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5be0c033561668e08e7c57384deed3e9

Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress .

A novel contrast-induced acute kidney injury model based on the 5/6-nephrectomy rat and nephrotoxicological evaluation of iohexol and iodixanol in vivo. Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress . In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. iohexol induced more severe CI-AKI than iodixanol in this model.

https://pubmed.ncbi.nlm.nih.gov/25478060/

dd2afd1aa818c0374ac103916a263e56

Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced .

Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Empiric combinations of vinca alkaloids with taxanes have been recently used in clinical oncology. To enhance the activity of these two classes of agents, we evaluated the sequence and duration of exposure, looking for synergistic effects. Cell lines DU 145, PC 3, LnCaP, LL 86, MCF7wt, and MCF7/ADR (NCI/ADR-RES) were incubated with varying concentrations of paclitaxel or vinorelbine. Cytotoxicity was evaluated by a semiautomated MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) method. Synergism or antagonism of these two agents either sequentially or in combination was determined by median effect analysis. Prolonged exposure of cells to either drug enhanced cytotoxic effect. Synergism or antagonism with vinorelbine and paclitaxel were both sequence dependent and cell line specific. In the case of MCF7wt, synergism was seen when a 48-hr exposure to vinorelbine preceded paclitaxel, whereas antagonism was noted when both agents were applied simultaneously or when the sequence was reversed. Concurrent vinorelbine and paclitaxel were synergistic in four of six cell lines when the exposure was extended to 96 hr but not for shorter durations of exposure. Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced . In addition, these studies suggest concurrent administration of these two agents may lead to a less than optimal cytotoxic result.

https://pubmed.ncbi.nlm.nih.gov/11107439/

2c73415d078bf6051c6a75b130a1dd05

On the other hand we observed that topoisomerase II ( Top2 ) poisons ( doxorubicin and etoposide ) did not affect 1 day post fertilization embryo viability , however in cells isolated from Top2 drug treated embryos the formation of DNA cleavage complexes was observed by comet assay .

Genotoxic effects of topoisomerase poisoning and PARP inhibition on zebrafish embryos. Topoisomerase poisons are known to stabilize covalent enzyme-DNA intermediates forming covalent cleavage complexes, which are highly cytotoxic especially for dividing cells and thus, make topoisomerases targets for cancer therapy. Topoisomerases have been extensively studied in mammalian model systems, whereas in other vertebrate models including zebrafish, they still remain less characterized. Here we show similarities in the genotoxic effects of zebrafish and mammalian systems towards topoisomerase I (Top1) poisons and PARP inhibitor - olaparib. On the other hand we observed that topoisomerase II ( Top2 ) poisons ( doxorubicin and etoposide ) did not affect 1 day post fertilization embryo viability , however in cells isolated from Top2 drug treated embryos the formation of DNA cleavage complexes was observed by comet assay . We explain this by cellular drug uptake limitation in live zebrafish embryos versus unimpeded drug influx in cells isolated from Top2 poisons pre-treated embryos. We also demonstrate that EDTA facilitates the extraction of Top2 from zebrafish nuclei and recovers both, basal and Top2 poison induced DNA damage.

https://pubmed.ncbi.nlm.nih.gov/31877465/

5b6f3e829336b9bcf226bd4297fd9644

Favorable Response of Metastatic Hepatocellular Carcinoma to Treatment with Trans-arterial Radioembolization Followed by Sorafenib and Nivolumab .

Favorable Response of Metastatic Hepatocellular Carcinoma to Treatment with Trans-arterial Radioembolization Followed by Sorafenib and Nivolumab . Trans-arterial radioembolization (TARE) with Y-90 microspheres is an endovascular, liver-directed therapy suitable for treatment of locally advanced hepatocellular carcinoma (HCC) often as a way to reduce tumor size and bridge patients to resection or liver transplant. Opdivo®, or nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is an immunotherapeutic drug approved in September 2017 for the treatment of HCC in patients who have received prior sorafenib. We report on a patient with hepatocellular carcinoma with right and left portal vein involvement, bony metastasis, and possible lung metastasis. The patient showed a significant response following consecutive treatment with TARE, sorafenib, and nivolumab. Our case suggests that TARE, sorafenib, and nivolumab may have a synergistic effect on the immune response to HCC.

https://pubmed.ncbi.nlm.nih.gov/31019861/

a246eb2bf16c1c9f400688f585b2422f

In 23 adult patients , surgery , postoperative radiotherapy ( 60 Gy in 30 daily fractions within 6 weeks ) , and adjuvant modified chemotherapy ( procarbazine 60 mg/m(2 ) on Days 1 - 14 , lomustine 100 mg/m(2 ) on Day 1 , and vincristine 1.4 mg/m(2 ) [ maximum 2 mg ] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred .

Combined treatment modality for anaplastic oligodendroglioma and oligoastrocytoma: a 10-year update of a phase II study. To provide updated outcome data (10 years) of a Phase II study of combined surgery, postoperative radiotherapy, and adjuvant chemotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma. ### Methods And Materials In 23 adult patients , surgery , postoperative radiotherapy ( 60 Gy in 30 daily fractions within 6 weeks ) , and adjuvant modified chemotherapy ( procarbazine 60 mg/m(2 ) on Days 1 - 14 , lomustine 100 mg/m(2 ) on Day 1 , and vincristine 1.4 mg/m(2 ) [ maximum 2 mg ] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred . ### results The median follow-up was 116 months for all patients. The median survival time was 118 months, and the 5-year and 10-year survival rate was 57% and 47%, respectively. The median time to tumor progression was 78 months, with a 5-year and 10-year progression-free survival rate of 52% and 39%, respectively. Gender, age, Karnofsky performance status, location, and histologic type did not influence survival. Patients with tumors <or=4 cm did better than those with tumors >4 cm (p = 0.0470), as did those with total tumor resection compared with those with subtotal tumor resection or biopsy only (p = 0.0024). Gender, Karnofsky performance status, location, and histologic type did not influence progression-free survival, but younger age (p = 0.0389), smaller tumor size (p = 0.0357), and more radical surgery (p = 0.0033) correlated positively with it. Acute high-grade (Grade 3 or worse) chemotherapy-related toxicity was mainly hematologic, with 3 patients (13%) experiencing acute Grade 4 toxicity. ### conclusion The results of this 10-year update confirmed that the trimodality approach is effective in patients with anaplastic oligodendroglioma and oligoastrocytoma.

https://pubmed.ncbi.nlm.nih.gov/15145170/

df203d9ca4b844fad8c40f6b04f5901c

In addition to prolonged survival , these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit , compared with dacarbazine in patients with advanced melanoma .

Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. ### Patients And Methods HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. ### results Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. ### conclusions In addition to prolonged survival , these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit , compared with dacarbazine in patients with advanced melanoma .

https://pubmed.ncbi.nlm.nih.gov/27405322/

727e9b098f960d5805c6e24577853358

This phase 1 trial determined the safety , pharmacokinetics , and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments .

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety , pharmacokinetics , and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments . Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).

https://pubmed.ncbi.nlm.nih.gov/33852104/

c82aa2a58d6b83b380210f70b2de28e7

Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes .

Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes . To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. ### methods In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. ### results Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). ### conclusions Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.

https://pubmed.ncbi.nlm.nih.gov/23782587/

0f70489fe451de475742c4dd8b30f15d

CD133 + cells ( CD133 is marker of CSC in some tumors ) isolated from NBL , osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin , carboplatin , etoposide and doxorubicin than the CD133- ones .

Neuroblastoma stem cells - mechanisms of chemoresistance and histone deacetylase inhibitors. Cancer stem cells (CSCs) form a small proportion of tumor cells that have stem cell properties: self-renewal capacity, the ability to develop into different lineages and proliferative potential. The interest in CSCs emerged from their expected role in initiation, progression and recurrence of many tumors. They are generally resistant to conventional chemotherapy and radiotherapy. There are two hypotheses about their origin: The first assumes that CSCs may arise from normal stem cells, and the second supposes that differentiated cells acquire the properties of CSCs. Both hypotheses are not mutually exclusive, as it is possible that CSCs have a diverse origin in different tumors. CD133 + cells ( CD133 is marker of CSC in some tumors ) isolated from NBL , osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin , carboplatin , etoposide and doxorubicin than the CD133- ones . Being resistant to chemotherapy, there were many attempts to target CSCs epigenetically including the use of histone deacetylase inhibitors. The diverse influence of valproic acid (histone deacetylase inhibitor) on normal and cancer stem cells was proved in different experiments. We have found an increase percentage of CD133+ NBL cells after their incubation with VPA in a dose that does not induce apoptosis. Further researches on CSCs and clinical application for their detection are necessary: (i) to define the CSC function in carcinogenesis, cancer development and their role in metastasis; (ii) to find a specific marker for CSCs in different tumors; (iii) to explain the role of different pathways that determine their behavior and (iv) to explain mechanisms of chemoresistance of CSCs.

https://pubmed.ncbi.nlm.nih.gov/22862175/

6989a1930bd6246fc018940dbfb91dae

The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC .

Targeted therapies for treatment of non-small cell lung cancer--Recent advances and future perspectives. Non-small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC . Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.

https://pubmed.ncbi.nlm.nih.gov/26537995/

d11330ba239670dfe84d3d8c19f4bbce

Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning .

Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning . The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.

https://pubmed.ncbi.nlm.nih.gov/7796854/

795b47de736ed4d9bb01e83a9296d968

Phase 3 data support the use of sunitinib , bevacizumab plus interferon-α and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma .

Advances in renal cell carcinoma treatment. The treatment of advanced renal cell carcinoma has been completely changed by the development of new therapeutic modalities during the past 3 years. In this time period six targeted agents have been approved for the treatment of advanced or metastatic disease. Phase 3 data support the use of sunitinib , bevacizumab plus interferon-α and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma . In the pivotal study of temsirolimus a significant longer overall survival compared with interferon-α in high-risk disease including non-clear-cell histology was observed. Patients pretreated with cytokines will benefit from sorafenib and pazopanib while everolimus has been shown to increase significantly progression-free survival after previous anti-angiogenesis therapy. In addition to these phase 3 data-based recommendations, several other factors have to be considered for treatment selection, for example, side effect profile and patients' comorbidities. Currently, the sequential use of the available targeted drugs and adjuvant treatment are the subject of ongoing clinical trials. However, medical treatment of renal cell carcinoma remains palliative and surgery remains the only curative approach in patients with localized, locally advanced and limited metastatic disease.

https://pubmed.ncbi.nlm.nih.gov/21789079/

bbc240b3838d705d6c0cd2afafb5a4ae

This study is designed to find out the efficacy and toxicity of the combination of oxaliplatin and gemcitabine in the treatment of advanced non-small cell lung cancer ( NSCLC ) .

[Oxaliplatin combined with gemcitabine in the treatment of patients with advanced non-small cell lung cancer]. The use of oxaliplatin is very little in the treatment of lung can- cer . This study is designed to find out the efficacy and toxicity of the combination of oxaliplatin and gemcitabine in the treatment of advanced non-small cell lung cancer ( NSCLC ) . ### methods There were 32 cases of advanced NSCLC patients who were treated with oxaliplatin 65mg/m² by intravenous infusion on the 1st and 8th days, and gemcitabine 800-1000mg/m² by intravenous infusion on the 1st and 8th days every 21 days. After 2 cycles the efficacy was evaluated. ### results There were 31 cases that could be evaluated. No complete response was observed and the overall response rate was 22.6% (7 partial response). The disease control rate was 71.0%. The median time to diease progression was 7 months and the median survival time was 14.5 months. The 1-year survival rate was 59.0% and 2-year survival rate was 45.8%. The main toxicities were myelosuppression and nausea and vomiting. ### conclusions The combination of oxaliplatin and gemcitabine is effective and well tolerated in the treatment of advanced NSCLC. The quality of life is little influenced and the regimen also can prolong the survival time in some patients.

https://pubmed.ncbi.nlm.nih.gov/21110933/

f6894ba00cbe854d18f5f0e2df20e5b3

All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h ( 50 mg/m2/d ) .

Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma. Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h ( 50 mg/m2/d ) . 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.

https://pubmed.ncbi.nlm.nih.gov/9858216/

4a7c5133266617e25068a30212208935

Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient .

Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient . A 48-year-old male patient with follicular lymphoma, grade II, stage IV, was treated with CHOP, ESHAP and MACOP-B, resulting in partial remission. After 9 months, the disease progressed and several chemotherapy agents, including three courses of rituximab combined with etoposide, sobuzoxane or methotrexate, only resulted in a stable disease response. However, the fourth course of rituximab combined with a small dose of melphalan produced excellent results and the complete response continued for more than 15 months. It is possible that these two drugs may act synergistically.

https://pubmed.ncbi.nlm.nih.gov/16321871/

f1d130a68922106ba443ad5d6b0a1df5

In this study , the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay .

Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin. Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP) is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking. ### methods In this study , the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay . ### results SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. mefloquine showed good activity against pneumococci but lower in vitro action against all other tested pathogens. ### conclusion These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.

https://pubmed.ncbi.nlm.nih.gov/21029476/

c7be1464e80f8842f897858a9f0a3a67

Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan

Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. The antifibrotic substance pirfenidone and the angiotensin II type I receptor antagonist candesartan cilexetil, given alone and in combination, were tested in rats with chronic anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). ### methods Male Wistar rats with anti-GBM GN were treated for 8 weeks with candesartan (4 mg/kg body weight/day), pirfenidone (500 mg/kg body weight/day) or a combination of both drugs. One GN group received no treatment and untreated non-GN-rats were used as controls. Blood pressure and urinary protein excretion were measured after 3 and 7 weeks. Kidney histology was complemented by ultrastructural investigation and by quantification of collagen Ialpha mRNA. ### results The percentage of glomeruli with adsorption droplets in podocytes correlated well with the amount of proteinuria (r = 0.873, P<0.01) and was significantly lowered in rats treated with candesartan (8.3 vs GN 24.6%), pirfenidone (9.8%) and combined treatment (2.6%, P<0.05 vs candesartan alone). A comparable lowering was seen for segmental sclerosis (GN 11%, candesartan 0.7%, P<0.05 vs GN, pirfenidone 1.8%, P = 0.09 vs GN, candesartan/pirfenidone 0.1%, P>0.5 vs candesartan alone). Cortical collagen Ialpha mRNA expression was significantly decreased in all treatment groups. Ultrastructural investigation showed an amelioration of basement membrane alterations and podocyte damage in the treatment groups. candesartan caused significant blood pressure reduction and the effect was significantly enhanced by combination therapy after 3 weeks. Rats treated with pirfenidone showed blood pressure values similar to control rats. ### conclusion Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan although with a trend to slightly better results with candesartan treatment. Moreover, our results suggest an additive effect of combination treatment.

https://pubmed.ncbi.nlm.nih.gov/15561744/

04dacdd4af1e82ee9156f2d141a35ddd

Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients : a randomized safety and efficacy study .

Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients : a randomized safety and efficacy study . PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).Conclusionsdifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.

https://pubmed.ncbi.nlm.nih.gov/27367745/

6da861a53f0a3f9e21425877fed8b5c7

Accumulated doses of cyclophosphamide , procarbazine , doxorubicin , mitoxantrone , and etoposide were 18,300 mg , 3000 mg , 580 mg , 100 mg , and 4150 mg , respectively , which had been administered for the treatment of NHL .

Therapy-related leukemia with a novel 21q22 rearrangement. We present a case of a 59-year-old Japanese man with therapy-related acute myeloblastic leukemia (AML) after the chemotherapy for non-Hodgkin's lymphoma (NHL). Accumulated doses of cyclophosphamide , procarbazine , doxorubicin , mitoxantrone , and etoposide were 18,300 mg , 3000 mg , 580 mg , 100 mg , and 4150 mg , respectively , which had been administered for the treatment of NHL . Myeloblasts in the peripheral blood increased 43 months after the onset of NHL. He was diagnosed as having AML (M2; FAB classification). The karyotype of the bone marrow cells in the present case contained the following abnormalities: t(2;21)(q21;q22), t(8;21)(q22;q22), and add(13)(q34). In the present case, 645 base pairs of chimeric mRNA were detected by reverse transcription-polymerase chain reaction, indicating the presence of AML1/MTG8 rearrangement. Translocation (2;21)(q21;q22) has not been described previously to our knowledge. It is interesting that the breakpoint of 21q22 existed both in t(2;21) and t(8;21). The disrupted AML1 gene resulting from two 21q22 rearrangements may be involved in the pathogenesis of AML in the present case. The clinical importance of therapy-related AML having the 21q22 rearrangement remains to be examined.

https://pubmed.ncbi.nlm.nih.gov/8780746/

629ee4e216dcdc05f98202ea86148bde

In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance .

Mantle cell lymphoma: therapeutic options in transplant-ineligible patients. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance . In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Novel targeted agents now offer more promise than traditional chemotherapy or immunochemotherapy for both previously treated and untreated disease, and should also improve outcomes for older MCL patients. Here, we review standard therapies currently in use and novel agents that may soon be available for MCL patients and particularly for those unsuitable for ASCT.

https://pubmed.ncbi.nlm.nih.gov/31018735/

671a98fbcc6aa7636084ec1b0a365f03

Here , we analyze the effects of the broad-spectrum HDAC inhibitors ( HDACi ) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity ( Transcription factor EB-TFEB , forkhead boxO-FOXO ) and autophagic flux in neuroblastoma cells .

Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma. Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here , we analyze the effects of the broad-spectrum HDAC inhibitors ( HDACi ) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity ( Transcription factor EB-TFEB , forkhead boxO-FOXO ) and autophagic flux in neuroblastoma cells . In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.

https://pubmed.ncbi.nlm.nih.gov/33923163/

2f4b519ad0cb470a172c725c002d462c

The postischemic decrease in total intensity and frequency index in EEG recovered rapidly when nitrendipine was pretreated , whereas the recovery of EEG parameters was not obtained by the nicardipine pretreatment .

Nitrendipine facilitates recovery of cerebral blood flow, EEG and metabolites following cerebral ischemia in anesthetized rabbits. The effect of nitrendipine, an antihypertensive calcium antagonist, on the impairment of cerebral blood flow and EEG observed after 10-min complete cerebral ischemia in anesthetized rabbits was compared with those of nicardipine. The ischemia was produced by neck tourniquet in combination with hypotension (50-60 mmHg). Blood flow was measured by hydrogen-clearance method. Transient reactive hyperemia was observed immediately after the cessation of ischemic procedure, and was followed by a decrease in blood flow in the range of 58-73% of corresponding basal values in the total brain, cortex and thalamus. The postischemic decrease in blood flow was suppressed when nitrendipine (0.3-1 mg/kg) or nicardipine (3-10 mg/kg) was given intraduodenally before ischemia. The postischemic decrease in total intensity and frequency index in EEG recovered rapidly when nitrendipine was pretreated , whereas the recovery of EEG parameters was not obtained by the nicardipine pretreatment . These results suggest that the effect of nitrendipine and nicardipine on the postischemic cerebral blood flow may be due to the inhibition of calcium-induced contraction in cerebral vessels, whereas the discrepancy between the effects of these agents on EEG may not be due solely to the improvement in cerebral circulation. Furthermore, the improvement in postischemic cerebral energy metabolism was confirmed by nitrendipine pretreatment (0.3 mg/kg).

https://pubmed.ncbi.nlm.nih.gov/1798973/

72710c472e00e8c0ebba324e82696897

The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels .

Effects of the serotonin-1A agonists buspirone and ipsapirone on field potentials in the hippocampus slice: comparison with carbamzepine and verapamil. The serotonin-1A agonists buspirone (BU) and ipsapirone (IPSA) have been demonstrated to exert antidepressant and anxiolytic effects. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, the interaction of BU and IPSA with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+ induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. BU and IPSA reduced the frequency of occurrence of low magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose dependent manner. The subthreshold concentrations which yielded no effect were 5 mumol/l for BU and IPSA, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels . It may be assumed that besides their action on 5-HT1A receptors BU and IPSA may also have calcium antagonistic properties.

https://pubmed.ncbi.nlm.nih.gov/7613104/

2a13a782996d6a4eb247ccb83958e7a6

The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity .

Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study. We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity .

https://pubmed.ncbi.nlm.nih.gov/12576933/

42aef7f95da0233dda2f19ac2be2ae91

Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume .

Choleretic actions of insulin-like growth factor-I, prednisolone, and ursodeoxycholic acid in rats. A recent study by our group demonstrated that a 1-week infusion of insulin-like growth factor-I increases bile flow volume and bile acid secretion in rats, suggesting it is important in in vivo choleresis. In the present study, the effect in rats of a single administration of insulin-like growth factor-I on bile flow volume was investigated and compared with the choleretic drugs prednisolone and ursodeoxycholic acid. A significant and long-lasting increase in bile flow volume was observed in rats treated with insulin-like growth factor-I or prednisolone. Ursodeoxycholic acid significantly, but transiently increased. Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume . Overall, this study demonstrated that the stimulatory effect of insulin-like growth factor-I on bile flow volume is almost equally potent to that of prednisolone and ursodeoxycholic acid, indicating the possible therapeutic potential of insulin-like growth factor-I in cholestatic liver diseases.

https://pubmed.ncbi.nlm.nih.gov/12870804/

7725b444e1f548fd763cf55a50c903ea

The AV3V-lesioned group of animals were characterized by an inability to excrete the excess sodium load and by a failure to increase secretion of both oxytocin and vasopressin into the general circulation in response to the salt-stimulus .

The effect of anteroventral third ventricular lesions on the changes in cholecystokinin receptor density in the rat supraoptic nucleus following saline drinking. Abstract Autoradiography and computerized image analysis were used to study the density of Cholecystokinin binding sites in the supraoptic nucleus of sham-lesioned and anteroventral third ventricle (AV3V)-lesioned animals in which the magnocellular system had been activated by salt-loading with 2% saline for 48 h. Rats were maintained in metabolic cages for 5 to 7 days prior to a sham- or AV3V-lesioning procedure, and the ratio of sodium intake:urinary sodium output used as a measure of sodium excretion. Following the sham or lesion procedure half of the rats had their drinking water replaced with 2% saline and the other half were maintained on normal drinking water. Neurohypophysial hormone levels were measured by specific radioimmunoassay in trunk blood samples taken 48 h after the saline or water treatment. The AV3V-lesioned group of animals were characterized by an inability to excrete the excess sodium load and by a failure to increase secretion of both oxytocin and vasopressin into the general circulation in response to the salt-stimulus . Despite this inappropriate response, [(125) l]cholecystokinin octapeptide binding in the oxytocin-rich dorsal portion of the supraoptic nucleus was similarly elevated in both sham- and AV3V-lesioned rats following 2 days of saline treatment. These results suggest that the magnocellular oxytocin system is capable of responding to an osmotic stimulus even when the release of hormone has been severely impaired.

https://pubmed.ncbi.nlm.nih.gov/19215354/

7add9dfc666dea880db503fa86a2fc53

Patients received BBFC ( n = 193 ) , brinzolamide 1 % ( n = 192 ) , or brimonidine 0.2 % ( n = 175 ) BID .

Twice-daily brinzolamide/brimonidine fixed combination versus brinzolamide or brimonidine in open-angle glaucoma or ocular hypertension. To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all dosed 2 times per day (BID). ### design Six-month, phase 3, randomized, multicenter, double-masked clinical trial. ### participants A total of 560 patients with primary open-angle glaucoma or ocular hypertension who had insufficient IOP reduction with their current therapeutic regimen or who were receiving ≥ 2 IOP-lowering medications. ### intervention Patients received BBFC ( n = 193 ) , brinzolamide 1 % ( n = 192 ) , or brimonidine 0.2 % ( n = 175 ) BID . ### Main Outcome Measures The primary end point was mean change in diurnal IOP from baseline to month 3. Supportive end points included mean diurnal IOP change from baseline at week 2, week 6, and month 6; and mean IOP, mean IOP change from baseline, mean percentage IOP change from baseline, and percentage of patients with IOP <18 mmHg at week 2, week 6, month 3, and month 6 at each assessment time point (i.e., 9 am, 11 am, and 4 pm). Adverse events were recorded throughout the study. ### results Baseline diurnal IOP was similar among groups (mean ± standard deviation: BBFC, 25.9 ± 0.19 mmHg; brinzolamide, 25.9 ± 0.20 mmHg; brimonidine, 26.0 ± 0.19 mmHg). At month 3, BBFC lowered mean diurnal IOP from baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: -1.4 mmHg; P < 0.0001; t test) and brimonidine (LS mean difference: -1.5 mmHg; P < 0.0001). All supportive end points corroborated the results of the primary efficacy analysis. Mean percentage reductions in IOP from baseline were 26.7% to 36.0% with BBFC, 22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine. The most common adverse drug reactions were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine. ### conclusions brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a significantly greater IOP-lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile consistent with its individual components.

https://pubmed.ncbi.nlm.nih.gov/25064721/

721a25c7ca5bc4f07e322c7320c43e11

Artemisinin ( ART ) is a sesquiterpene lactone extracted from Chinese herb qinghao , and artemether ( ARM ) , artesunate ( ARS ) and dihydroartemisinin ( DHA ) were synthesized derivatives of artemisinin , which also have anti-malarial and anti-cancer effects such as artemisinin .

Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-β signaling in breast cancer. Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin ( ART ) is a sesquiterpene lactone extracted from Chinese herb qinghao , and artemether ( ARM ) , artesunate ( ARS ) and dihydroartemisinin ( DHA ) were synthesized derivatives of artemisinin , which also have anti-malarial and anti-cancer effects such as artemisinin . ### methods In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. ### results We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. ### conclusions artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.

https://pubmed.ncbi.nlm.nih.gov/30477536/

815c59e8446f996f0e187eba6304b302

Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells .

Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells . This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. ### methods Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations. ### results Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. ### conclusions The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.

https://pubmed.ncbi.nlm.nih.gov/26604207/

6795bdc912a74f3c0792c3e8ec20011d

Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis .

Inhibition of cyclin E1 sensitizes hepatocellular carcinoma cells to regorafenib by mcl-1 suppression. To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition. ### methods Western blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment. ### results Our results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis . The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib. ### conclusions Combining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs.

https://pubmed.ncbi.nlm.nih.gov/31349793/

fc15eb12c35c136b2d8960b1ef35e819

Levofloxacin hemihydrate ( LEV ) and ambroxol HCl ( AMB ) are available for the treatment of upper and lower respiratory tract infections .

Micellar liquid chromatographic method for the simultaneous determination of Levofloxacin and Ambroxol in combined tablets: Application to biological fluids. Levofloxacin hemihydrate ( LEV ) and ambroxol HCl ( AMB ) are available for the treatment of upper and lower respiratory tract infections . A survey of the literature reveals that two reversed phase HPLC methods were e reported for the simultaneous determination of LEV and AMB in pharmaceutical preparations. However the reported methods suffers from the low sensitivity, no application of the method in the combined tablets and no application to biological fluids. Also the toxic effects of the used solvents which are harmful to human beings. For this reason, our target was to develop a simple sensitive, less hazardous micellar HPLC method for the simultaneous determination of LEV and AMB in their combined dosage forms and plasma. ### results The method showed good linearity over the ranges of 1-44 μg/mL and 1-20 μg/mL with limits of detection 0.26 and 0.07 μg/mL and limits of quantification 0.80 and 0.20 μg/mL for LEV and AMB, respectively. The method was further extended to the determination of LEV in spiked human plasma with mean percentage recoveries of 100.10% ± 1.14 as well as determination of LEV in real human plasma without prior extraction. Statistical evaluation of the data was performed according to ICH Guidelines. ### conclusion The suggested method was successfully applied for the simultaneous analysis of the studied drugs in their co-formulated tablets and human plasma. The mean percentage recoveries in combined tablets were 100.20 ± 1.64 and 100.72 ± 1.11 for LEV and AMB, respectively and 100.10 ± 1.14 for LEV in spiked human plasma. Statistical comparison of the results with those of the comparison method revealed good agreement and proved that there were no significant difference in the accuracy and precision between the two methods respectively.

https://pubmed.ncbi.nlm.nih.gov/24079576/

2416572d3a4560a066355df81040dcd2

Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % .

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. ### Patients And Methods Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. ### results mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % . The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). ### conclusion mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

https://pubmed.ncbi.nlm.nih.gov/12885813/

cb064ac7581f1895a51363066960d6b8

After initiating warfarin plus lenvatinib , INR assays are necessary .

Drug interactions between warfarin and lenvatinib in a patient with the CYP2C9*1/*3 and VKORC1-1639G/A genotype. lenvatinib inhibits CYP2C8. (S)-warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. ### Case Summary The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3 ng/mL and 0.67 μg/mL, respectively. On day 10, his INR increased to 3.48. ### What Is New And Conclusion lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib , INR assays are necessary .

https://pubmed.ncbi.nlm.nih.gov/31468576/

ace8dd79aefc245c868d9dfd7db7224a

Treatment with the DNA topoisomerase inhibitors etoposide , doxorubicin , and camptothecin , and with the alkylating agents cisplatin and melphalan , caused peroxide accumulation and apoptosis in U-937 human promonocytic cells .

Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. Treatment with the DNA topoisomerase inhibitors etoposide , doxorubicin , and camptothecin , and with the alkylating agents cisplatin and melphalan , caused peroxide accumulation and apoptosis in U-937 human promonocytic cells . Preincubation with the reduced glutathione (GSH) synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H(2)O(2) instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (DeltaPsim), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-l-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated DeltaPsim decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells.

https://pubmed.ncbi.nlm.nih.gov/11602574/

427f3561697bddffb6580da3c3b40bfd

We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan .

[Chemotherapy-induced myelosuppression and treatment efficacy in limited-stage disease small cell lung cancer]. We examined the association between chemotherapy-induced myelosuppression and prognosis in limited-stage disease small cell lung cancer (LD SCLC). We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan . Patients were categorized into two groups (grade 0 to 2 or grade 3 to 4) according to the worst neutropenia, anemia, or thrombocytopenia during first-line chemotherapy and were analyzed for overall survival (OS) and time to progression (TTP). From univariate analysis, OS was significantly better in patients who developed grade 0 to 2 anemia or thrombocytopenia than those who developed grade 3 to 4. In addition, performance status, neuron-specific enolase (NSE), and pro-gastrin-releasing protein were identified as prognostic factors. By multi-variate analysis, NSE was an independent prognostic factor for OS. There were no independent prognostic factors for TTP. Myelosuppression during chemotherapy is not a prognostic factor in LD SCLC. Our results show doses of platinum doublet chemotherapy were adequate in patients with LD SCLC.

https://pubmed.ncbi.nlm.nih.gov/20154478/

a7445d337ce87106b31b40f827cfe077

MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ ∆Akt-1(CA ) ] were more resistant to doxorubicin , etoposide and 4-OH-tamoxifen ( 4HT ) than cells lacking ∆Akt-1(CA ) .

Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ ∆Akt-1(CA ) ] were more resistant to doxorubicin , etoposide and 4-OH-tamoxifen ( 4HT ) than cells lacking ∆Akt-1(CA ) . Cells which expressed ∆Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed ∆Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies.

https://pubmed.ncbi.nlm.nih.gov/21730367/

5f21f1c49c6de43c2bcdd11b02ee1b73

that , in response to mitomycin C and doxorubicin , human hepatocellular carcinoma cells generate conflicting signals , mediated by cyclin E and p21WAF1/CIP1 , which respectively accelerates and represses cell cycle transition .

Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma cells. Proteins involved in the G1 phase of the cell cycle are aberrantly expressed, sometimes in mutated forms, in human cancers including human hepatocellular carcinoma. Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G1 phase; this is a safety feature prohibiting entry of DNA-damaged cells into S-phase. p21WAF1/CIP1 prevents damaged cells from progressing to the next cell cycle. Here, we show that , in response to mitomycin C and doxorubicin , human hepatocellular carcinoma cells generate conflicting signals , mediated by cyclin E and p21WAF1/CIP1 , which respectively accelerates and represses cell cycle transition . Exposure to these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin E accumulation influenced the G1-S-phase transition, but not DNA fragmentation-mediated death. In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase in the level of p53-dependent p21WAF1/CIP1, thereby inhibiting further the G1-S-phase transition. Sublethal drug concentrations also induced rapid accumulation of cyclin E, but p21WAF1/CIP1 accumulation was delayed, further facilitating the G1-S-phase transition. Eventually, most cells arrested in G2/M. Thus, mitomycin C- or doxorubicin-induced conflicting signals, mediated by cyclin E and p21WAF1/CIP1, are in play in human hepatocellular carcinoma cells. Damaged G1 cells either immediately enter S-phase, or do not do so at all, depending on the extent of DNA damage.

https://pubmed.ncbi.nlm.nih.gov/21887464/

b04b7ef796a12ef625cad5773c25d555

In the last years , the main topoisomerase I inhibitors ( TP1-I ) ( i.e. topotecan and irinotecan ) have been used in combination chemotherapy in non-small cell lung cancer .

Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer. In the last years , the main topoisomerase I inhibitors ( TP1-I ) ( i.e. topotecan and irinotecan ) have been used in combination chemotherapy in non-small cell lung cancer . Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.

https://pubmed.ncbi.nlm.nih.gov/11742701/

f4558f7eed0e676239a76530501a8b34

Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) .

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders. Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) . We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. ### conclusion The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.

https://pubmed.ncbi.nlm.nih.gov/19852040/

f64fae61c888b6de0c2525dec44a77f4

Of the antibacterial agents examined , only carbenicillin and , to a lesser extent , gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration .

The use of antibiotics in the culture of non-sterile plant protoplasts. The use of antibiotics to control infections in cultures of protoplasts of leaf mesophyll cells has been examined. The antifungal agents nystatin and amphotericin B were non-toxic to protoplasts at concentrations that controlled fungal growth (25 units and 2.5 μg/ml respectively). Of the antibacterial agents examined , only carbenicillin and , to a lesser extent , gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration . The most satisfactory control of contaminating microorganisms was obtained with a combination of nystatin (25 units/ml) or amphotericin B (2.5 μg/ml) and carbenicillin (250 μg/ml).

https://pubmed.ncbi.nlm.nih.gov/24468958/

58ae13fafd1ae26654f91eecd42f14ca

Chemosensitization is one of the anti-tumor effects of E1A , increasing in vitro and in vivo sensitization of anti-cancer drugs , including cisplatin , gemcitabine , etoposide , doxorubicin , paclitaxel , and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells .

The anti-tumor activity of E1A and its implications in cancer therapy. The adenovirus type 5 E1A protein (E1A) plays a critical role in anti-cancer gene therapy and has been tested in clinical trials. The expression of E1A significantly reduces tumorigenesis, promotes cell death, and inhibits cancer cell mobility. Chemosensitization is one of the anti-tumor effects of E1A , increasing in vitro and in vivo sensitization of anti-cancer drugs , including cisplatin , gemcitabine , etoposide , doxorubicin , paclitaxel , and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells . E1A also demonstrates anti-metastasis activity through various molecular mechanisms such as the repression of protease expression, suppression of HER2/neu and downregulation of microRNA (miR-520h). Moreover, E1A has been reported to reprogram transcription in tumor cells and stabilize tumor suppressors such as PP2A/C, p21 and p53. Because E1A plays a potentially significant role in anti-tumor therapy, there exists an urgent need to study the anti-cancer activities of E1A. This paper presents a review of our current understanding of the tumor-suppressive functions and molecular regulation of E1A, as well as the potential clinical applications of E1A.

https://pubmed.ncbi.nlm.nih.gov/24504082/

14798260886c7b0c8d279b38d05b4cc5

A strong correlation was only found between the level of MRP3 expression and the IC(50 ) values of etoposide , doxorubicin and pirarubicin ( r = 0.86 - 0.98 , P<0.05 ) .

Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined. ### methods Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC(50) values and the ratios of gene expression were analyzed by linear regression to predict their relationship. ### results Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC(50) values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC(50) values (<5 mumol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC(50 ) values of etoposide , doxorubicin and pirarubicin ( r = 0.86 - 0.98 , P<0.05 ) . ### conclusion Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.

https://pubmed.ncbi.nlm.nih.gov/15884115/

6dc0a36ba66aeb79ec26c4be2bc068c5

In addition to the typical cross-resistance to doxorubicin , daunorubicin , vincristine and etoposide , we observed a significant resistance of the C6,5 x 10(-7 ) Dox cell line to irradiation , which can not be explained by Pgp-expression .

Multiple drug-resistant C6 glioma cells cross-resistant to irradiation. Although many advances in antineoplastic therapy have taken place, a clinical breakthrough in the therapy of malignant gliomas is still required. One of the reasons for this is the poor response to cytotoxic drugs and irradiation. We established a subline of the rat glioma cell line C6, named C6,5 x 10(-7) Dox, by exposure to increasing doses of doxorubicin for 5 months. C6,5 x 10(-7) Dox cells expressed high levels of P-glycoprotein (Pgp), known to function as an energy-dependent efflux pump for lipophilic drugs causing the multidrug resistance phenotype. Pgp, which normally has a molecular weight of 170 to 180 kd, appears in C6,5 x 10(-7) Dox cells as two bands with a molecular weight of 140 and 120 kd in western blots. In addition to the typical cross-resistance to doxorubicin , daunorubicin , vincristine and etoposide , we observed a significant resistance of the C6,5 x 10(-7 ) Dox cell line to irradiation , which can not be explained by Pgp-expression .

https://pubmed.ncbi.nlm.nih.gov/9494563/

cfc8d72201c15e205dfa65f372a8228a

[ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] .

[ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] . To investigate the effects of endostatin and doxycycline on microcirculation patterns in melanoma and their molecular mechanisms. ### methods To establish mouse B16 melanoma model by subcutaneous injection of B16 melanoma cell suspension. The mice were divided into 3 experimental groups and 1 control group. To treat the mice in the 3 experimental groups with endostatin, doxycycline, endostatin and doxycycline, respectively, and the control group without any treatment. The tumor volume was measured and recorded to make comparison of their growth rate. To assess the expression of MMP-2, MMP-9 and TIMP-2 by immunohistochemical staining. The three microcirculation patterns of endothelium-dependent vessels, mosaic vessels and vasculogenic mimicry were counted. The activity of MMP-2, MMP-9 between different groups was examined by gelatin zymography. ### results Tumor growth in the three experimental groups was statistically significantly slower than that in the control group. The expression of MMP-2, MMP-9 and TIMP-2 in each treated group was significantly different with that in the control group. The amount of three microcirculation patterns in three experimental groups was less than that of the control group, and the amount of MV and VM in each experimental group was significantly less than that in the control group. By gelatin zymography, the enzyme activity of MMP-9, actived-MMP-2 and MMP-2/proMMP-2 in ES, DOX and ES + DOX group was lower than that in the control group, but the enzyme activity of pro-MMP-2 among the four groups was not significantly different. ### conclusion The combined use of doxycycline and endostatin in melanoma can inhibit the expression of MMPs, influencing the formation of different microcirculation patterns in melanoma.

https://pubmed.ncbi.nlm.nih.gov/18069628/

8048a8eef6fed20013431209617b227c

It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy , potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus .

FLT3 inhibitors for the treatment of acute myeloid leukemia. The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy , potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus . This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.

https://pubmed.ncbi.nlm.nih.gov/20733555/

7c1045ff7227c040eb9dcd75a533501d

Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively .

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation. In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively . In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.

https://pubmed.ncbi.nlm.nih.gov/27764813/

47a943623f242fd6dc450c698de16055

Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine .

Gemcitabine and oxaliplatin: a safe and active regimen in poor prognosis advanced non-small cell lung cancer patients. Most patients with non-small cell lung cancer (NSCLC) cannot tolerate a cisplatin-based chemotherapy because of old age, general conditions, and/or multiorgan metastatic sites. Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine . The aims of this phase II study were to evaluate the response rate and toxicity of the gemcitabine-oxaliplatin combination in patients with advanced NSCLC and poor prognosis. ### methods Patients were given a gemcitabine infusion (1000 mg/m(2) over 30 min on days 1 and 8) followed by oxaliplatin (65 mg/m(2) over 120 min on days 1 and 8) every 21 days for six cycles. ### results Thirty-two patients with poor-prognosis advanced NSCLC received 136 cycles. There were 25 males and seven females, and the median age was 65 years (range 29-76). Fifty-six percent of patients had adenocarcinoma, and 31% had squamous cell carcinoma. Sixty-six percent of patients had stage IV disease, and 34% had stage IIIB disease. Eastern cooperative oncology group (ECOG) performance status was 2-3 in 50%, 1 in 44%, and 0 in 6% of patients. Eight patients (25%) had been previously treated with cisplatin or carboplatin. All patients were symptomatic. Of the 32 patients who received study drug, five (16%) achieved partial response, six (19%) had minor response, three (9%) had stable disease, and 15 (47%) progressed. The median overall survival was 27 weeks. Thirty-one patients were evaluable for toxicity: seven patients (23%) had grade 3-4 thrombocytopenia with no bleeding; four patients (13%) had grade 3-4 neutropenia with no febrile neutropenia, and three patients (10%) had grade 3 anemia. Two patients (6%) had grade 3, and six patients (19%) had grade 1-2 neurotoxicity. ### conclusion The combination of gemcitabine and oxaliplatin seems to be well tolerated and active in patients with poor prognosis advanced NSCLC and deserves further evaluation in phase II clinical trials.

https://pubmed.ncbi.nlm.nih.gov/12826318/

9f520f0a2b7375cbd106d2b03d54c8fd

A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel , abiraterone acetate , enzalutamide , cabozantinib , carboplatin or cabazitaxel .

Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy. A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel , abiraterone acetate , enzalutamide , cabozantinib , carboplatin or cabazitaxel . Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51-86 years). The mean follow-up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.

https://pubmed.ncbi.nlm.nih.gov/28123517/

640a3c9a82e16798bccd7249bd3a43ca

Pharmacological interventions with a proton pump inhibitor ( PPI ) , H2 receptor antagonist ( H2RA ) , antacid , bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants .

Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants. Upper gastrointestinal bleeding is typically a mild, self-limiting condition that can affect both preterm and term neonates, although it can be severe particularly when associated with co-morbidities. Pharmacological interventions with a proton pump inhibitor ( PPI ) , H2 receptor antagonist ( H2RA ) , antacid , bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants . ### objectives To assess how different pharmacological interventions (PPIs, H2RAs, antacids, sucralfate or bismuth salts) administered to preterm and term neonates for the prevention or treatment of upper gastrointestinal bleeding to reduce morbidity and mortality compare with placebo or no treatment, supportive care, or each other. ### Search Methods We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 6), MEDLINE via PubMed (1966 to 12 July 2018), Embase (1980 to 12 July 2018), and CINAHL (1982 to 12 July 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials, and online for Chinese literature articles. ### Selection Criteria We selected randomised, quasi-randomised and cluster-randomised trials involving preterm and term neonates. Trials were included if they used a proton pump inhibitor, H2 receptor antagonist, antacid, sucralfate or bismuth either for the prevention or treatment of upper gastrointestinal bleeding. ### Data Collection And Analysis Two review authors independently assessed the eligibility of studies for inclusion, extracted data and assessed methodological quality. We conducted meta-analysis using a fixed-effect model. We used the GRADE approach to assess quality of evidence. ### Main Results Eleven studies with 818 infants met the criteria for inclusion in this review.Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) -0.20, 95% CI -0.28 to -0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low.Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference -1.06 days, 95% CI -1.28 to -0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD -0.26, 95% CI -0.33, -0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment.Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities - including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay - were not reported. Long-term outcome was not reported. ### Authors Conclusions There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.

https://pubmed.ncbi.nlm.nih.gov/31265739/

77d8064af9c3e21a554ef1c5daf0a918

Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer .

Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer . Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded micelles using a film dispersion method. Micelles were characterized by determining critical micelle concentration (CMC), particle size distribution, and drug loading. The anticancer effects were determined in vitro with MTT assays as well as with lactate dehydrogenase (LDH) release studies. In addition, the cellular uptake of drug-loaded micelles was determined with fluorescence microscopy and flow cytometry. Finally, in vivo anticancer activity and tolerance of developed formulations were evaluated in resistant breast tumor bearing mice. PEG5K-PBC7K polymer synthesized in this study had a low CMC value (1.5 mg/L) indicating an excellent dynamic stability. PEG-PBC micelles could efficiently load both doxorubicin and lapatinib drugs with a loading density of 21% and 8.4%, respectively. The mean particle size of these micelles was 100 nm and was not affected by drug loading. The use of lapatinib as an adjuvant sensitized drug resistant MCF-7/ADR cells to doxorubicin treatment. Cellular uptake studies showed enhanced doxorubicin accumulation in MCF-7/ADR cells in the presence of lapatinib. The doxorubicin and lapatinib combination therapy showed a significant decrease in tumor growth compared to doxorubicin monotherapy. In conclusion, we have developed PEG-PBC micelle formulations for the delivery of doxorubicin and lapatinib. The combination therapy of doxorubicin plus lapatinib has a great potential for treating MDR breast cancer.

https://pubmed.ncbi.nlm.nih.gov/24405470/

e4e17068283d443afce7f6f729118c40

The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel .

Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. docetaxel (Taxotere(®)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel . Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity.

https://pubmed.ncbi.nlm.nih.gov/26297509/

33c10cbad0525179d74c6d25b5e93bfa

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC .

Phase 1 Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer. We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR TKI osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant NSCLC. ### Experimental Design This open-label, single-arm phase 1 study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose de-escalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. ### results Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common Grade 3 or higher treatment-related adverse events (TRAEs) were hypertension (8%) and platelet count decreased (16%); Grade 5 TRAE (subdural hemorrhage) occurred in one patient. Patients with (N=10) and without CNS metastasis (N=15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months (90% CI: 9.6-21.2). Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations post progression included C797S, MET amplification, and EGFR amplification. ### conclusions Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC .

https://pubmed.ncbi.nlm.nih.gov/33046516/

dedf04d0b8a7521028b1091c88e41780

The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone .

[Refractory acute myeloid leukemia developed malignancy-associated hemophagocytic lymphohistiocytosis during treatment of invasive fungal infection]. We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3'-RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone . Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription-polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients.

https://pubmed.ncbi.nlm.nih.gov/23666221/

4b3bb26a64999b4abc090d469be4cad8

On the other hand , cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism .

Cyclosporine: advantages versus disadvantages vis-à-vis tacrolimus. Despite a different molecular structure and biochemical properties, cyclosporine and tacrolimus--by inhibiting calcineurin activity--have been shown in the previous two decades of solid organ transplantation to be well tolerated and effective immunosuppressants. Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine. But in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear. In general, short- and medium-term outcome variables (1-year serum creatinine, graft and patient survival) with cyclosporine and tacrolimus are excellent, and (almost) identical, with both substances having the same intrinsic nephrotoxic potential. On the other hand , cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism . However, at present no data are available to discern that these differences in risk profile alter patient or graft survival or long-term cardiovascular morbidity/mortality. Therefore, prospective long-term trials are needed to study the quantitative impact of different immunosuppressive agents and concomitant cardiovascular risk factors on long-term patient and graft survival, before evidence-based (patient, graft, or cardiovascular) risk reduction can be firmly claimed by tailoring calcineurin inhibitors.

https://pubmed.ncbi.nlm.nih.gov/15041305/

4a2741e8f251bf34f99d7969b7f536cb

Isoniazid , streptomycin , rifampin , and ethambutol were each tested at 3 concentrations by the radiometric method and the reference ( agar dilution ) method .

Rapid radiometric susceptibility testing of Mycobacterium tuberculosis. A 48-hour radiometric test for determining the drug susceptibility of Mycobacterium tuberculosis has been developed. The test is based on the measurement of 14CO2 produced by the oxidation of formate labeled with carbon-14. The test system uses 5 X 10(7) organisms in 1 ml of Middlebrook 7H9 medium plus albumin-dextrose-catalase enrichment and 1 muCi of [14C]formate. The 14CO2 produced is measured in an ionization chamber at 24-, 48-, and 72-hour intervals, with and without the addition of antituberculous drugs. Isoniazid , streptomycin , rifampin , and ethambutol were each tested at 3 concentrations by the radiometric method and the reference ( agar dilution ) method . Six standard strains and 21 patient isolates were compared by both methods. Production of 14CO2 was quantitatively decreased in the presence of drugs that inhibit the organism. The radiometric method requires 2 days; the agar dilution, 14 to 21 days.

https://pubmed.ncbi.nlm.nih.gov/417650/

14560985da268f584dee6d70f4a91607

Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas .

Enhancement of haloperidol-induced increase in rat striatal or mesolimbic 3,4-dihydroxyphenylacetic acid and homovanillic acid by pretreatment with chronic methamphetamine. After a drug-free period of 1 week following 2 weeks of haloperidol treatment, the increased response of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a challenge dose of haloperidol was significantly reduced. Tolerance to this effect was not, however, seen in the mesolimbic system. Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas . The reduced response of striatal DOPAC or HVA after chronic haloperidol was prevented by pretreatment with MAP. The data suggest that the long-term dopamine receptor stimulation induced by MAP may antagonize the tolerance produced by chronic haloperidol treatment.

https://pubmed.ncbi.nlm.nih.gov/6794073/

62abad5bc762dd8e9abb9a04fd693feb

The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents : low-dose cyclophosphamide , anti-CD25 monoclonal antibody daclizumab , and the IL-2/diphtheria toxin fusion protein denileukin diftitox .

Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Regulatory T cells (Tregs) are thought to inhibit antitumor immune responses, and their depletion could therefore have a synergistic effect with therapeutic cancer vaccines. We investigated the impact of three medications on blood Treg frequency in vaccinated cancer patients. ### Experimental Design To date, the most specific marker for human Tregs is demethylation in the DNA that encodes the transcription factor FOXP3. Thus, we used a FOXP3 methylation-specific quantitative PCR assay (MS-qPCR) to measure Treg frequencies in the peripheral blood mononuclear cells (PBMCs) of melanoma patients. The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents : low-dose cyclophosphamide , anti-CD25 monoclonal antibody daclizumab , and the IL-2/diphtheria toxin fusion protein denileukin diftitox . ### results In the nine control patients, blood Treg frequencies varied over time; there was a 46% reduction in one patient. In treated patients, a more than 2-fold decrease in Tregs was observed in one out of 11 patients receiving cyclophosphamide and in four out of 13 receiving daclizumab, but there was no such Treg decrease in any of the six patients who received denileukin diftitox. As a positive control, a more than 2-fold increase in blood Tregs was detected in four out of nine patients who were treated with interleukin-2. ### conclusions We used a MS-qPCR method that detects Tregs but not other activated T lymphocytes; however, none of the Treg-depleting strategies that we tested led, in the majority of patients, to a conservative 50% reduction in blood Tregs.

https://pubmed.ncbi.nlm.nih.gov/21177412/

6d7c9fb77c622f5e2f023fe97b07a848

The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin .

Related Enteric Viruses Have Different Requirements for Host Microbiota in Mice. Accumulating evidence suggests that intestinal bacteria promote enteric virus infection in mice. For example, previous work demonstrated that antibiotic treatment of mice prior to oral infection with poliovirus reduced viral replication and pathogenesis. Here, we examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a picornavirus closely related to poliovirus. We treated mice with a mixture of five antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis following oral inoculation. We found that, as seen with poliovirus, CVB3 shedding and pathogenesis were reduced in antibiotic-treated mice. While treatment with just two antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and pathogenesis, this treatment had no effect on poliovirus. The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin . To determine whether more-subtle changes in bacterial populations impact viral replication, we examined viral infection in mice treated with milder antibiotic regimens. Mice treated with one-tenth the standard concentration of the normal antibiotic cocktail supported replication of poliovirus but not CVB3. Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 shedding and pathogenesis while having no effect on poliovirus shedding and pathogenesis. Overall, replication and pathogenesis of CVB3 are more sensitive to antibiotic treatment than poliovirus, indicating that closely related viruses may differ with respect to their reliance on microbiota.

https://pubmed.ncbi.nlm.nih.gov/31511379/

a2fcf8649db52726b1ccb01786b9ba09

Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy .

Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy .

https://pubmed.ncbi.nlm.nih.gov/30305476/

4fe7ef8a981494fabcb16d1a1dc34a73

Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer .

A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. ### Patients And Methods gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. ### results From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). ### conclusion Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer . ### Clinicaltrialsgov Id NCT00556023.

https://pubmed.ncbi.nlm.nih.gov/24907635/

406cc45dcc6f28cc137e7b4ea45a2236

The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone ( AZQ ) , etoposide and doxorubicin ( DOX ) using a [ (35)S ] methione uptake assay .

Response of short-term cultures derived from human malignant glioma to aziridinylbenzoquinone, etoposide and doxorubicin: an in vitro phase II trial. The relative resistance of malignant glioma to chemotherapy makes the identification of new cytotoxic drugs critically important. The use of short-term cultures derived from these tumors to screen drugs at doses that can be attained within human intracranial tumors provides a model system that should be capable of identifying effective drugs suitable for clinical evaluation. The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone ( AZQ ) , etoposide and doxorubicin ( DOX ) using a [ (35)S ] methione uptake assay . The ID(50) of each culture was compared to the levels of drug which could be achieved in the tumor using standard doses. There was marked heterogeneity between cultures in response to each drug. Whilst there was no evidence that cultures derived from grade III astrocytoma were more sensitive to any of the drugs than cultures derived from grade IV astrocytoma, cultures derived from oligodendroglioma tended to be more sensitive to the alkylating agent AZQ, but not to either of the other drugs. The sensitivity of these short-term cultures at concentrations that can be achieved in situ corresponded well with the clinical efficacy of AZQ and etoposide. Although DOX appeared to be toxic to human gliomas cells in vitro, its limited penetration into the intact brain would seem to preclude its use i.v., but it is likely to be effective if local drug delivery techniques could be employed. The study suggests that short-term cultures derived from malignant glioma should be used to screen investigational agents for potential clinical efficacy.

https://pubmed.ncbi.nlm.nih.gov/11593057/

39a8733290490861e7886845d3222f69

Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups .

Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. ### Experimental Design Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. ### results Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups . PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. ### conclusions Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR.

https://pubmed.ncbi.nlm.nih.gov/26920887/

6cde22570e75d729825322fcd3bb8706

Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study .

Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study . apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). ### Patients And Methods Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. ### results Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. ### conclusions Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

https://pubmed.ncbi.nlm.nih.gov/32366670/

e94d4ba7604e7b25944f13484e92fbe8

Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials .

Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition. The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. ### Patients And Methods Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). ### results A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. ### conclusion Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials . However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. ### Trial Registration This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.

https://pubmed.ncbi.nlm.nih.gov/31126332/

ded8a5fdc1e6b60a2cbad5fbf2761e9e

A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation .

A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation . Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients.

https://pubmed.ncbi.nlm.nih.gov/31118664/

8653897a48e7d6eb3f5dcfc08388cfa3

Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide .

Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide. Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide . No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.

https://pubmed.ncbi.nlm.nih.gov/14528069/

3214d11b86f9a3f4d5b6f1d4973dc814

After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy .

The association between dermatomyositis and papillary thyroid cancer: a case report. We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy . However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions.

https://pubmed.ncbi.nlm.nih.gov/21243494/

4db36c9c0dfcd102155276b3f8deaf81

The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines .

Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. This study evaluated the cytotoxic effects of imexon (NSC-714597) in tumor cells when combined with a broad panel of chemotherapeutic drugs. ### methods The sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays were used to analyze the degree of growth inhibition for the combination studies in the A375 human malignant melanoma and RPMI 8226 human multiple myeloma cell lines, respectively. Cells were continuously exposed to both drugs at a constant molar ratio for 4-5 days. Combination effects were analyzed using the Median Effect method. Statistical significance was inferred if the 95% confidence interval for the combination interaction (C.I.) values for a particular two-drug combination did not include 1.0 (additivity). Synergy was inferred for C.I. values<1.0 and antagonism for CI values>1.0. ### results Imexon was synergistic when combined with DNA-binding agents (cisplatin, dacarbazine, melphalan) and pyrimidine-based antimetabolites (cytarabine, fluorouracil, gemcitabine) in both cell lines. Antagonistic combinations with imexon included methotrexate and the topoisomerase I (TOPO I) and II (TOPO II) inhibitors irinotecan, doxorubicin, mitoxantrone and etoposide. docetaxel was synergistic with imexon in both cell lines whereas paclitaxel and fludarabine showed a mixed result. dexamethasone and the proteasome inhibitor bortezomib showed synergy in myeloma cells and additivity in the melanoma cells. The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines . ### discussion The consistent synergy seen for imexon and alkylating agents may relate to the sulfhydryl-lowering effect of imexon, which would render cells more sensitive to electrophilic species from the alkylators. The marked synergy noted with pyrimidine-based antimetabolites was unexpected and may relate to the induction of cell cycle arrest in S-phase. The strong antagonism noted for imexon with topoisomerase I and II inhibitors may be due to the effect of imexon at increasing oxidant levels which are known to antagonize the cytotoxic effects of topoisomerase poisons. In contrast, the synergy seen with bortezomib in myeloma cells may be related to an increase in reactive oxygen species (ROS) from both drugs. These results suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in therapeutic studies in vivo.

https://pubmed.ncbi.nlm.nih.gov/17333195/

c97520cf4ea0ffbd75af6ff891594eee

Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) .

Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker.

https://pubmed.ncbi.nlm.nih.gov/2832102/

da53ead9de194fbbbfd4fbf115119337

To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer .

Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer . ### Patients And Methods Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. ### results All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. ### conclusion Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.

https://pubmed.ncbi.nlm.nih.gov/14966088/

2b4b20609f32c318d94165458d3ead40

Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma ( RCC ) in both the US and Europe .

The bevacizumab experience in advanced renal cell carcinoma. Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma ( RCC ) in both the US and Europe . Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative.

https://pubmed.ncbi.nlm.nih.gov/21049084/

393f92352c19f9ae226d09ba0b920e66

YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients .

A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. This phase II study evaluated ym155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received ym155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients .

https://pubmed.ncbi.nlm.nih.gov/26857688/

4d375de169095f455d7feec13343392b

Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) .

[Dolasetron, droperidol and a combination of both in prevention of postoperative nausea and vomiting after extracapsular cataract extraction under general anesthesia]. Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) . It was the aim of this prospective double blind placebo controlled study to determine the efficacy of low-dose droperidol, dolasetron, and a combination of both drugs in the prevention of PONV after extracapsular cataract extraction. ### methods 148 inpatients undergoing cataract surgery were stratified according to gender and then randomised to receive one of four antiemetic regimens: placebo, droperiodol (10 micrograms x kg-1), dolasetron (12.5 mg), or the combination of both drugs (10 micrograms x kg-1 + 12.5 mg). The drugs were administered intravenously 5-10 minutes before the end of anaesthesia. General anaesthesia and the perioperative management of the patients were standardised: benzodiazepine premedication, induction with etomidate, alfentanil and mivacurium. Maintenance using desflurane in N2O/O2, and a continuous infusion of mivacurium was used. Postoperative analgesia (diclofenac or paracetamol) and antiemetic rescue medication (dimenhydrinate and metoclopramide) was standardised. Nausea, episodes of vomiting, retching and the need for additional antiemetics were recorded for 24-hours. The severity of PONV was categorised using a standardised scoring algorithm. The main aim of the study was the number of patients who stayed completely free from PONV. ### results There were no differences between the two groups with regard to biometric data, type of surgery, and distribution of risk factors for developing PONV. In all three treatment groups significantly less patients suffered from PONV (placebo: 66%; droperidol: 89%, dolasetron: 92%, combination: 89%; p = 0.011). Furthermore, the severity of PONV was reduced (p = 0.012). ### conclusion Low-dose droperidol and dolasetron are equally effective to reduce the incidence of PONV after cataract surgery under general anaesthesia. The combination of both drugs revealed no additional effect.

https://pubmed.ncbi.nlm.nih.gov/10429772/

a7970e11e38af84aa3c563f2b60c7e06

Use of doxycycline or azithromycin had little effect on the likelihood of removal of the IUD within 90 days of insertion ( OR 1.05 ; 95 % CI 0.68 - 1.63 ) .

Antibiotic prophylaxis for intrauterine contraceptive device insertion. Concern about the risk of upper genital tract infection (pelvic inflammatory disease) often limits use of the IUD, a highly effective contraceptive. Prophylactic antibiotic administration around the time of induced abortion significantly reduces the risk of postoperative endometritis.(Sawaya, 1996) Since the risk of IUD-related infection is limited to the first few weeks to months after insertion,(Lee, 1983; Farley, 1992) contamination of the endometrial cavity at the time of insertion(Mishell, 1966) appears to be the mechanism, rather than the IUD or string itself. Thus, antibiotic administration before IUD insertion might reduce the risk of upper genital tract infection from passive introduction of bacteria at insertion. ### objectives To assess the effectiveness of prophylactic antibiotic administration before IUD insertion in reducing IUD-related complications and discontinuations within three months of insertion. The primary outcome was pelvic inflammatory disease (four reports) or early removals of the device (two reports). ### Search Strategy We searched both MEDLINE and EMBASE, handsearches of journals through CENTRAL, and lists of references. We also wrote to international experts in the field to identify unpublished studies. ### Selection Criteria We included randomized controlled trials using any antibiotic compared with a placebo. We found four such trials; two had pilot study data available. ### Data Extraction We used searches of MEDLINE, EMBASE, and handsearches of journals available through CENTRAL. We also reviewed lists of references in original research and in review articles. We wrote to experts to identify unpublished trials and made telephone calls to authors to supply missing information. Two independent reviewers abstracted data. We assessed the validity of each study using methods suggested in the Cochrane Handbook. ### Data Synthesis We generated 2x2 tables for the principal outcome measures. We used the Peto modified Mantel-Haenszel technique to calculate odds ratios and assessed statistical heterogeneity between studies. ### Main Results The odds ratios for pelvic inflammatory disease associated with use of prophylactic doxycycline or azithromycin compared with placebo or no treatment was 0.89 (95%CI 0.53-1.51). Use of prophylaxis was associated with a small reduction in unscheduled vists to the provider (OR 0.82; 95% CI 0.70-0.98). Use of doxycycline or azithromycin had little effect on the likelihood of removal of the IUD within 90 days of insertion ( OR 1.05 ; 95 % CI 0.68 - 1.63 ) . Significant heterogeneity did not exist between studies. ### Reviewer S Conclusions Use of either doxycycline 200 mg or azithromycin 500 mg by mouth before IUD insertion confers little benefit. While the reduction in unscheduled visits to the provider was marginally significant, the cost-effectiveness of routine prophylaxis remains questionable. A uniform finding in these trials was the low risk of IUD-associated infection, with or without use of antibiotic prophylaxis.

https://pubmed.ncbi.nlm.nih.gov/10796777/

185a0df36f0bbe26afde08a20ba31179

Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial .

Management of platinum-sensitive recurrent ovarian cancer. The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial . The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens.

https://pubmed.ncbi.nlm.nih.gov/16716798/

e43d4d1e7e7b7d7db5fa281723b77e6a

We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared .

Tazarotene cream (0.1%) in combination with betamethasone valerate foam (0.12%) for plaque-type psoriasis. A combination of multiple agents is often required to achieve treatment success for plaque-type psoriasis. We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared . Erythema, scale, and thickness along with an aggregate severity score were determined at weeks 4, 8, and 12. One patient was lost to follow-up. Eight of the other 9 patients experienced improvement in their disease by week 12. Two patients were clear of their psoriasis at week 4 and 4 were clear at week 8. No adverse events, including irritation were reported; the use of the corticosteroid foam may protect against potential local irritation reported with tazarotene. The combination of tazarotene cream and betamethasone valerate foam is an effective combination approach to treating localized plaque-type psoriasis.

https://pubmed.ncbi.nlm.nih.gov/15776784/

f4bbaf3dafcd80da3dde3ed4380d023c

Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration .

The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration . Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis.

https://pubmed.ncbi.nlm.nih.gov/33628160/

2b68661394691dcb80f0b77a179ad330

Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone , occurring in the two patients who had previously been treated with Glatiramer Acetate .

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone , occurring in the two patients who had previously been treated with Glatiramer Acetate . In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of mitoxantrone, no enhancing lesions were identified on MRI brain scans. glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

https://pubmed.ncbi.nlm.nih.gov/16990994/

8ca4537381cf706758f57cc0a9ac5516

Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer .

Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.

https://pubmed.ncbi.nlm.nih.gov/19695243/

699f2e2cf2eb7133facfc4ee10aab5ca

Several epidemiological , clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs ( NSAIDs ) ( aspirin , naproxen , sulindac , celecoxib , and licofelone ) , statins and other natural agents-both individually , and in combinations .

Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives. Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological , clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs ( NSAIDs ) ( aspirin , naproxen , sulindac , celecoxib , and licofelone ) , statins and other natural agents-both individually , and in combinations . Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.

https://pubmed.ncbi.nlm.nih.gov/30096840/

21b69c12af9158b87a5b0f5917acfdb5

Lenalidomide is an approved medication for relapsed mantle cell lymphoma in patients who received at least two lines of therapy , including bortezomib .

Lenalidomide for mantle cell lymphoma. Mantle cell lymphoma accounts for 6% of all non-Hodgkin lymphomas. It is a biologically and clinically heterogeneous disease and treatment may be difficult, since most patients present at an older age, being unable to undergo intensive chemotherapy. Lenalidomide is an approved medication for relapsed mantle cell lymphoma in patients who received at least two lines of therapy , including bortezomib . New insights into the mechanisms of action of lenalidomide provided ground for novel combinations that may be more tolerable, while still efficient, for this patient population. In this review, we evaluate the current paradigm for lenalidomide in mantle cell lymphoma.

https://pubmed.ncbi.nlm.nih.gov/25952533/

1af53bee0469e8864ff0d747d76a9c51

Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone .

Therapeutic effect of mefloquine on Schistosoma mansoni in experimental infection in mice. Schistosomiasis is one of the most prevalent parasitic infections worldwide. praziquantel is the drug of choice for treatment of schistosomiasis for its high efficacy. The present work was carried out on 160 mice to evaluate the therapeutic effect of mefloquine on experimental schistosomiasis mansoni. Mice were classified into 3 groups; group I (20 infected non-treated mice), group II included 60 infected mice which were further divided into group IIm (20 mice treated with 400 mg/kg mefloquine), group IIp (20 mice treated with 1,000 mg/kg/2 days praziquantel) and group IIpm (20 mice treated with 200 mg/kg mefloquine and 500 mg/kg praziquantel), group III included 80 non-infected mice subdivided into group IIIn (20 non-treated mice), group IIIm (20 mice treated with 400 mg/kg mefloquine), group IIIp (20 mice treated with 1,000 mg/kg/2 days praziquantel), group IIIpm (20 mice treated with 200 mg mefloquine and 500 mg praziquantel). mefloquine significantly reduced worm burden, tissue egg load, number of liver granulomas and increased the percent of dead ova within granulomas. Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone .

https://pubmed.ncbi.nlm.nih.gov/27413290/

d0b32ba93cfb030781614840a4f9e9eb

The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites .

Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients. Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites . ### Patients And Methods Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). ### results No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. ### conclusion Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.

https://pubmed.ncbi.nlm.nih.gov/12881383/

7500cc285dc26dbd5642ffff0b28d687

Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial .

Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial . To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. ### Patients And Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. ### results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. ### conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

https://pubmed.ncbi.nlm.nih.gov/18250349/

69aab0d7ca9444e4b1295a8f4ea70482

Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice .

Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice . The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1-2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1-20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Experiment 1b). Mice were administered vehicle or bupropion (1-20 mg/kg) 15 (Experiment 2b) or 30 (Experiment 2c) minutes (min) prior to vehicle or nicotine during CPP training. The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP. bupropion dose-dependently blocked nicotine CTA. For the 15-min pretreatment interval, bupropion dose-dependently increased locomotor activity and produced CPPs when administered alone; whereas for the 30-min pretreatment interval, only the highest bupropion dose increased locomotor activity and produced a CPP. However, bupropion failed to alter nicotine CPP and the co-administration of bupropion and nicotine did not increase locomotor activity more so than when bupropion was administered alone regardless as to the pretreatment interval. Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice.

https://pubmed.ncbi.nlm.nih.gov/18556053/

798ec9703dcfe46033a3f97ad645abba

We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin , clarithromycin , metronidazole , tetracycline and levofloxacin in Bangladesh .

Helicobacter pylori antibiotic susceptibility patterns in Bangladesh: Emerging levofloxacin resistance. The most recent study to report Helicobacter pylori antibiotic resistance rates in Bangladesh was published 15 years ago and did not include levofloxacin. We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin , clarithromycin , metronidazole , tetracycline and levofloxacin in Bangladesh . ### methodology This study included 133 consecutive patients who underwent endoscopy examination at Dhaka Medical College in November 2014. The serial two-fold agar dilution method was used to determine the minimum inhibitory concentrations of the five antibiotics. ### results Among 56 cultured strains, H. pylori showed high rates of resistance to clarithromycin and metronidazole (39.3% and 94.6%, respectively). Moreover, levofloxacin showed an emerging antimicrobial resistance pattern (66.1%), which was higher in patients with gastritis than that in those with peptic ulcers (p = 0.02). The resistance rate of levofloxacin was significantly higher in patients living in Dhaka city compared to those living in the village (p = 0.049). However, amoxicillin and tetracycline resistance rates were very low. Resistance to both metronidazole and levofloxacin was most commonly observed. ### conclusions The rates of resistance to clarithromycin, metronidazole, and levofloxacin were high in Bangladesh, which suggests that triple therapy based on these drugs may not be useful as first-line therapies in Bangladesh. Alternative strategies such as furazolidone-based triple therapy, bismuth-based quadruple therapies, or sequential therapy may be more effective for patients in in Bangladesh.

https://pubmed.ncbi.nlm.nih.gov/27031456/

a6bdd8378e693d7a72d57a3b0d89f174

With the exception of one Y. enterocolitica isolate which was resistant to tetracycline and streptomycin , the isolates were sensitive to the non-beta-lactam antibiotics .

Antibiotic susceptibilities of Yersinia enterocolitica and Y. intermedia isolates from aquatic environments. Of 37 Yersinia isolates from various aquatic environments, seven were Y. enterocolitica and 30 Y. intermedia. These isolates were biotyped, serotyped and tested for their susceptibility to 20 antibiotics. All Y. enterocolitica isolates were of biovar 1; those of Y. intermedia were distributed amongst four biovars (1, 2, 4 and 6). On the basis of combined biotyping and serotyping results, Y. enterocolitica isolates were distributed in five and Y. intermedia in 17 groups. With the exception of one Y. enterocolitica isolate which was resistant to tetracycline and streptomycin , the isolates were sensitive to the non-beta-lactam antibiotics . In contrast, various patterns of beta-lactam insensitivity were detected, including ampicillin and ticarcillin (35 isolates), cephalothin (33 isolates), carbenicillin (32 isolates), amoxycillin/clavulanate (23 isolates) and cefoxitin (22 isolates). No correlation between biotype or serotype and the susceptibility pattern of the isolates was apparent. Both inducible cephalosporinase activity against third-generation cephalosporins and inhibition of resistance to penicillins were detected in all Y. enterocolitica and Y. intermedia isolates by double-disk tests.

https://pubmed.ncbi.nlm.nih.gov/9989643/

d962e3a836ee82e855e8c51bd15f7b82

Meropenem ( 84.5 % ) and vancomycin ( 100 % ) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria , respectively .

[Colonization of cental venous catheter in the Intensive Care Units at the Institute of Cardiovascular Disease "Dedinje"--one year study]. The application of Central Venous Catheters (CVC) is associated with increased risk of microbial colonization and infection. The aim of present study was to assess the frequency of pathogens colonizing CVC and to determine their susceptibility pattern to various antimicrobial agents. ### Materials And Methods A total of 253 samples of CVC from intensive care units (ICU) patients were received for culture during 2003. All microorganisms were identified by standard microbiological methods and the susceptibility to antimicrobial agents was determined according to NCCLS recommendations. ### results A total of 184 (72.7%) cultures were positive and 223 pathogens were isolated. Coagulase negative staphylococci (CNS) were the dominant isolates (24.7%), followed by Enterobacter spp. (12.1%), Pseudomonas spp. (11.7%), Enterococcus spp. (9.9%), Klebsiella spp. (8.6%), Candida spp. (7.6%), Acinetobacter spp. (7.6%), other Gram negative nonfermentative bacilli (5.8%), Serratia spp. (4.5%), Staphylococcus aureus (2.6%), Proteus mirabilis (2.2%), E. coli (1.8%) and Citrobacter spp. (0.9%). Meropenem ( 84.5 % ) and vancomycin ( 100 % ) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria , respectively . ### conclusion Gram negative bacilli and CNS are the commonest microorganisms colonizing CVC from ICU patients. The increasing resistance of the bacteria to antimicrobial agents is the major problem in spite of restricted policy of using antimicrobial agents in ICU.

https://pubmed.ncbi.nlm.nih.gov/16812991/

22493c5e296bf637da1a3a4d317c9fe2

Troublesome coughing , as observed by the operator , was less frequent with glycopyrrolate ( control 51 % , atropine 42 % , glycopyrrolate 30 % ) , as was patient movement ( 40 % , 32 % , 19 % , respectively ) .

Anticholinergic premedication for fibreoptic bronchoscopy. atropine is routinely used as part of the premedication regimen for fibreoptic bronchoscopy. This study was performed, firstly, to evaluate the effect of anticholinergic agents on the ease of bronchoscopy, haemodynamic parameters and patient comfort during the procedure; and secondly, to compare atropine with glycopyrrolate, a newer acetylcholine antagonist which is claimed to cause less tachycardia and sedation, whilst suppressing salivation more effectively. One hundred and ninety consecutive patients were randomly allocated to three treatment groups: diazepam 5 mg; diazepam 5 mg + atropine 600 micrograms; and diazepam 5 mg + glycopyrrolate 300 micrograms. Diazepam was given orally one hour before bronchoscopy, and glycopyrrolate/atropine intramuscularly 30 min before bronchoscopy. All patients received thalamonal intravenously, lignocaine gel into one nostril, and lignocaine by transtracheal injection just prior to the procedure. The incidence of bronchoscopy related haemodynamic problems was similar in all three groups. Troublesome coughing , as observed by the operator , was less frequent with glycopyrrolate ( control 51 % , atropine 42 % , glycopyrrolate 30 % ) , as was patient movement ( 40 % , 32 % , 19 % , respectively ) . Uncomfortable dryness of the mouth was most common with glycopyrrolate (37%, 32%, 66%, respectively), but overall assessment of discomfort, and the number of patients who would agree to a repeat bronchoscopy (73%, 76%, 70%, respectively) were very similar in all three groups. In conclusion, the differences between the three groups were slight. glycopyrrolate made the bronchoscopy slightly easier for the operator because of significantly improved cough and movement suppression, though atropine was marginally preferable in terms of patient comfort.

https://pubmed.ncbi.nlm.nih.gov/8049691/

fb2aef24db7a72de42f51884b108ba26

The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab .

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. ### methods The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab . All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. ### results Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. ### conclusions Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.

https://pubmed.ncbi.nlm.nih.gov/16150805/

96a9fd8b397223abbea02baa3dfbe9fc

Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients .

Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients . We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.

https://pubmed.ncbi.nlm.nih.gov/16767309/

1c3e878969df3a2cbcad911937d77bd6

Simultaneous determination of pyrimethamine and mefloquine in human plasma by high-performance liquid chromatography with ultraviolet detection .

Simultaneous determination of pyrimethamine and mefloquine in human plasma by high-performance liquid chromatography with ultraviolet detection . A rapid, sensitive and selective method was developed for the simultaneous determination of pyrimethamine and mefloquine, two of the active ingredients of Fansimef, in human plasma. The procedure involved extraction of the compounds and the internal standard nitrazepam from basified plasma with dichloromethane and chromatography on a C18 column (microBondapak, 300 X 3.9 mm I.D.) with acetonitrile-phosphate buffer as the mobile phase and UV detection at 222 nm. The limit of quantification was 10 ng/ml for both substances, using a 1-ml plasma specimen. The mean inter-assay precision was 2.8% for pyrimethamine and 4.7% for mefloquine up to 800 ng/ml. The practicability of the method was demonstrated by the analysis of more than 1200 plasma samples from several pharmacokinetic studies involving single-dose administration of Fansimef to both patients and volunteers.

https://pubmed.ncbi.nlm.nih.gov/2584319/

9a67aa7bd71f87b823a2f61c598580c8

We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions .

Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study. Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions . Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.

https://pubmed.ncbi.nlm.nih.gov/24085777/

1354ecde1f0efa09e4ae9da54b16a013

Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel , cetuximab , methotrexate , carboplatin , 5-fluorouracil and everolimus .

A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option. Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel , cetuximab , methotrexate , carboplatin , 5-fluorouracil and everolimus . Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers.

https://pubmed.ncbi.nlm.nih.gov/25404014/

a5a37111778a7e5eac53c5f529927814

Apart from progesterone , the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil , trifluoperazine and reserpine .

Comparison of effects of surfactants with other MDR reversing agents on intracellular uptake of epirubicin in Caco-2 cell line. P-glycoprotein (P-gp) actively pumps out a number of anticancer drugs, such as epirubicin, from tumor cells. P-gp is also expressed in the small intestine under normal physiological conditions. Inhibition of intestinal P-gp function using MDR reversing agents may enhance the oral bioavailability of some chemotherapeutic agents. Human colon adenocarcinoma (Caco-2) cell line expresses many characteristics of differentiated cells of the normal small intestine. Using Caco-2 as an in vitro intestinal model, the overall goal of the present study was to evaluate the MDR-reversing effects of some commonly used nonabsorptive pharmaceutical surfactants, such as Tween 20, Tween 80 and acacia on the intracellular accumulation of epirubicin by flow cytometry. Tween 20, Tween 80 or acacia all significantly increased intracellular accumulation of epirubicin with the highest enhancing effect for acacia and the lowest for Tween 20. Apart from progesterone , the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil , trifluoperazine and reserpine . In conclusion, our results demonstrate that progesterone, acacia, Tween 20 and Tween 80 are potent MDR modifiers of epirubicin in Caco-2 at concentrations that could be achieved in vivo. Use of surfactants in excipients may increase the intestinal absorption of some drugs through P-gp inhibition and thus improve drug bioavailability for P-gp substrate.

https://pubmed.ncbi.nlm.nih.gov/9713500/

8fdaeaa5a546d9cdb6e3f2ad87336e00

A549-Gem is cross-resistant to vincristine and etoposide , but not resistant to adriamycin , cisplatin , cytarabine and paclitaxel .

[Development and characterization of a gemcitabine-resistant variant of human lung adenocarcinoma cell line A549]. gemcitabine (2',2-difluorodeo- xycytide) has antitumor activity in both experimental and clinical treatment of solid tumors. Although resistance to gemcitabine in ovarian cancer cell line and erythroleukemic cell line was described, there was no report on the lung cancer resistant variant. In order to elucidate the mechanism by which gemcitabine induce resistance in lung cancer, we have established the resistance to gemcitabine in human lung adenocarcinoma cell line A549 and described the characteristics of its resistant variant. ### methods Resistance to gemcitabine was established by exposing A549 cells to increasing concentration of gemcitabine, which was designated as A549-Gem. The IC(50) and resistance index(RI) were tested by MTT assay and colony formation test. The growth curve and cell cycle of A549 and A549-Gem were compared. The cross-resistance profile of A549-Gem was also tested. ### results The IC(50) increased from 6.56+/-1.19 micromol/L in A549 to 921.09+/-225.27 micromol/L in A549-Gem as tested by MTT assay at 72h exposure, the RI was 140.52 (P=0.019 5). The RI of colony formation test was 132.95. Double time of A549 and A549-Gem were 29.7 h and 36.4 h, respectively, as evaluated by the growth curve. A549-Gem was cross-resistant to vincristine and etoposide(54.38-fold and 6.18-fold)(P< 0.01), but not to adriamycin, cisplatin, cytarabine, and paclitaxel. ### conclusion A549-Gem, the gemcitabine resistant phenotype, is stable and suitable for the study of gemcitabine resistance in lung cancer. A549-Gem is cross-resistant to vincristine and etoposide , but not resistant to adriamycin , cisplatin , cytarabine and paclitaxel .

https://pubmed.ncbi.nlm.nih.gov/15191667/

20514f75a386ccc202c4c1745f22bc91

[ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] .

[ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] . To evaluate the efficacy of combination therapy of lamivudine (LAM) and adefovir dipivoxyl (ADV) for patients with hepatitis B-induced decompensated cirrhosis. ### methods A total of 81 patients were randomly divided into a combination group and an ADV group over 48 week treatment course. The combination group were treated with LAM (100 mg/d) plus ADV (10 mg/d), and the ADV group with ADV (10 mg/d ) for 48 weeks. All patients received hepatic function support and symptomatic treatment. The levels of HBV DNA, liver function, Child-Pugh scores and HBV DNA indicators were observed before and after the treatment. ### results At week 4, the mean reduction of HBV DNA was 1.83 lgIU/mL, 17.9% of the patients achieved undetectable HBV DNA and 28.2% showed normal ALT in the combination group. The counterpart in the ADV group was 0.96 lgIU/mL, 5.3% and 10.5%. At week 4, 12, 24 and 48, the differences in the mean reduction of HBV DNA, undetectable HBV DNA and ALT normalization were statistically significant between the 2 groups. The difference in HBeAg negative conversion rates and HBeAg seroconversion at week 24 and 48 was not significant. ### conclusion The combination therapy results in HBV suppression and improved liver function and Child-Pugh score. The combination treatment has an advantage over ADV due to low drug resistance rate and good tolerance.

https://pubmed.ncbi.nlm.nih.gov/23281382/

18d0d9d7869efb79ddddcc8959b06715

The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects .

Aspirin in the treatment of acute migraine attacks. Acetylsalicylic acid (aspirin or ASA) has been used for many years as an analgesic, antipyretic and anti-inflammatory drug. In recent years, evidence for its effectiveness in migraine headache has been demonstrated in several clinical trials. The effervescent highly buffered preparation of aspirin was shown to be effective, safe and well tolerated compared with placebo or other treatment options. The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects . This review summarizes and analyzes clinical data of aspirin in the treatment of acute migraine attacks with respect to the different galenic formulations.

https://pubmed.ncbi.nlm.nih.gov/16623655/

8661d62eebfe82d61a8747df95d0c3d1

Several agents are now available in this setting , including neratinib , tucatinib , ado-trastuzumab emtansine , and trastuzumab deruxtecan .

Neratinib: an option for HER2-positive metastatic breast cancer. Metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is currently incurable. The primary goals of treatment are to prolong survival while optimizing quality of life. Several agents are now available in this setting , including neratinib , tucatinib , ado-trastuzumab emtansine , and trastuzumab deruxtecan . neratinib in combination with capecitabine was recently approved for the treatment of adult patients with advanced or metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. neratinib is an oral pan-HER inhibitor that binds covalently to the kinase site, providing irreversible binding. Phase 3 data showed that the combination of neratinib plus capecitabine improved progression-free survival vs lapatinib plus capecitabine. The duration of response was longer among patients in the neratinib arm. neratinib plus capecitabine was also active against brain metastases associated with refractory, HER2-positive breast cancer, and this combination is listed in guidelines from the National Comprehensive Cancer Network for this indication. When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status. Ongoing trials are evaluating the ability of neratinib to treat brain metastases, as well as the efficacy and safety of the triplet combination of neratinib, fulvestrant, and trastuzumab in this setting.

https://pubmed.ncbi.nlm.nih.gov/33843838/

a33444511331956df6350a73604e4fa2

This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis .

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. ### methods This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis . The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. ### discussion OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. ### Trial Registration NTR4499 . Registered on 7 April 2014.

https://pubmed.ncbi.nlm.nih.gov/28148280/