artery resistance, urgent transplant, receptor/donor weight relation and time of extracorporeal circulation. ### conclusions We believe that the results of our experience can help to stratify the risk in the orthotopic heart transplant recipient and even to contraindicate the procedure in some cases showing an accumulation of poor prognostic factors in borderline recipients.

https://pubmed.ncbi.nlm.nih.gov/9380932/

a30e9207f775411973062008ed2b4768

Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma .

Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma . A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-alpha) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. ### Patients And Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-alpha 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. ### results Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-alpha group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). ### conclusion sunitinib demonstrates longer overall survival compared with IFN-alpha plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

https://pubmed.ncbi.nlm.nih.gov/19487381/

59354e45aad85a9d345a328c1ae46f7d

All patients received chemotherapy regimens that included doxorubicin ( 6 ) or etoposide ( 1 ) , and six were treated with infradiaphragmatic irradiation .

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group. This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. ### Patients And Methods The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. ### results Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin ( 6 ) or etoposide ( 1 ) , and six were treated with infradiaphragmatic irradiation . The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. ### conclusions The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.

https://pubmed.ncbi.nlm.nih.gov/11216701/

b503fc2fdf98c99285b21e109f520a8b

Of 1490 articles identified , we included 3 papers and 1 abstract with patients on aspirin and/or NSAIDs , 1 paper on warfarin , 2 abstracts on clopidogrel , and 2 papers on clopidogrel plus aspirin and/or NSAIDs .

Systematic review with meta-analysis: the risk of gastrointestinal haemorrhage post-polypectomy in patients receiving anti-platelet, anti-coagulant and/or thienopyridine medications. For patients undergoing colonoscopy with polypectomy, current guidelines recommend temporary cessation of blood-thinning medications. The data regarding periprocedural management of these medications are sparse. ### aim To perform a systematic review and meta-analysis to determine the risk of post-polypectomy bleeding (PPB) in patients taking anti-platelet, anti-coagulant and/or thienopyridine medications. ### methods We searched Pubmed, Scopus, Web of Science, Biosis and Proceedings First from 1970 to 2015. PPB was defined as overt haemorrhage or drop in haemoglobin of at least 2 g/dL. ### results Of 1490 articles identified , we included 3 papers and 1 abstract with patients on aspirin and/or NSAIDs , 1 paper on warfarin , 2 abstracts on clopidogrel , and 2 papers on clopidogrel plus aspirin and/or NSAIDs . While the rate of immediate PPB on aspirin and/or NSAIDs was not increased (OR = 1.1, 95% CI 0.7-1.9, P = 0.7), the risk of delayed PPB was increased (OR = 1.7, 95% CI 1.0-2.4, P = 0.0009, I(2)  = 60%) but rendered non-significant with elimination of a small study. There was an elevated risk of delayed PPB on clopidogrel (OR = 9.7, 95% CI 3.1-30.8, P = 0.0, I(2)  = 0). There was an increased risk of delayed PPB in patients on clopidogrel + aspirin and/or NSAIDs (OR = 3.4, 95% CI 1.3-8.8, P = 0.01, I(2)  = 0). Based on a single study on warfarin, the PPB rate was elevated. There were no data regarding PPB and usage of the newer anti-coagulant agents. ### conclusions Usage of aspirin or NSAIDs does not increase risk of post-polypectomy bleeding. clopidogrel and warfarin should be discontinued in the periprocedural period to prevent the occurrence of post-polypectomy bleeding.

https://pubmed.ncbi.nlm.nih.gov/26290157/

0ee5facfd933895edac8cca7e2f1c707

Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide .

Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide . In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.

https://pubmed.ncbi.nlm.nih.gov/9862568/

8432d329c360d59237a984529cc02420

We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4 .

A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs. Molecular docking is a reliable method with which to identify the binding conformations of substrates, inducers and inhibitors of cytochrome P450 (CYP) enzymes. We used the docking method to explore possible binding modes of an entry inhibitor (maraviroc) and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and etravirine) to cytochrome P450 3A4 (CYP3A4). In addition, docking results were compared with the binding conformations of HIV protease drugs to infer the binding site residues and potential drug-drug interaction profiles for combination therapy in the treatment of AIDS. We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4 . Dosage adjustment is required for delavirdine and maraviroc when combined with HIV protease drugs. The present results are in good agreement with experimental data from drug interaction profiles. The information provided in this paper will be helpful in furthering our understanding the functions of CYP3A4, and could aid in the design of new drugs that would be metabolized easily without having any drug-drug interaction profile.

https://pubmed.ncbi.nlm.nih.gov/21080015/

7ba792e04aba157338edb97b548221a7

First , we searched for the most synergistic combination of KPT-8602 with dexamethasone , vincristine , or doxorubicin

The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia. KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL. ### Experimental Design First , we searched for the most synergistic combination of KPT-8602 with dexamethasone , vincristine , or doxorubicin ### results KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as ### conclusions Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.

https://pubmed.ncbi.nlm.nih.gov/32826328/

e5be67692bd5bdc02b9cf9d8fc2fe673

In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of severe or multidrug resistant falciparum malaria .

The rational use of qinghaosu and its derivatives: what is the future of new compounds? In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of severe or multidrug resistant falciparum malaria . However, their availability (supply) and the registration requirements are the major limitations for their large-scale use. At Bangkok Hospital for Tropical Diseases, Thailand, we have studied the new artemisinin derivatives, dihydroartemisinin and arteether, and artesunate suppositories. We found that the three preparations are well tolerated, safe, and efficacious.

https://pubmed.ncbi.nlm.nih.gov/10212910/

33ce13cf1b55df095019be91cf6bb3db

Epidural analgesia during labor--0.5 % lidocaine with fentanyl vs. 0.08 % ropivacaine with fentanyl .

Epidural analgesia during labor--0.5 % lidocaine with fentanyl vs. 0.08 % ropivacaine with fentanyl . Although lidocaine is a cheap and globally available local anesthetic, yet it is not a popular drug for labor analgesia. This is claimed to its higher intensity of motor block, possibility of transient neurological symptoms (TNS) and its placental transfer with probable drawbacks on fetal well-being. However, these effects could be concentration dependent and, the evidence linking them to lidocaine is still lacking. This study was designed to evaluate the efficacy and safety of 0.5% epidural lidocaine plus fentanyl during labor. ### methods One hundred and twenty healthy full term nulliparous women in early labor with a single fetus presented by the vertex were enrolled in this randomized, double-blind clinical trial. Parturient were assigned to receive epidural analgesia either with lidocaine 0.5% plus fentanyl 2 microg(-1 mL) (LF), or ropivacaine 0.08% plus fentanyl 2 microg(-1 ml) (RF) when their cervix was dilated to 4 centimeters. Analgesia was provided with 20 ml bolus of the study solution and maintained at 10 ml(-1) h. Upper level of sensory loss to cold, Visual Analogue Pain Score (VAPS), motor block (modified Bromage score), the duration of the first and second stages of labor, numbers of instrumental vaginal and cesarean deliveries, the neonatal apgar score, patient satisfaction and side effects, were recorded. ### results There were no significant differences in sensory level, pain scores, duration of the first and second stages of labor, numbers of instrumental and cesarean deliveries, the neonatal apgar scores, patient satisfaction or side effect between groups. Although motor block was significantly high in lidocaine group compared to ropivacaine group (p < 0.05), all parturient were moving satisfactorily in bed. ### conclusions Dilute epidural lidocaine (0.5%) with fentanyl effectively and safely initiates epidural analgesia clinically indistinguishable from 0.08% epidural ropivacaine with fentanyl. Although it induces significant motor block compared to ropivacaine, it still preserves maternal ability to move satisfactorily in bed. Whether further reduction in lidocaine concentration could trim down the motor block, remains to be investigated.

https://pubmed.ncbi.nlm.nih.gov/20394248/

64a3b76e2b54f5ee4881a58c79d310d1

Inhibition of Boyden Chamber migration of MNL 's in a MNL-lymphocyte mixture was achieved after 1/2 hr incubation by 10(-3 ) and 10(-4 ) mol/L. concentrations of chloroquine ( maximum inhibition 63 % + /- 2.8 ) , dexamethasone ( 58 % + /- 8.6 ) , 6-mercaptopurine ( 62 % + /- 4.2 ) , methotrexate ( 66 % + /- 6.4 ) , and vinblastine ( 100 % ) .

The effect of immunosuppressive and anti-inflammatory drugs on monocyte function in vitro. MNL cellular chemotaxis, bacterial killing and phagocytosis, and Oil Red O phagocytosis were studied in vitro in the presence of eight anti-inflammatory or immunosuppressive drugs. Inhibition of Boyden Chamber migration of MNL 's in a MNL-lymphocyte mixture was achieved after 1/2 hr incubation by 10(-3 ) and 10(-4 ) mol/L. concentrations of chloroquine ( maximum inhibition 63 % + /- 2.8 ) , dexamethasone ( 58 % + /- 8.6 ) , 6-mercaptopurine ( 62 % + /- 4.2 ) , methotrexate ( 66 % + /- 6.4 ) , and vinblastine ( 100 % ) . Bacterial killing was not significantly affected by any of the drugs studied. Bacterial phagocytosis was improved by vinblastine at 10(-3) and 10(-4)M and by 6-mercaptopurine at 10(-5)M, but there was apparent interference with the assay at high drug concentrations. Modification of the Oil Red O technique showed inhibitions of MNL phagocytosis by vinblastine at 10(-3)M (69% +/- 2.8 inhibition), chloroquine at 10(-3)M (49% +/- 8.5), and mercaptopurine at 10(-3)M (32.5% +/- 0.7). cyclophosphamide, although reported to require hepatic conversion in vivo, may be partially activated in a lymphocyte-MNL mixture in vitro, producing a decrease in cell viability but no statistically significant impairment of MNL function. These results support direct inhibition of MNL cellular function as one of the mechanisms of the anti-inflammatory action of chloroquine, dexamethasone, methotrexate, 6-mercaptopurine, and vinblastine.

https://pubmed.ncbi.nlm.nih.gov/894108/

5c48e47b075eca5367f30d260ec18b82

The proactive intense care strategy was applied , which includes : ( i ) an education and training course on the topic of SLE-PAH for ED physicians ; ( ii ) a SLE-PAH patient triage protocol with prompt specialist consultation and admission ; and ( iii ) intensive care with prompt initiation of combination PAH-targeted therapy , that is , at least two drugs from the three categories as represented by iloprost , bosentan and sildenafil .

Severe pulmonary arterial hypertension secondary to lupus in the emergency department: proactive intense care associated with a better short-term survival. Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE) and could be an acute critical condition presenting to the emergency department (ED). Our previous retrospective study revealed that the ED-related mortality of such patients was over 50%. The aim of the current prospective study is to initiate a proactive intense care strategy on severe SLE-PAH patients in the emergency setting and evaluate its impact on the short-term survival. ### methods The proactive intense care strategy was applied , which includes : ( i ) an education and training course on the topic of SLE-PAH for ED physicians ; ( ii ) a SLE-PAH patient triage protocol with prompt specialist consultation and admission ; and ( iii ) intensive care with prompt initiation of combination PAH-targeted therapy , that is , at least two drugs from the three categories as represented by iloprost , bosentan and sildenafil . Consecutive SLE-PAH patients with WHO functional class III or IV who attended the ED were enrolled following the aforementioned protocol. A historical group of SLE-PAH patients in the ED (n = 11) was set up as a comparison, and 3-month short-term survival was calculated. ### results During October 2010 to December 2012, a total of 11 consecutive severe SLE-PAH patients were included in the present study. Compared with the historical group, an improved short-term survival can be appreciated over time (historical group vs. proactive group, 27.3% vs. 72.7%, P = 0.033). The application of PAH-targeted combination therapy apparently contributed to the better outcome (P = 0.0099). ### conclusions Proactive care and combination PAH-targeted treatment can improve short-term survival of severe SLE-PAH in the emergency setting.

https://pubmed.ncbi.nlm.nih.gov/24946184/

e0ce038cda2c1b7018b761f0c218ef45

Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa ( 53 - 57 % in either 2:1 or 4:1 ratios ) and A. baumannii ( 38 - 46 % in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam ) isolates .

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data. We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC(90) values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa ( 53 - 57 % in either 2:1 or 4:1 ratios ) and A. baumannii ( 38 - 46 % in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam ) isolates . Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.

https://pubmed.ncbi.nlm.nih.gov/16815690/

6e67d5265ebd6238ff666027cd88d6a6

Senescence can be efficiently induced in cultured cells by DNA-damaging drugs , including doxorubicin ( DOX ) , cisplatin and etoposide .

Occurrence of senescence-escaping cells in doxorubicin-induced senescence is enhanced by PD0332991, a cyclin-dependent kinase 4/6 inhibitor, in colon cancer HCT116 cells. Cancer treatment induces cellular senescence, and it is considered to be one of the factors that determines treatment outcome. Senescence can be efficiently induced in cultured cells by DNA-damaging drugs , including doxorubicin ( DOX ) , cisplatin and etoposide . Cells in senescence cease proliferation; however, it has been demonstrated that colonies that are formed from cells escaping senescence appear in drug-induced senescence; however, the conditions influencing the emergence of such senescence-escaping cells (SECs) remain unclear. The present study aimed to investigate the relevance of the cell cycle phase and colony formation in the DOX-induced senescence of human colon cancer HCT116 cells. After release from serum starvation in the presence of DOX, cells synchronously progressed through the cell cycle and were arrested in the G

https://pubmed.ncbi.nlm.nih.gov/30655877/

4536a87da2d436767647005f00c2039b

Preoperative treatment was 5 fractions radiation therapy ( 25 Gy to involved mesorectum , 20 Gy to elective nodes ) , followed by 4 cycles of FOLFOX [ 5-fluorouracil , oxaliplatin , leucovorin ] .

Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer. Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. ### Methods And Materials Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy ( 25 Gy to involved mesorectum , 20 Gy to elective nodes ) , followed by 4 cycles of FOLFOX [ 5-fluorouracil , oxaliplatin , leucovorin ] . Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. ### results 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). ### conclusion This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/24606849/

57bb15b3534944dc4b84b3425ec59ca6

The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus .

The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus . To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. ### methods Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. ### results The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY. ### conclusions dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy.

https://pubmed.ncbi.nlm.nih.gov/25817050/

9498c5215c5fc49f8655cbf2b2ec2198

The mean reduction of night time points was statistically lower than that of day time points for latanoprost ( P = 0.031 ) , timolol ( P = 0.032 ) , and brimonidine ( P = 0.050 ) , but not for dorzolamide ( P = 0.60 ) , bimatoprost ( P = 0.057 ) , travoprost ( P = 0.064 ) .

Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines. To evaluate efficacy and safety data of currently available ocular hypotensive medicines derived from 24-hour studies, of similar design, in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma, or ocular hypertension (OH). ### design Meta-analysis of published articles evaluating patients with POAG, exfoliative glaucoma, or OH. ### methods We included articles that were randomized, prospective, single- or double-masked, comparative studies of ocular hypotensive therapies over 24 hours. Each article selected contained an untreated baseline, >or=4-week treatment period, >/=20 patients per treatment arm, and >or=6 time points not spaced >5 hours apart and used Goldmann applanation or Tonopen tonometry (supine measurements) to measure intraocular pressure (IOP). ### Main Outcome Measure Twenty-four-hour IOP efficacy. ### results This analysis included 864 separate 24-hour treatment curves from 386 patients in 28 treatment arms from 11 studies. A statistical difference in the mean diurnal pressure decrease existed between monotherapy treatments for POAG/OH patients, with bimatoprost (29%) and travoprost (27%) showing the greatest 24-hour reduction (P = 0.026). timolol 0.5% was less effective than latanoprost (24% vs. 19% reduction) but decreased the pressure at each night time point (P = 0.0003). dorzolamide showed a 19% 24-hour pressure reduction and brimonidine 0.2% a 14% one. In exfoliative glaucoma patients, latanoprost and travoprost showed higher baseline and treatment pressures, although the pressure reductions (29% and 31%, respectively) were greater generally than observed with POAG/OH. An evening-dosed latanoprost/timolol fixed combination reduced the pressure 33%, and the dorzolamide/timolol fixed combination (DTFC), 26%. However, the power to detect a difference for this specific comparison was probably low, due to the limited number of patients (n = 20) in the DTFC group. A statistical difference between evening-dosed (24%) and morning-dosed (18%) latanoprost (P<0.0001) was noted, but not between evening (27%) and morning (26%) travoprost (P = 0.074). The mean reduction of night time points was statistically lower than day time points for latanoprost (P = 0.031), timolol (P = 0.032), and brimonidine (P = 0.050), but not for dorzolamide. dorzolamide (P = 0.60), travoprost (P = 0.064), and bimatoprost (P = 0.057) did not demonstrate nighttime pressures lower than daytime ones. The mean reduction of night time points was statistically lower than that of day time points for latanoprost ( P = 0.031 ) , timolol ( P = 0.032 ) , and brimonidine ( P = 0.050 ) , but not for dorzolamide ( P = 0.60 ) , bimatoprost ( P = 0.057 ) , travoprost ( P = 0.064 ) . ### conclusions Similar relative efficacies generally exist in various classes of ocular hypotensive agents during night and day hours.

https://pubmed.ncbi.nlm.nih.gov/18082886/

2f57f437e23ddbbccfa7c89638e083d0

Moreover , the beneficial effects of dronedarone , amiodarone analogues , against Trypanosoma cruzi and Leishmania mexicana have recently been demonstrated and such treatment regimens resulted in lower side effects .

Emerging role of amiodarone and dronedarone, as antiarrhythmic drugs, in treatment of leishmaniasis. Leishmaniasis is a group of human and animal diseases causing 20,000-40,000 annual deaths and its etiological agents belong to the Leishmania genus. The most current treatment against leishmaniasis is chemotherapy. Pentavalent antimonials such as glucantime and pentostam have been administrated as the first-line drugs in treatment of various forms of leishmaniasis. The second-line drugs such as amphotericin B, liposomal amphotericin B, miltefosine, pentamidine, azole drugs and paromomycin are used in resistant cases to pentavalent antimonials. Because of drawbacks of the first-line and second-line drugs including adverse side effects on different organs, increasing resistance, high cost, need to hospitalization and long-term treatment, it is necessary to find an alternative drug for leishmaniasis treatment. Several investigations have reported the effectiveness of amiodarone, the most commonly used antiarrhythmic drug, against fungi, Trypanosomes and Leishmania spp. in vitro, in vivo and clinical conditions. Moreover , the beneficial effects of dronedarone , amiodarone analogues , against Trypanosoma cruzi and Leishmania mexicana have recently been demonstrated and such treatment regimens resulted in lower side effects . The anti- leishmanial and anti- trypanosomal effectiveness of amiodarone and dronedarone has been attributed to destabilization of intracellular Ca

https://pubmed.ncbi.nlm.nih.gov/29689189/

b391e83b6f4e8652576666a65eb55339

This study aimed to investigate the efficacy and safety of iguratimod ( T-614 ) in combination with methotrexate ( MTX ) for active rheumatoid arthritis ( RA ) patients .

Efficacy and safety evaluation of a combination of iguratimod and methotrexate therapy for active rheumatoid arthritis patients: a randomized controlled trial. This study aimed to investigate the efficacy and safety of iguratimod ( T-614 ) in combination with methotrexate ( MTX ) for active rheumatoid arthritis ( RA ) patients . Sixty active RA patients were enrolled according to the 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria, and were randomized into MTX + T-614 group and MTX group. T-614 was orally administered at a dosage of 50 mg/day (25 mg twice daily) for 24 weeks. MTX was orally administered to RA patients at a stable weekly dosage of 10 mg/week for the first 4 weeks and subsequent 12.5 mg/week for the later 20 weeks. Clinical features at baseline and efficacy endpoints of the ACR 20 % response (ACR20), ACR50, ACR70, and adverse events at 24 weeks were evaluated, respectively. After 24 weeks of treatment, clinical features at baseline, including counts for tender joints and swelling joints, visual analog scale for pain, patient's and physician's global assessment, erythrocyte sedimentation rate, C-reactive protein, disease activity score 28, health assessment questionnaire, simplified disease activity index, and ACR50 in the MTX + T-614 group, showed statistically significant differences comparing with the MTX group (P < 0.05). There was no significant increase in adverse events in the MTX + T-614 group comparing with the MTX group (P > 0.05). The combination of MTX and T-614 therapy appeared to have a good efficacy and safety for active RA and was superior to MTX-alone therapy after 24 weeks of treatment.

https://pubmed.ncbi.nlm.nih.gov/26139202/

d5a2bde71955f6f2fbed75223c47d79f

Cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide , vincristine , doxorubicin , high-dose methotrexate/ifosfamide , etoposide , high-dose cytarabine ( CODOX-M/IVAC ) , or dose-adjusted etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( DA-EPOCH ) are possible options .

Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions. Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV) infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM). PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide , vincristine , doxorubicin , high-dose methotrexate/ifosfamide , etoposide , high-dose cytarabine ( CODOX-M/IVAC ) , or dose-adjusted etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( DA-EPOCH ) are possible options . Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs) and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.

https://pubmed.ncbi.nlm.nih.gov/26357515/

2cd79396bfa06a9c42c9eb3059f89db1

Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did , but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen .

Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis. To compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. ### methods Literature search was performed by keywords "irinotecan", "oxaliplatin" and "colorectal cancer" on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register (CCTR) and CBMdisc (Chinese Biology and Medicine disc) before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2. ### results According to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group (relative risk (RR) = 0.82, 95% confidence interval (95%CI) (0.70, 0.96), P = 0.01), and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group (95%CI (-3.54, -0.54), P = 0.008). In the comparison of grade 3 - 4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group (RR = 1.94, 95%CI (1.22, 3.09), P = 0.005; 1.71, 95%CI (1.34, 2.18), P < 0.001; 14.56, 95%CI (4.11, 51.66), P < 0.0001), respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group (RR = 0.06, 95%CI (0.03, 0.14), P < 0.00001; 0.70, 95%CI (0.55, 0.91), P = 0.006; 0.18, 95%CI (0.05, 0.61), P = 0.006), respectively. ### conclusions Both irinotecan and oxaliplatin combined with 5-fluorouracil and leucovorin were effective in the first-line therapy of advanced colorectal cancer. However, the combined regimen of oxaliplatin plus 5-fluorouracil and leucovorin is more excellent. Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did , but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen .

https://pubmed.ncbi.nlm.nih.gov/21163137/

964216668a8e62cda52cb0268e6ede6b

[ Intraoperative anaphylactic shock induced by methylergometrine and oxytocin ] .

[ Intraoperative anaphylactic shock induced by methylergometrine and oxytocin ] . We report a case of intraoperative anaphylactic shock in a 32-year-old multigravida woman undergoing elective cesarean section for partial placenta previa. Anesthesia was performed using combined spinal and epidural technique. After the baby was born, methylergometrine was administered i.v. simultaneously with oxytocin, the latter injected directly into the uterine muscle by an obstetrician. Several minutes later, she presented with dyspnea and became agitated. Because of the potential risk of pulmonary embolism, the patient was immediately intubated and mechanical ventilation was started. Her systolic blood pressure decreased to 50 mmHg and SpO2 to 87% under 100% oxygen administration. After catecholamine infusion, however, her respiratory condition soon improved. Postoperatively, her conjunctiva and vulva were not edematous. From the clinical course, it was considered that the patient was very likely to have suffered an anaphylactic reaction to oxytocin or methylergometrine. Forty days later, serological examinations as well as skin tests for those two drugs were carried out. While the serological tests were negative, the skin tests indicated the patient was allergic to both drugs. It is concluded that the endogenous peptide oxytocin can induce anaphylactic shock in multiparous women.

https://pubmed.ncbi.nlm.nih.gov/16634548/

dcfbf5ae688ecd29ac90163f21d6fbff

Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide .

Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo. Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide . Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.

https://pubmed.ncbi.nlm.nih.gov/24083030/

6d1ec19f332c2fdafef2d6f1ecdf91c9

The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel , gemcitabine , pemetrexed , and erlotinib and for patients with target-specific oncogenes afatinib , osimertinib , crizotinib , alectinib , and ceritinib .

Second-Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological, and Molecular Aspects of Nintedanib. Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel , gemcitabine , pemetrexed , and erlotinib and for patients with target-specific oncogenes afatinib , osimertinib , crizotinib , alectinib , and ceritinib . In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.

https://pubmed.ncbi.nlm.nih.gov/28293555/

de4688dd3f066547588c91f65dfc3edc

an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews .

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews . This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. ### objectives we set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment ### Search Strategy trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. ### Selection Criteria controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. ### Data Collection And Analysis two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. ### Main Results eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma. There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively. There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. No studies were found in children. ### Authors Conclusions the seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children. Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.

https://pubmed.ncbi.nlm.nih.gov/21181075/

ad63705caf5963c9313fbcab36b8fd43

[ An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide ] .

[ An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide ] . A 73-year-old man was given a diagnosis of myelodysplastic syndrome in October 1997. He was treated with red blood cell transfusion and granulocyte-colony stimulating factor (G-CSF). In February 1998, he was admitted due to progression of pancytopenia. Bone marrow aspiration revealed refractory anemia with excess of blasts in transformation. The patient was treated with continuous-drip infusion of low-dose cytarabine and etoposide with G-CSF (AVG therapy). Complete remission (CR) was obtained after 2 courses of AVG therapy. Non-hematologic adverse effects were mild enough to be tolerated. CR has been maintained for 16 months with 1 course of consolidation therapy and 3 courses of intensification therapy using the AVG regimen.

https://pubmed.ncbi.nlm.nih.gov/10774251/

47a4d9d3f5318ec4636de288bc670d2e

Among the GNB , a higher prevalence of resistance was observed against cefoxitin ( 93.1 % ) followed by ampicillin ( 79.4 % ) , chloramphenicol ( 72.6 % ) , ceftizoxime ( 65.7 % ) , aztreonam ( 64.9 % ) , cefotaxime ( 53.6 % ) , imipenem ( 38.3 % ) , ceftazidime ( 33.5 % ) , gentamicin ( 32.6 % ) , tetracycline ( 22.2 % ) , and ciprofloxacin ( 19.8 % ) .

Prevalence of multiple antibiotic-resistant Gram-negative bacteria on bagged, ready-to-eat baby spinach. In this study, multiple antibiotic-resistant (MAR) Gram-negative bacteria (GNB) were isolated from triple-washed, bagged, ready-to-eat (RTE) baby spinach. Biochemical identification of randomly selected bacterial colonies showed the predominance of cytochrome oxidase-positive Pseudomonas species. Among the GNB , a higher prevalence of resistance was observed against cefoxitin ( 93.1 % ) followed by ampicillin ( 79.4 % ) , chloramphenicol ( 72.6 % ) , ceftizoxime ( 65.7 % ) , aztreonam ( 64.9 % ) , cefotaxime ( 53.6 % ) , imipenem ( 38.3 % ) , ceftazidime ( 33.5 % ) , gentamicin ( 32.6 % ) , tetracycline ( 22.2 % ) , and ciprofloxacin ( 19.8 % ) . Multiple antibiotic resistance (MAR) linked to two or more antibiotics was found in 95.3% of isolates, and resistance was transferable in the strains tested. These findings confirm the presence of MAR bacteria on RTE baby spinach and suggest that human consumption of this produce would amplify the MAR gene pool via conjugal transfer of MAR genes to commensal gut microflora and bacterial pathogens.

https://pubmed.ncbi.nlm.nih.gov/22838727/

4bde78413693b71b460a3ea9799bd664

The results suggested that irinotecan , 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer .

Phase II study of irinotecan, 5-fluorouracil, and leucovorin in relapsed or metastatic colorectal cancer as first-line therapy. The purpose of this study was to assess the efficacy and toxicity of biweekly irinotecan plus 5-fluorouracil (FU) and leucovorin (LV) in patients with relapsed or metastatic colorectal cancer. ### Materials And Methods Between March 2002 and May 2004, 24 patients with histologically confirmed relapsed or metastatic colorectal cancer were enrolled in this study. One chemotherapy cycle consisted of irinotecan 180 mg/m(2) on days 1 and 15; 5-FU 400 mg/m(2) bolus IV with 600 mg/m(2) by a 22 hour intravenous infusion on days 1, 2, 15 and 16; and leucovorin 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. ### results The median age of the 24 was 57.5 years (range, 38 approximately 69). Their metastatic sites included: the liver (62.5%), lung (20.8%), peritoneum (16.7%), lymph node (12.5%), ovary (8.3%) and pelvis/vagina (8.3%). Twenty-two patients were evaluable for a response. Six and 7 patients achieved partial responses and stable diseases, respectively. The overall response rate was 27.3% (95% Confidence interval; 10.3 approximately 44.5%). The median follow-up duration for surviving patients was 14.7 months (range, 1.7 approximately 26.5). Median overall survival (OS) and 1-year OS rates were 19 months and 86.3%, respectively. Median response duration and median progression free survival were 7.47 and 5.57 months, respectively. A total of 83 cycles (median 4 cycles) were administered. The main non-hematologic toxicities were nausea/vomiting (44.5%/18.1%) and diarrhea (8.4%). The most common hematologic toxicity was NCI grade I/II anemia (31.3%) and grade I/II neutropenia was 10.8%. There was no life-threatening toxicity. ### conclusion The results suggested that irinotecan , 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer .

https://pubmed.ncbi.nlm.nih.gov/20368840/

e57d2540d079fe3c4c317a7ef55f2581

Fifty-three consecutive patients with active duodenal ulcer ( DU ) were randomly included in a double-blind , double-dummy study to test the healing and relapsing rate of two treatment regimens : famotidine 40 mg nocte for 4 - 8 weeks , followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth ( CBS ) ( 240 mg bid ) for 4 - 8 weeks , followed by placebo maintenance treatment .

Colloid bismuth versus famotidine in the treatment and prevention of duodenal ulcer relapse: results of a double-blind, double dummy randomized study. Fifty-three consecutive patients with active duodenal ulcer ( DU ) were randomly included in a double-blind , double-dummy study to test the healing and relapsing rate of two treatment regimens : famotidine 40 mg nocte for 4 - 8 weeks , followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth ( CBS ) ( 240 mg bid ) for 4 - 8 weeks , followed by placebo maintenance treatment . The results of the short term period confirmed the efficacy of CBS in healing DU (24/25 in CBS group and 19/23 in famotidine group). However, the relapse rate in the CBS-treated group was higher (77.8% at 12 months) than in the famotidine group (35.7%) (p = 0.041). Only 7 patients (41.2%) were cleared from Helicobacter pylori (HP) after CBS treatment. In conclusion, the high relapse rate observed in CBS treated patients may be related to the high percentage of patients with HP infection in the tested group and support the hypothesis that lack of efficacy of CBS in preventing DU recurrence is related to its poor eradication of HP.

https://pubmed.ncbi.nlm.nih.gov/7557824/

1a73cbf60711bfb9042ed9003466b731

Cytotoxic monotherapy was the most frequently prescribed regimen ( N = 60 , 46 % ) in 2L , followed by combination therapies ( N = 45 , 35 % ) , pembrolizumab monotherapy ( N = 19 , 15 % ) , and bevacizumab monotherapy ( N = 6 , 5 % ) .

Patient characteristics, treatment patterns, and clinical outcomes among patients with previously treated recurrent or metastatic cervical cancer: A community oncology-based analysis. There is no standard systemic treatment for recurrent or metastatic cervical cancer (r/mCC) after failure of first-line (1L) therapy. This study characterizes the patient experience, treatment patterns, and clinical outcomes of patients who initiated second-line (2L) therapy for r/mCC in a US community oncology setting. ### methods This is an observational study of cervical cancer patients who failed 1L systemic treatment for r/mCC and initiated 2L systemic therapy between 2014 and 2019 within the US Oncology Network (USON). USON's electronic health records were used to identify eligible patients and abstract data. Overall survival (OS), time to treatment discontinuation (TTD), and time to first subsequent treatment (TFST) were estimated using Kaplan-Meier methods. ### results A total of 130 patients were identified (mean age 53 years). Over 60% of patients had Eastern Cooperative Oncology Group score of 0-1. Cytotoxic monotherapy was the most frequently prescribed regimen ( N = 60 , 46 % ) in 2L , followed by combination therapies ( N = 45 , 35 % ) , pembrolizumab monotherapy ( N = 19 , 15 % ) , and bevacizumab monotherapy ( N = 6 , 5 % ) . Median OS was 9.1 months (95% CI: 7.2-12.2) after initiation of 2L therapy. Median TTD was 2.8 months (95% CI: 2.5-3.3), and median TFST was 4.9 months (95% CI: 4.2-5.7). No significant difference in outcomes was found when stratified by 2L treatments. ### conclusions The observed heterogeneity in 2L r/mCC therapy suggests no clear standard-of-care in this setting. Additionally, short duration of OS observed was consistent across 2L regimens. New, effective treatment options in this setting are needed.

https://pubmed.ncbi.nlm.nih.gov/33741208/

a1d1c9a7eb89a7f9e645d79ee15ca140

Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure , portal tributary blood flow and increased hepatocollateral vascular resistance ; terlipressin increased arterial pressure and further decreased cardiac index .

Haemodynamic responses to a combination of terlipressin and octreotide in portal hypertensive rats. An enhancement of the haemodynamic effects of terlipressin by octreotide (and vice versa) may be useful in the treatment of portal hypertension. The aim of this study was to investigate the short-term effects of terlipressin, octreotide or a combination of these substances on splanchnic and systemic haemodynamics in rats with portal vein stenosis. ### methods Eight rats received an intravenous (i.v.) infusion of isotonic saline (10 microL/min for 15 min). Eight rats received terlipressin first (0.05 mg/kg) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min) 15 min later. Eight other rats first received an i.v. infusion of octreotide and then terlipressin 15 min later. Splanchnic and systemic haemodynamics (radioactive microsphere method) were measured after saline, after terlipressin or octreotide alone, and after the combined treatments. ### results terlipressin and octreotide alone significantly decreased portal pressure, portal tributary blood flow and cardiac index. terlipressin, but not octreotide, significantly increased heptocollateral vascular resistance and arterial pressure. octreotide administration in rats pre-treated with terlipressin did not change portal pressure, caused portal tributary blood flow to increase and decreased hepatocollateral vascular resistance; it also decreased arterial pressure but not cardiac index. Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure , portal tributary blood flow and increased hepatocollateral vascular resistance ; terlipressin increased arterial pressure and further decreased cardiac index . ### conclusions In rats with portal vein stenosis, octreotide decreased short-term splanchnic and systemic vasoconstriction due to terlipressin. In contrast, terlipressin enhanced the splanchnic and systemic vasoconstriction due to octreotide. Thus, the haemodynamic responses to the combination of octreotide and terlipressin depend on the order of administration of these substances.

https://pubmed.ncbi.nlm.nih.gov/9354212/

ea378b3a02bedc9af503f0fdabfbc871

Results confirmed the antidepressant action of alprazolam and imipramine .

The effect of sympathetic antagonists on the antidepressant action of alprazolam. alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam-induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine . Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

https://pubmed.ncbi.nlm.nih.gov/21499463/

f692286c20dae2c0dbb64ce180cf9fe8

Cell viability of two human hepatoma cell lines ( Huh7 and Hep-G2 ) was quantitatively investigated under the treatment of two drugs ( doxorubicin and etoposide ) .

Towards a high throughput impedimetric screening of chemosensitivity of cancer cells suspended in hydrogel and cultured in a paper substrate. In order to achieve high predictive value of cell chemosensitivity test for clinical efficacy, cancer cells were suggested to be encapsulated and cultured in hydrogel to mimic the natural microenvironment of tumors. However, handling 3D cells/hydrogel culture construct is tedious and cellular response is difficult to be quantitatively analyzed. In the current study, a novel platform for conducting 3D cell culture and analyzing cell viability has been developed towards a high throughput drug screening. Cells encapsulated in the hydrogel were cultured in the microwells of a paper substrate. The substrate was then immersed in the culture medium containing drug for 2 days. At 24 and 48h during the culture course, the paper substrate was placed on the measurement electrodes for conducting the impedance measurement in order to quantify the cell viability in the hydrogel. Cell viability of two human hepatoma cell lines ( Huh7 and Hep-G2 ) was quantitatively investigated under the treatment of two drugs ( doxorubicin and etoposide ) . The results represented by IC

https://pubmed.ncbi.nlm.nih.gov/28946107/

ff6667a3254f6d44fc3a3900ef49a8b6

MIF , TRH , and its analog PR-546 , the paraopioid RP , leuenkephalin , dalargin , the ACTH analogue Semax , tafcin , thymosine , interleukin-1 , vasopressin , oxytocin , bradykinin , defencin , and some proline-containing oligopeptides , such as Pro-Gly , Gly-Pro , Trp-Pro , Pro-Gly-Pro , Gly-Pro-Gly-Gly were studied .

[The modulation of hemostatic reactions in vitro and in vivo by representatives of regulatory peptide families]. Data available in the literature and the author's own findings of the effects of regulatory peptide (RP) and their analogues are summarized. MIF , TRH , and its analog PR-546 , the paraopioid RP , leuenkephalin , dalargin , the ACTH analogue Semax , tafcin , thymosine , interleukin-1 , vasopressin , oxytocin , bradykinin , defencin , and some proline-containing oligopeptides , such as Pro-Gly , Gly-Pro , Trp-Pro , Pro-Gly-Pro , Gly-Pro-Gly-Gly were studied . A complex of in vitro and in vivo tests identified three groups of RP: 1) neutral ones as to the hemostatic reactions studied; 2) stimulants of hypercoagulation and fibrin polymerization; 3) inhibitors of blood coagulation, increased fibrinolysis, and fibrin demopolymerization. The fibrinolytic and antithrombotic effects of Semax (in vivo), the procoagulative action of defencin, and the enhanced anticoagulant effects in the combinations of Semax-heparin and tafcin (in vivo) attract particular attention. Semax alone and in combination with heparin is recommended for clinical studies in respective hemostatic abnormalities.

https://pubmed.ncbi.nlm.nih.gov/8924838/

7f23e845124671e1faa7b73a1fb4bd9e

In both cohorts , more than 40 % of patients discontinued their index drugs ( 46.4 % pazopanib and 44.1 % sunitinib , P = 0.732 ) .

Persistence and compliance among U.S. patients receiving pazopanib or sunitinib as first-line therapy for advanced renal cell carcinoma: a retrospective claims analysis. For first-line therapy options for advanced renal cell carcinoma (RCC), clinical trials have demonstrated similar efficacy for pazopanib and sunitinib as well as differing side-effect profiles, which may affect patient persistence in self-administration of these oral medications. However, the treatment patterns of each drug in real-world clinical practice, as opposed to the controlled environment of a trial, have not been directly compared. ### objective To compare persistence and compliance (adherence) with pazopanib versus sunitinib in a real-world setting. ### methods This was a retrospective claims analysis using 2 databases: Optum Research Database and Impact National Benchmark Database. Eligible patients included adult patients (aged ≥ 18 years) with ≥ 2 RCC diagnoses and evidence of first-line therapy with ≥ 1 subsequent pharmacy claim for pazopanib or sunitinib between October 2009 and July 2012. The date of the first pazopanib or sunitinib claim was defined as the index date. Additional requirements included continuous enrollment in the health plan for 2 months prior (baseline period) through 6 months after (follow-up period) the index date and no cancers other than those associated with RCC. Propensity score matching was used to minimize selection bias. Persistence with the index drug was compared using days to discontinuation, estimated level of persistence (ELPT) at 180 days, and proportion of days covered (PDC). PDC was defined by dividing the number of days covered with the index drug by the number of follow-up days. Compliance was estimated using medication possession ratio (MPR). For matched cohort pairs with > 1 fill, MPR was defined by dividing the number of days covered with the index drug by the number of days between the first and last index medication fill. ### results We identified 84 matched pairs among 97 patients prescribed pazopanib and 349 prescribed sunitinib. Among the matched population, mean comorbidity index score was 5.8 (95% CI = 1.8-6.0) for pazopanib, and 6.1 (95% CI =1.8-6.0) for sunitinib (P = 0.133). Evidence of any radiation therapy during the baseline period was significantly higher among the sunitinib cohort prior to matching (9% vs. 18%, P = 0.043), and evidence of surgery was higher in the pazopanib cohort after matching (12% vs. 7%, P = 0.046). Cohorts were balanced according to demographic and clinical characteristics with mean (SD) age of 63.0 (9.0) years and 77.4% male. During the 6-month period after drug initiation, there was no significant difference (P > 0.05) by drug cohort in the duration of index drug therapy or the percentage of patients who discontinued their index drugs. The mean (SD) time to discontinuation was 133.4 (62.8) days and 139.9 (55.6) days among the matched pazopanib and sunitinib cohorts, respectively (P = 0.445). In both cohorts , more than 40 % of patients discontinued their index drugs ( 46.4 % pazopanib and 44.1 % sunitinib , P = 0.732 ) . In addition, there was no significant difference by drug cohort in the ELPT at any time examined between 30 and 180 days after initiation of therapy. PDC with the index drug during the fixed 6-month follow-up was also examined. Although the mean PDC was significantly higher among the sunitinib cohort (0.77 vs. 0.68 for pazopanib, P = 0.037), there was no difference by cohort in the percentage of patients with high PDC (defined as ≥ 80%): 52.4% versus 56.0% for pazopanib and sunitinib, respectively (P = 0.622). Mean MPR among matched pairs with at least 2 fills for the index drug was significantly higher among the sunitinib cohort, although there was no difference by cohort in the percentage of patients with high MPR (defined as ≥ 80%): 81.4% versus 93.2% for pazopanib and sunitinib, respectively (P > 0.071). ### conclusions In the first 6 months of treatment, persistence and compliance to pazopanib and sunitinib were similar. Future studies are needed, including those assessing larger cohorts and longer follow-up periods.

https://pubmed.ncbi.nlm.nih.gov/26011553/

e0dbd07b99f4b724b1f5fbc279bc2212

The patients were heavily pretreated with anthracycline ( 100 % ) , taxane ( paclitaxel or docetaxel ) ( 100 % ) , capecitabine ( 100 % ) , vinorelbine ( 71 % ) , and mitomycin ( 69 % ) .

Efficacy of S-1 in heavily pretreated patients with metastatic breast cancer: cross-resistance to capecitabine. It is not clear what the optimal treatment of chemotherapy is for patients with heavily treated metastatic breast cancer (MBC). We have retrospectively examined the efficacy and safety of S-1 in patients with MBC who had been previously treated with anthracycline, taxane, and capecitabine. ### methods Patients with MBC who had been administered S-1, an oral modulated compound containing a fluoropyrimidine derivative, between November 2001 and June 2003 at the Cancer Institute Hospital were retrospectively reviewed. S-1 at a standard dose of 50 mg/body was administered twice daily for four weeks, followed by a two-week rest period. This was repeated every six weeks until disease progression or unacceptable toxicity. ### results Thirty-five patients were assessed. The patients were heavily pretreated with anthracycline ( 100 % ) , taxane ( paclitaxel or docetaxel ) ( 100 % ) , capecitabine ( 100 % ) , vinorelbine ( 71 % ) , and mitomycin ( 69 % ) . Median follow-up time of patients was 9.6 months (range, 1.2-26.6). ORR was 3% (95% confidence interval: 0-9%), and CBR was 20% (95% confidence interval: 6-33%). Time to treatment failure was 2.8 months. Overall survival was 21.4 months. Grade 1 or 2 adverse events were observed in 17% and 13%, respectively. Grade 3 events occurred as anorexia (9%), nausea (9%), vomiting (9%), diarrhea (14%), fatigue (3%), and elevation of AST/ALT (3%). No grade 3 was seen as hand-foot syndrome. Neither grade 3 nor 4 was observed in bone marrow suppression. ### conclusions S-1 was fairly well tolerated, but demonstrated very limited activity in capecitabine-pretreated patients who had already been exposed to anthracycline and taxane. It was suggested that S-1 clinically exhibited cross-resistance to capecitabine.

https://pubmed.ncbi.nlm.nih.gov/18807123/

35657fbbeccb726f1fb2a4764c0e3450

Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin .

Aspergillus osteomyelitis. Report of a case and review of the literature. Aspergillus is a ubiquitous saprophytic fungus seldom pathogenic for normal hosts. Aspergillus osteomyelitis occurs infrequently and is typically limited to patients with predisposing factors, including leukocyte dysfunction, malignancy with neutropenia, steroid or antibiotic therapy, pulmonary aspergillosis, and surgical manipulation. The spine is most frequently affected, and the clinical presentation is nonspecific (50% afebrile). Diagnosis requires demonstration of characteristic, acutely branching, broad, septate hyphae in biopsy material, and culture of Aspergillus. Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin .

https://pubmed.ncbi.nlm.nih.gov/4064611/

5846f8aa22262ba57ea026616c35439a

Docetaxel and cisplatin were given at 75 mg/m(2 ) , while capecitabine was initially given at 500 mg/m(2 ) twice a day and subsequently escalated .

Induction chemotherapy with docetaxel, cisplatin and capecitabine, followed by combined cetuximab and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck: a phase I-II study. To replace 5-fluorouracil with capecitabine within a trial of induction chemotherapy followed by cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Also, to replace cisplatin with cetuximab after induction chemotherapy. ### methods Docetaxel and cisplatin were given at 75 mg/m(2 ) , while capecitabine was initially given at 500 mg/m(2 ) twice a day and subsequently escalated . The maximum tolerated dose was used for the phase II study. ### results Seven patients were enrolled. At dose level 1, two dose-limiting toxicities were observed in the first 4 patients (grade 4 neutropenia and grade 3 diarrhea). In both patients, capecitabine was withdrawn and toxicities resolved. Dose escalation was halted and a lower capecitabine dose (750 mg/m(2) daily) was selected. Two complete responses and five partial responses were observed after induction chemotherapy. Four patients were evaluable for response after cetuximab-RT (3 complete response and 1 partial response). ### conclusion Combined chemoradiotherapy is still the gold standard in LA SCCHN and no studies currently support the use of early induction chemotherapy. Our study did not contribute toward addressing this issue since it was discontinued early because of toxicity.

https://pubmed.ncbi.nlm.nih.gov/23428719/

8bd6b10ee379d41f0b0d3c5ed6104e9a

A colorectal cancer cell line ( LOVO cell ) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model .

Proteomic analysis identifies proteins associated with curcumin-enhancing efficacy of irinotecan-induced apoptosis of colorectal cancer LOVO cell. We wish to implement a proteomics-based approach to pick and identify the proteins associated with curcumin enhancing efficacy of irinotecan inducing apoptosis of colorectal cancer LOVO cells, and further explore their synergy mechanism by bioinformatics. ### methods A colorectal cancer cell line ( LOVO cell ) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model . Protein spots were analyzed through MALDI-TOF/TOF. The location and function of differential protein spots were analyzed through UniProt database. Protein-protein interactions were examined through String software. ### results A total of 54 protein spots differentially expressed with 1.5-fold difference were picked, 11 of which were repeated. They mainly were involved in intracellular calcium pathways, cellular respiratory chain pathway and intracellular redox reaction pathways of LOVO cell. According to the function of various protein points, combining with varying curves of protein points in each treatment groups, we selected five interesting protein spots, 4 of which exists Protein-protein interactions, and they were close to the formation and reduction of disulfides in intracellular endoplasmic reticulum (ER). ### conclusion We selected preliminary but comprehensive data about differential expression protein spots of LOVO cell. Among these, the five interesting differential expression protein spots identified in this study may provide new insight into LOVO cell therapeutic biomarkers. curcumin may suppress GSTM5 expression to enhance the lethal effect of irinotecan on LOVO cells, and maybe their combination via the affection of PDI and PRDX4 to disturb the formation and reduction of disulfides results in inducing apoptosis of LOVO cell.

https://pubmed.ncbi.nlm.nih.gov/24427321/

9518550be80156aba0f21621c9edb969

The use of ceftriaxone plus doxycycline as an initial empiric therapy for patients hospitalized with CAP appears safe and effective , and its potential superiority should be evaluated prospectively .

Effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia. Limited data exist on the effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia (CAP). ### methods We performed a retrospective cohort study of all adults hospitalized for pneumonia between January 1999 and July 2001 at an academic medical center. Outcomes were compared for patients with CAP treated with ceftriaxone plus doxycycline versus other appropriate initial empiric antibiotic therapies. Outcomes were adjusted with the use of a propensity score to account for differences in patient characteristics and illness severity between groups. ### results A total of 216 patients were treated with ceftriaxone plus doxycycline and 125 received other appropriate initial empiric antibiotic therapies. After adjustment, use of ceftriaxone plus doxycycline was associated with reduced inpatient mortality (OR = 0.26, 95% CI: 0.08-0.81) and 30-day mortality (OR = 0.37, 95% CI: 0.17-0.81), but not with length of stay or readmission rates. Analysis of a subset of the sample that excluded patients admitted from nursing homes, patients admitted to the ICU, and patients diagnosed with aspiration also showed reduced inpatient mortality with the use of ceftriaxone plus doxycycline. ### conclusions The use of ceftriaxone plus doxycycline as an initial empiric therapy for patients hospitalized with CAP appears safe and effective , and its potential superiority should be evaluated prospectively .

https://pubmed.ncbi.nlm.nih.gov/17219465/

3d3ae8bbe9535081977b3941cd0ae869

Metformin ( 50 mg/kg/day ) , genistein ( 20 mg/kg/day ) and combination of genistein and metformin was administered in alloxan-induced diabetic rats .

Genistein enhances the secretion of glucagon-like peptide-1 (GLP-1) via downregulation of inflammatory responses. Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin ( 50 mg/kg/day ) , genistein ( 20 mg/kg/day ) and combination of genistein and metformin was administered in alloxan-induced diabetic rats . We found that genistein alone and/or in combination with metformin significantly increased the serum level (P < 0.01) and tissue content (P < 0.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P < 0.001), glucose tolerance (P < 0.01), insulin sensitivity (P < 0.0001), hyperlipidemia (P < 0.01), liver and kidney function biomarkers (P < 0.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-α and C-reactive protein in serum (P < 0.05) and intestine (P < 0.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.

https://pubmed.ncbi.nlm.nih.gov/30784939/

6aa7633459e4ecb48ae1c169622c608e

CYP3A5 ( intron 3 ) and MDR1 ( exons 12 , 21 , 26 ) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus .

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. ### methods Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 ( intron 3 ) and MDR1 ( exons 12 , 21 , 26 ) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus . ### results There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. ### conclusions Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

https://pubmed.ncbi.nlm.nih.gov/16249748/

4676399f4bc7e4dfa83e4eaa3a5b3adb

Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen , which combines yttrium-90-labeled ibritumomab tiuxetan ( Zevalin ) with high-dose BEAM ( carmustine , etoposide , cytarabine , melphalan ) chemotherapy .

Autologous transplantation for transformed non-Hodgkin lymphoma using an yttrium-90 ibritumomab tiuxetan conditioning regimen. Transformation from indolent non-Hodgkin lymphoma (NHL) to diffuse large B cell lymphoma (DLBCL) has historically been associated with a poor prognosis. A small series of autologous stem cell transplantation (ASCT) studies using conventional conditioning regimens has demonstrated durable progression-free survival (PFS) rates ranging from 25% to 47%, but data in the rituximab era are lacking. Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen , which combines yttrium-90-labeled ibritumomab tiuxetan ( Zevalin ) with high-dose BEAM ( carmustine , etoposide , cytarabine , melphalan ) chemotherapy . Sixty-three patients from 4 institutions were treated between 2003 and 2011. Histological confirmation of transformation was required and defined as a diagnosis of DLBCL in patients with either a prior history or concomitant diagnosis of low-grade B cell NHL. Median patient age at ASCT was 59.5 years, median number of prior regimens was 2, and all patients were exposed to rituximab. Disease status at ASCT was as follows: first complete remission (CR) (n = 30), first partial remission (n = 11), first relapse (n = 14), and at least second CR (n = 8). The median time from diagnosis of histological transformation to ASCT was 7.5 months (range, 2.8 to 116). Two-year nonrelapse mortality was 0%. Median follow-up for living patients was 28 months (range, 5 to 103). Two-year PFS was 68% (95% confidence interval, 58% to 75%), and overall survival was 90% (95% confidence interval, 80% to 95%). In conclusion, the Z-BEAM conditioning regimen for ASCT is well tolerated by patients with transformed lymphoma and demonstrates encouraging clinical outcomes.

https://pubmed.ncbi.nlm.nih.gov/25079874/

cca0fb8ed158442e36b07b073bc595a4

Palbociclib is a selective cyclin-dependent kinase ( CDK ) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive ( HR+ ) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer ( ABC/MBC ) .

Real-World Palbociclib Use in HR+/HER2- Advanced Breast Cancer in Canada: The IRIS Study. Palbociclib is a selective cyclin-dependent kinase ( CDK ) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive ( HR+ ) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer ( ABC/MBC ) . palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2- ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. ### methods This retrospective chart review included women with HR+/HER2- ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan-Meier analysis. ### results Thirty-three physicians examined medical records for 247 patients (P+L, ### conclusions Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.

https://pubmed.ncbi.nlm.nih.gov/33498797/

9750dd0503c6e26b90a93f82a904af2d

Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer : a dose-finding and phase II study .

Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer : a dose-finding and phase II study . A weekly administration of alternating irinotecan or oxaliplatin associated to 5-fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).

https://pubmed.ncbi.nlm.nih.gov/20428819/

949504286ba6bc44ce85c9fa5dd1b301

After larvae were infected with S. aureus , larval survival was enhanced by administering the antistaphylococcal antibiotics daptomycin or vancomycin .

Wax moth larva (Galleria mellonella): an in vivo model for assessing the efficacy of antistaphylococcal agents. To investigate whether the wax moth larva, Galleria mellonella, is a suitable host for assessing the in vivo efficacy of antistaphylococcal agents against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infections. ### methods Wax moth larvae were infected with increasing doses of S. aureus to investigate the effect of inoculum size on larval survival. In addition, infected wax moth larvae were treated with daptomycin, penicillin or vancomycin to examine whether these agents were effective against S. aureus and MRSA infections in vivo. ### results Increasing inoculum doses of live S. aureus cells resulted in greater larval mortality, but heat-killed bacteria and cell-free culture filtrates had no detrimental effects on survival. Larval mortality rate also depended on the post-inoculation incubation temperature. After larvae were infected with S. aureus , larval survival was enhanced by administering the antistaphylococcal antibiotics daptomycin or vancomycin . Larval survival increased with increasing doses of the antibiotics. Moreover, penicillin improved survival of larvae infected with a penicillin-susceptible methicillin-susceptible S. aureus (MSSA) strain, but it was ineffective at similar doses in larvae infected with MRSA (penicillin resistant). daptomycin and vancomycin were also effective when administered to the larvae prior to infection with bacteria. ### conclusions This is the first report to demonstrate that antibiotics are effective in the wax moth larva model for the treatment of infections caused by Gram-positive bacteria. The new wax moth larva model is a useful preliminary model for assessing the in vivo efficacy of candidate antistaphylococcal agents before proceeding to mammalian studies, which may reduce animal experimentation and expense.

https://pubmed.ncbi.nlm.nih.gov/21622972/

a000945f4ace572bd2cf8e5cd4ed2383

In terms of progression-free survival ( PFS ) , axitinib was superior compared with placebo ( HR = 0.25 , 95 % CrI : 0.17 - 0.38 ) , sorafenib ( HR = 0.46 , 95 % CrI : 0.32 - 0.68 ) and pazopanib ( HR = 0.47 , 95 % CrI : 0.26 - 0.85 ) .

Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. ### methods Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). ### results Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival ( PFS ) , axitinib was superior compared with placebo ( HR = 0.25 , 95 % CrI : 0.17 - 0.38 ) , sorafenib ( HR = 0.46 , 95 % CrI : 0.32 - 0.68 ) and pazopanib ( HR = 0.47 , 95 % CrI : 0.26 - 0.85 ) . An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. ### conclusion Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.

https://pubmed.ncbi.nlm.nih.gov/23256638/

f8183c84625b670fd1d5ee81a12d76bf

Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS .

Combination versus sequential paclitaxel plus gemcitabine as first-line chemotherapy for women with metastatic breast cancer: a prospective randomized phase II study. paclitaxel (T) plus gemcitabine (G) is an active concomitant combination for the treatment of metastatic breast cancer (MBC). However, the efficacy of sequential administration of these two drugs is unclear. This randomized phase II study was conducted to evaluate the efficacy of T and G administered either as a concomitant or as a sequential regimen in patients with MBC. ### methods Patients with MBC (n=66) were randomized to either receive 6 cycles of concomitant T and G or 4 cycles of T followed by 4 cycles of G, as first line chemotherapy. With no progression, the arms would switch to maintenance with paclitaxel. Progression free survival (PFS) was defined as the primary endpoint; secondary endpoints were the overall response rate (ORR), overall survival (OS), and toxicity. In total, 33 patients were randomized to the concomitant or sequential arms. Patient characteristics were well balanced. The median number of chemotherapy cycles was 6 for the concomitant arm and 8 for the sequential arm. ### results No significant difference was observed in terms of PFS, ORR, and OS. Only 13 (39.4%) patients progressed in the sequential arm. Although there was no significant difference between the two arms (p=0.056),the sequential arm had a remarkable trend of longer PFS than the concomitant arm. Toxicities were manageable and similar in both arms.The incidence of neutropenia was significantly higher in the concomitant arm (90.9%) than in the sequential arm (60.6%). Grade 3 or 4 neutropenia was not significantly different between the two arms. ### conclusions Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS .

https://pubmed.ncbi.nlm.nih.gov/30610781/

4c3f1b6f9750900aeb10170e8b4cf94f

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer : A Phase 3 Randomized Clinical Trial .

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer : A Phase 3 Randomized Clinical Trial . ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. ### objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. ### Design Setting And Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. ### interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. ### Main Outcomes And Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. ### results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. ### Conclusions And Relevance In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. ### Trial Registration ClinicalTrials.gov Identifier: NCT02492711.

https://pubmed.ncbi.nlm.nih.gov/33480963/

1b6797e6b26dc93d0b4ece9dcce79972

She was treated with a combination of four cycles of cyclophosphamide , hydroxydaunorubicin , vincristine , and prednisolone ( CHOP ) regimen followed by local radiotherapy ( 36 Gray/20 fractions/4 weeks ) by three-dimensional conformal technique .

Combined Modality Management of Sinonasal Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma in a Young Adult-Report of a Rare Case. Sinonasal anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) without nodal involvement is extremely rare and the rarity of this tumor often leads to diagnostic dilemma. It has been predominantly reported in pediatric, adolescent and young adult patients, mostly of Asian origin. A 21-year-old female patient presented with history of epistaxis for 1 year. On clinical and radiological examination, there was a 5 cm mass in the right nasal cavity, ethmoid, and frontal sinus. Biopsy at a local center had shown moderately differentiated squamous cell carcinoma. Rebiopsy at our center showed possibility of a hematolymphoid malignancy(pancytokeratin-, CD45+, CD3-, CD20-) and further immunohistochemistry studies(CD4+, CD43+, CD30+, ALK+) revealed ALK-positive ALCL. Rest of the lymphoma work-up was essentially normal and she had stage IE disease. She was treated with a combination of four cycles of cyclophosphamide , hydroxydaunorubicin , vincristine , and prednisolone ( CHOP ) regimen followed by local radiotherapy ( 36 Gray/20 fractions/4 weeks ) by three-dimensional conformal technique . She tolerated the treatment well without any severe toxicity and had complete clinical and radiological response. At last follow-up visit, 40 months from the initial diagnosis, she was alive and disease free. Sinonasal ALK-positive ALCL is a rare tumor, which can be effectively treated with a combination of multiagent CHOP/CHOP-like regimen and local conformal radiotherapy.

https://pubmed.ncbi.nlm.nih.gov/30994389/

7b2d63dc01a8cf947fa8d797c1e4fbc7

We compared such treatment with docetaxel plus prednisone in men with this disease .

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease . ### methods From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. ### results As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. ### conclusions When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

https://pubmed.ncbi.nlm.nih.gov/15470213/

11ee75a48ed1d61aaaebf94dde6088f6

Magnocellular neurons of the hypothalamo-neurophypophysial system synthesize either vasopressin or oxytocin ; water deprivation and chronic saline ingestion are potent stimuli for the expression of both of the genes encoding these neuropeptides .

Simultaneous detection of neuropeptides and messenger RNA in the magnocellular hypothalamo-neurohypophysial system by a combination of non-radioactive in situ hybridization histochemistry and immunohistochemistry. A protocol was developed combining non-radioactive in situ hybridization histochemistry with enzyme based immunohistochemistry, detect the expression of mRNA in phenotypically defined neurons. Free-floating brain sections were hybridized with the oligonucleotide probes which have been 3'-end labelled with biotin-11-dUTP. The hybridized probe was visualized by a combined avidin-biotin bridge method, anti-avidin immunohistochemistry, and horseradish peroxidase detection using diaminobenzidine as a substrate. The in situ hybridization step yielded a very stable reaction product enabling subsequent immunohistochemical reactions using horseradish peroxidase and benzidine dihydrochloride as a chromogen. Magnocellular neurons of the hypothalamo-neurophypophysial system synthesize either vasopressin or oxytocin ; water deprivation and chronic saline ingestion are potent stimuli for the expression of both of the genes encoding these neuropeptides . A number of other neuropeptides with putative transmitter action are synthesized in magnocellular neurons during such stimulation. Experiments were performed to explore whether neuropeptide y immunoreactivity is present within magnocellular vasopressin mRNA-expressing neurons of the hypothalamo-neurophypophysial system. The results clearly demonstrated that neuropeptide y-immunoreactive elements were present within a number of magnocellular vasopressin mRNA-containing cells. In addition, immunohistochemical detection of the neuropeptides ocytocin and cholecystokinin was carried out on sections hybridized non-radioactively for vasopressin; as expected vasopressin mRNA did not co-exist with cholecystokinin, whereas a few oxytocin immunoreactive neurons in osmotically stimulated animals also contained vasopressin mRNA. The developed method makes possible the immunohistochemical detection of intracellular antigens with concomitant detection of intracellular mRNA.

https://pubmed.ncbi.nlm.nih.gov/7698898/

fe4c90d21c59eca0e7c6c24e30779155

Combination chemotherapy has been established to have superior response rates and progression-free survival and -- in some instances , for fluorouracil and irinotecan combinations -- improved overall survival compared to fluorouracil alone .

Update on chemotherapy for advanced colorectal cancer. Efforts to improve the length and quality of life, as well as to expand treatment options, for patients with metastatic colorectal cancer have only recently become more successful. With maximization of dose and schedule schemes for fluoropyrimidine therapy, new drugs such as irinotecan (CPT-11, Camptosar) and oxaliplatin have also become part of the standard therapy for patients. Combination chemotherapy has been established to have superior response rates and progression-free survival and -- in some instances , for fluorouracil and irinotecan combinations -- improved overall survival compared to fluorouracil alone . There is still much to be learned about the optimal management of patients with colorectal cancer, including the role of second- and third-line chemotherapy in the overall survival outcome, and the role of salvage therapy in patients with limited metastatic disease. Most importantly, the development of a biological marker of prognosis and response should help to select appropriate chemotherapy programs for patients on a rational and individual basis, not only in the setting of metastatic disease, but also in the adjuvant population.

https://pubmed.ncbi.nlm.nih.gov/11301834/

03eff5ead4fbffb23ee6efc363538950

Phase IV study of bevacizumab in combination with infusional fluorouracil , leucovorin and irinotecan ( FOLFIRI ) in first-line metastatic colorectal cancer .

Phase IV study of bevacizumab in combination with infusional fluorouracil , leucovorin and irinotecan ( FOLFIRI ) in first-line metastatic colorectal cancer . bevacizumab (Avastin) significantly improves overall survival (OS) and progression-free survival (PFS) when combined with first-line irinotecan (IFL) plus bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer (CRC). This open-label, phase IV trial evaluated the efficacy and safety of first-line bevacizumab in combination with IFL and infusional 5-FU/LV (FOLFIRI). ### methods Two-hundred and nine treatment-naïve metastatic CRC patients were enrolled and received bevacizumab and FOLFIRI every 2 weeks. Treatment was continued until disease progression. The primary objective was PFS, with additional determinations of OS, response and toxicity. ### results Median PFS was 11.1 months and is comparable to that observed in published phase III and community-based trials using first-line bevacizumab plus FOLFIRI, and to phase III trials using bevacizumab in combination with bolus 5-FU/LV plus IFL. Median OS was 22.2 months. Overall response rate was 53.1% and the disease control rate 85.6%. Most adverse events were grade 1/2 and were manageable. The most common grade 3/4 adverse events (> or =10%) were neutropenia, venous thromboembolic events, diarrhea, and fatigue. ### conclusion bevacizumab combined with first-line FOLFIRI is an effective and well-tolerated therapy option for patients with metastatic CRC.

https://pubmed.ncbi.nlm.nih.gov/19628950/

a83574308995e37ffd7007d1f457b04f

In addition , multidrug resistance of Hep-2-CSCs to vincristine , etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics .

Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Chemoresistance is a major obstacle in chemotherapy of laryngeal carcinoma. Recently, studies indicate that cancer stem cells are responsible for chemotherapy failure. In addition, microRNAs play important roles in tumor initiation, development and multidrug resistance. In the present study, we found that the expression of microRNA-125a was decreased in laryngeal carcinoma tissues and Hep-2 laryngeal cancer stem cells (Hep-2-CSCs). MicroRNA-125a gain-of-function significantly increased the sensitivity of Hep-2-CSCs to cisplatin in vitro and in vivo. Combination with microRNA-125a mimics can decrease the half maximal inhibitory concentration of Hep-2-CSCs to cisplatin. Mechanically, we found that microRNA-125a reverses cisplatin resistance in Hep-2-CSCs by targeting Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1). Inhibition of HAX-1 by microRNA-125a significantly promotes the cisplatin-induced apoptosis in Hep-2-CSCs through mitochondrial pathway. In addition , multidrug resistance of Hep-2-CSCs to vincristine , etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics . These dates strongly suggested the promotion of microRNA-125a/HAX-1 axis on chemotherapy of laryngeal carcinoma.

https://pubmed.ncbi.nlm.nih.gov/27880721/

c1eafdf83c00572f96e0bbd3f6615400

Nine patients received a combination of cisplatin and etoposide ( EP ) , 5 had cyclophosphamide , doxorubicin and vincristine , 1 had cyclophosphamide , etoposide and vincristine and 1 had monotherapy with oral etoposide .

Resolution of superior vena cava obstruction in small cell lung cancer patients treated with chemotherapy. Small cell lung cancer is a highly chemo-sensitive malignancy. As it often presents with a central lesion, superior vena cava obstruction (SVCO) is not an uncommon manifestation. From January 1990 to December 1993, 161 patients with small cell lung carcinoma were seen at our institution. Twenty (12.4%) of these patients presented with symptoms and signs of SVCO. Initial therapy consisted of radiotherapy in 4 patients and chemotherapy in 16 patients. Of those treated with chemotherapy, patient characteristics included 13 males, median age of 62.5 years (range 51 to 78 years), Eastern Co-operative Oncology Group (ECOG) performance status of 3 to 4 in 7 patients; 1 to 2 in 9 patients, and limited stage disease in 8 patients. The median period of follow-up was 5 months. Nine patients received a combination of cisplatin and etoposide ( EP ) , 5 had cyclophosphamide , doxorubicin and vincristine , 1 had cyclophosphamide , etoposide and vincristine and 1 had monotherapy with oral etoposide . Overall response to chemotherapy was 81% (with 31% complete responses). All responders had resolution of SVCO. Only 3 patients did not respond (1 patient defaulted, 1 patient died of neutropenic sepsis at week one and 1 patient had stable disease). Resolution of SVCO was noted within the first 2 weeks after the first cycle; the earliest being 3 days. The only patient given single-agent oral etoposide responded within 10 days after initiation of treatment. Of the 7 patients with poor performance status (ECOG 3 to 4), 3 died from treatment-related complications. Chemotherapy is highly effective as a primary treatment of small cell lung carcinoma despite presentation with SVCO. However, caution is advised in the use of combination chemotherapy for those presenting with poor performance status. Initial therapy with oral etoposide or radiotherapy should be considered as possible alternatives for these patients.

https://pubmed.ncbi.nlm.nih.gov/8838986/

af8fae5caf46f6b613c1169c260a5c5c

Tetracycline ( TC ) and chlortetracycline ( CTC ) are used extensively for growth promotion and therapeutic purposes in livestock production .

Sorption of tetracycline and chlortetracycline on K- and Ca-saturated soil clays, humic substances, and clay-humic complexes. Tetracycline ( TC ) and chlortetracycline ( CTC ) are used extensively for growth promotion and therapeutic purposes in livestock production . The sorption of TC and CTC on clays, humic substances (HS), and clay-humic complexes (clay-HC) derived from two agricultural soils was quantified using dilute CaCl2 (Ca) and KCI (K) as background solutions. In all systems, the soil components sorbed > 96% of added tetracyclines. Strongest sorption was observed for clays, followed by HS, and then clay-HC. Greater sorption by the Ca systems than the K systems and decreased sorption with increasing pH suggests that cation bridging and cation exchange contribute to sorption. X-ray diffraction analysis showed that TC and CTC were sorbed in the interlayers of smectites and that the presence of HS reduced interlayer sorption of tetracyclines by smectites in clay-HC. The results indicate that tetracyclines are dominantly sorbed on soil clays and that HS in clay-HC either mask sorption sites on clay surfaces or inhibit interlayer diffusion of tetracyclines.

https://pubmed.ncbi.nlm.nih.gov/17410786/

01fab8aba01515b6ee53f10614e5a77e

Comparing the combination of nalidixic acid and metronidazole with metronidazole alone , 17.5 % more children treated with the combination recovered by day 3 of treatment ( p = 0.08 ) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8 % less in them ( p = 0.05 ) .

Efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. To determine the efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. ### methods In this double-blind field trial, 156 children aged 4-36 months with persistent diarrhoea not associated with Giardia lamblia infestation seeking treatment in a community outpatient clinic, were randomized to receive a combination of nalidixic acid and metronidazole, metronidazole alone, or placebo for 7 days. ### results In comparison with placebo, metronidazole treatment did not result in a significant reduction in the mean post-enrollment diarrhoeal duration and stool frequency, increase in the proportion of patients recovered by days 3, 5 and 7 of treatment, and increase in weight gain at days 7 and 14. Comparing the combination of nalidixic acid and metronidazole with metronidazole alone , 17.5 % more children treated with the combination recovered by day 3 of treatment ( p = 0.08 ) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8 % less in them ( p = 0.05 ) . The weight gains at days 7 and 14 were similar in the two groups. ### conclusions These findings indicate that metronidazole offers no therapeutic benefit in persistent diarrhoea not associated with Giardia lamblia and nalidixic acid has only a modest clinical benefit, which is not substantial enough to warrant its routine use.

https://pubmed.ncbi.nlm.nih.gov/8955454/

4e07f5335a8ef944f397d3b0150c4384

The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy .

Topiramate for essential tremor. Essential tremor (ET) is one of the most common movement disorders. The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy . However, these treatments can be ineffective in 25% to 55% of people and are frequently associated with serious adverse events (AEs). For these reasons, it is worthwhile evaluating other treatments for ET. topiramate has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. ### objectives To assess the efficacy and safety of topiramate in the treatment of ET. ### Search Methods We carried out a systematic search without language restrictions to identify all relevant trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to January 2017), Embase (January 1988 to January 2017), National Institute for Health and Care Excellence (1999 to January 2017), ClinicalTrials.gov (1997 to January 2017) and World Health Organization International Clinical Trials Registry Platform (ICTRP; 2004 to January 2017). We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and the reference lists of identified studies and reviews. ### Selection Criteria We included all randomised controlled trials (RCTs) of topiramate versus placebo/open control or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in people presenting with secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. ### Data Collection And Analysis Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence. We used a fixed-effect meta-analysis for data synthesis. ### Main Results This review included three trials comparing topiramate to placebo (309 participants). They were all at high overall risk of bias. The quality of evidence ranged from very low to low. Compared to placebo, participants treated with topiramate showed a significant improvement in functional disability and an increased risk of withdrawal (risk ratio (RR) 1.78, 95% confidence interval (CI) 1.23 to 2.60). There were more AEs for topiramate-treated participants, particularly paraesthesia, weight loss, appetite decrease and memory difficulty. ### Authors Conclusions This systematic review highlighted the presence of limited data and very low to low quality evidence to support the apparent efficacy and the occurrence of treatment-limiting AEs in people with ET treated with topiramate. Further research to assess topiramate efficacy and safety on ET is needed.

https://pubmed.ncbi.nlm.nih.gov/28409827/

85819fff08050e6eb88089ae579eed80

In vitro sensitivity of HT29 human colon cancer cells to doxorubicin ( DXR ) , vincristine ( VCR ) , etoposide ( VP16 ) , cisplatin ( CDDP ) , melphalan ( L-PAM ) and 5-fluorouracil ( 5FU ) was markedly reduced when cell-culture density increased .

Confluence-dependent resistance in human colon cancer cells: role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells. In vitro sensitivity of HT29 human colon cancer cells to doxorubicin ( DXR ) , vincristine ( VCR ) , etoposide ( VP16 ) , cisplatin ( CDDP ) , melphalan ( L-PAM ) and 5-fluorouracil ( 5FU ) was markedly reduced when cell-culture density increased . For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/1544702/

d0e8063d3b74acc979234b2e580a4eb2

ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy .

ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy . To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer. ### Patients And Methods Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction. ### results The median TS gene expression level from 50 metastasized tumors was 3.4 x 10(-3) (minimum expression, 0.18 x 10(-3);maximum expression, 11.5 x 10(-3)), and the median ERCC1 gene expression level was 2.53 x 10(-3) (minimum, 0.0; maximum, 14.61 x 10(-3)). The gene expression cutoff values for chemotherapy nonresponse were 7.5 x 10(-3) for TS and 4.9 x 10(-3) for ERCC1. The median survival time for patients with TS <or= 7.5 x 10(-3) (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 x 10(-3) (P < .001). Patients with ERCC1 expression <or= 4.9 x 10(-3) (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 x 10(-3) (P < .001). A TS of 7.5 x 10(-3) segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29). ### conclusion These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU-resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.

https://pubmed.ncbi.nlm.nih.gov/11731512/

9c7a78358ae8529066cbe99c14c5bccc

7 patients ( 53 % ) receiving pamidronate and thalidomide therapy demonstrated good response involving at least 25 % reduction of monoclonal protein levels in comparison with baseline .

Combination of pamidronate and thalidomide in the therapy of treatment-resistant multiple myeloma. Bisphosphonates inhibit the activity of osteoclasts and demonstrate antitumor effect, involving induction of plasmocyte apoptosis, blocking of angiogenesis, stimulation of Tgd lymphocytes and inhibition of metalloproteinases. Bisphosphonates combined with thalidomide, a drug possessing confirmed anti-myeloma activity, seem to have potential favorable effect in patients with treatment-resistant multiple myeloma with advanced osteolytic lesions. ### Material Methods 13 patients with treatment-resistant multiple myeloma with advanced osteolytic lesions received combined pamidronate and thalidomide therapy. All the patients underwent detailed clinical and laboratory control once a month. pamidronate was used at 90 mg i.v. dose administered at 4-week intervals, and thalidomide at doses escalated from 200 mg/d in the first week to 400 mg/d after 3 weeks of the therapy. The mean duration of treatment was 12 weeks with a range of 3 to 36 weeks. ### results 7 patients ( 53 % ) receiving pamidronate and thalidomide therapy demonstrated good response involving at least 25 % reduction of monoclonal protein levels in comparison with baseline . All these patients reported improvement of osteodynia symptoms, and 3 of them - their complete regression. 70% patients experienced side effects (dizziness, constipation, somnolence, polyneuropathy) due to thalidomide administration ### conclusions Good response to combined pamidronate and thalidomide therapy can be expected in at least 50% of patients with treatment-resistant multiple myeloma with advanced osteolytic lesions.

https://pubmed.ncbi.nlm.nih.gov/11951079/

dd638765ce283cb888de1cf23ec47c17

Growth inhibition was measured by 3H-thymidine incorporation assays for doxorubicin hydrochloride ( ADM ) , mitomycin C ( MMC ) , cisplatin ( CDDP ) , and etoposide ( VP-16 ) , and by Alamar Blue assay for ( AB assay ) 5-fluorouracil ( 5-FU ) .

In vitro chemosensitivity of human pancreatic cancer cell lines. These results show that eight pancreatic cancer cell lines are broadly sensitive to CDDP, and that chemotherapy for pancreatic cancer may improve the prognosis by more effective drug delivery to cancer cells. ### background Chemotherapy for pancreatic cancer does not satisfactorily improve prognosis. The efficacy of chemotherapy depends on choosing sensitive anticancer drugs. ### methods The in vitro chemosensitivity of eight human pancreatic cancer cell lines was investigated. Growth inhibition was measured by 3H-thymidine incorporation assays for doxorubicin hydrochloride ( ADM ) , mitomycin C ( MMC ) , cisplatin ( CDDP ) , and etoposide ( VP-16 ) , and by Alamar Blue assay for ( AB assay ) 5-fluorouracil ( 5-FU ) . The cells were exposed to ADM, MMC, CDDP, and VP-16 for 2 h, and 5-FU for 72 h. From the dose-response curves, the 50% growth inhibition (IC50) level for each drug was estimated. ### results The IC50 after 2 h of exposure of each of the eight kinds of cell lines to each anticancer drug ranged from 0.12-8.2 micrograms/mL for ADM, 0.066-25 micrograms/mL for MMC, 0.57-7 micrograms/mL for CDDP, 0.68-300 micrograms/mL for VP-16. IC50 after 72 h of exposure to 5-FU ranged from 1.8-23 micrograms/mL.

https://pubmed.ncbi.nlm.nih.gov/9013279/

a873ff57f7d76116404d4cc23749820f

A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207 , moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide .

Sterilizing activity of second-line regimens containing TMC207 in a murine model of tuberculosis. The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. ### Objective And Methods Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model). ### measurements Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment. ### Main Results The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207 , moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide . ### conclusions In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18-24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.

https://pubmed.ncbi.nlm.nih.gov/21408613/

f034a10cf015ac9c562d19fd9cfd8396

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma : Safety , Tolerability , and Preliminary Evidence of Antitumor Activity .

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma : Safety , Tolerability , and Preliminary Evidence of Antitumor Activity . Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. ### Patients And Methods A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. ### results Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. ### conclusions Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

https://pubmed.ncbi.nlm.nih.gov/33127652/