B1tta/Drug-ACE huggingface dataset:
[Title]: Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy.
[Abstract]: AIM: To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase (TS) gene expression in a rectal cancer patient cohort treated according to a standardized recommended neoadjuvant treatment regimen. METHODS: Formalin fixed, paraffin embedded pre-therapeutical tumor biopsies (n = 22) and post-therapeutical resection specimens (n = 40) from patients with rectal adenocarcinoma (clinical UICC stage II/III) receiving standardized neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan real-time PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system. RESULTS: Responders (patients with high tumor regression) showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies (81.2% vs 16.7%; P &lt; 0.05) as well as in the post-therapeutical resection specimens (75.8% vs 14.3%; P &lt; 0.01). High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a low Ki67 index in the pre-therapeutical tumor biopsies (corr. coef. = 0.46; P &lt; 0.01) as well as in the post-therapeutical resection specimens (corr. coef. = 0.40; P &lt; 0.05). No significant association was found between p53 and TS mRNA expression or tumor regression. CONCLUSION: Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.
[Drug-Disease]: 5-FU - rectal adenocarcinoma
[Title]: Renal protective effect in hypertensive patients: the high doses of angiotensin II receptor blocker (HARB) study.
[Abstract]: Angiotensin receptor blockers (ARBs) are the recommended first-line antihypertensive treatment for managing chronic kidney disease, and strict blood pressure (BP) regulation is crucial for the reduction of proteinuria. Valsartan and candesartan are commonly used ARBs in Japan, with maximum permissible doses of 160 mg/day and 12 mg/day, respectively. We evaluated BP and proteinuria after changeover from the maximum dose of candesartan to the maximum dose of valsartan, in 55 poorly controlled hypertensive patients undergoing candesartan treatment who were unable to achieve optimal BP according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). We measured BP and pulse rate and assessed urinary protein excretion (UPE) before and after changeover. Changeover was associated with decreases in systolic BP and diastolic BP from 158/89 mmHg to 150/86 mmHg (p&lt;0.01). Changeover was also associated with a reduction in UPE adjusted to urinary creatinine from 0.35+/-0.19 g/g creatinine to 0.19+/-0.37 g/g creatinine (p=0.0271) in patients who had high urinary protein levels prior to changeover without significant decreases in BP (p=0.0184). According to multiple regression analysis, higher UPE (p&lt;0.0001) and a lower glomerular filtration rate (GFR) (p=0.0011) prior to changeover were independently correlated with reduction in UPE. Our results suggest that the maximum dose of valsartan is more effective than the maximum dose of candesartan for reducing BP and proteinuria.
[Drug-Disease]: valsartan - Hypertension
[Title]: Renal protective effect in hypertensive patients: the high doses of angiotensin II receptor blocker (HARB) study.
[Abstract]: Angiotensin receptor blockers (ARBs) are the recommended first-line antihypertensive treatment for managing chronic kidney disease, and strict blood pressure (BP) regulation is crucial for the reduction of proteinuria. Valsartan and candesartan are commonly used ARBs in Japan, with maximum permissible doses of 160 mg/day and 12 mg/day, respectively. We evaluated BP and proteinuria after changeover from the maximum dose of candesartan to the maximum dose of valsartan, in 55 poorly controlled hypertensive patients undergoing candesartan treatment who were unable to achieve optimal BP according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). We measured BP and pulse rate and assessed urinary protein excretion (UPE) before and after changeover. Changeover was associated with decreases in systolic BP and diastolic BP from 158/89 mmHg to 150/86 mmHg (p&lt;0.01). Changeover was also associated with a reduction in UPE adjusted to urinary creatinine from 0.35+/-0.19 g/g creatinine to 0.19+/-0.37 g/g creatinine (p=0.0271) in patients who had high urinary protein levels prior to changeover without significant decreases in BP (p=0.0184). According to multiple regression analysis, higher UPE (p&lt;0.0001) and a lower glomerular filtration rate (GFR) (p=0.0011) prior to changeover were independently correlated with reduction in UPE. Our results suggest that the maximum dose of valsartan is more effective than the maximum dose of candesartan for reducing BP and proteinuria.
[Drug-Disease]: valsartan - proteinuria
[Title]: A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia.
[Abstract]: Weight gain and other metabolic disturbances have now become discouraging, major side effects of atypical antipsychotic drugs (AAPDs). The novel strategies required to counteract these serious consequences, however, should avoid modulating the activities of the neurotransmitter receptors involved because those receptors are the therapeutic targets of AAPDs. Adenosine monophosphate-activated protein kinase is an enzyme that plays a pivotal role in energy homeostasis. We hypothesized that alpha-lipoic acid (ALA), which is known to modulate adenosine monophosphate-activated protein kinase activity in the hypothalamus and peripheral tissues, would ameliorate AAPD-induced weight gain. We describe the case series of a 12-week ALA trial in schizophrenia patients treated with AAPDs. Two of 7 enrolled subjects were dropped from the study because of noncompliance and demand for new medication to treat depressive symptoms, respectively. The mean (SD) weight loss was 3.16 (3.20) kg (P = 0.043, last observation carried forward; median, 3.03 kg; range, 0-8.85 kg). On average, body mass index showed a significant reduction (P = 0.028) over the 12 weeks. During the same period, a statistically significant reduction was also observed in total cholesterol levels (P = 0.042), and there was a weak trend toward the reduction in insulin resistance (homeostasis model assessment of insulin resistance) (P = 0.080). Three subjects reported increased energy subjectively. The total scores on the Brief Psychiatric Rating Scale and the Montgomery-Asberg Depression Rating Scale did not vary significantly during the study. These preliminary data suggest the possibility that ALA can ameliorate the adverse metabolic effects induced by AAPDs. To confirm the benefits of ALA, more extended study is warranted.
[Drug-Disease]: ALA - weight gain
[Title]: Successful treatment of vancomycin-resistant Enterococcus faecium pyelonephritis with daptomycin during pregnancy.
[Abstract]: OBJECTIVE: To report successful treatment using daptomycin for pyelonephritis associated with vancomycin-resistant Enterococcus faecium (VRE) in a 27-week pregnant woman. CASE SUMMARY: A 20-year-old 27-week pregnant patient with a history of spina bifida, neurogenic bladder, and multiple hospitalizations for recurrent urinary tract infections (UTIs) was diagnosed with pyelonephritis. She was treated with daptomycin 260 mg (4 mg/kg) daily for 14 days on the basis of a urine culture that revealed E. faecium resistant to ampicillin, nitrofurantoin, and vancomycin. All cultures following treatment revealed no growth, and the patient as well as the neonate displayed no adverse effects. DISCUSSION: VRE UTIs can be treated safely in pregnancy with nitrofurantoin, if the organism is susceptible. Other viable options in the treatment of VRE, including linezolid, doxycycline, and quinupristin/dalfopristin, have lower urinary concentrations, teratogenic risk, or limited findings regarding their safety in pregnancy. Daptomycin was selected in this case due to its efficacy in the treatment of VRE, high urinary concentrations, pregnancy category B, and one case report indicating its successful use in pregnancy. CONCLUSIONS: Treatment of VRE in pregnancy can be challenging due to the teratogenicity or unknown safety of available options. The use of daptomycin in our patient enabled a successful outcome of multidrug-resistant E. faecium in a complicated pregnant patient without observed neonatal abnormalities.
[Drug-Disease]: daptomycin - pyelonephritis
[Title]: Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension.
[Abstract]: Angiotensin II type-1 receptor blockers (ARBs) are regarded as first-line treatments for type-2 diabetes with hypertension. Despite the availability of various types of ARBs, there are no comparative studies of their effects on patients with diabetes. In this open-label prospective crossover study, we compared the effects of olmesartan (20 mg/day) and telmisartan (40 mg/day). Twenty Japanese early-stage type-2 diabetes patients with hypertension treated with valsartan (80 mg/day) for at least 8 weeks were recruited to this study. At study entry, valsartan was changed to olmesartan (20 mg/day) or telmisartan (40 mg/day) and administered for 8 weeks. The drugs were then switched and treatment was continued for another 8 weeks. We analyzed the blood pressure lowering effects of each drug by 24-h ambulatory blood pressure monitoring at 0, 8, and 16 weeks. Simultaneously, we measured metabolic parameters and inflammation markers. Olmesartan lowered mean systolic and diastolic blood pressure more significantly than did telmisartan. While there were no differences between the groups in metabolic parameters, including HbA1c and adiponectin, the decreases in serum interleukin-6 and highly sensitive C-reactive protein were more significant by olmesartan treatment. Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan.
[Drug-Disease]: olmesartan - hypertension
[Title]: Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis.
[Abstract]: OBJECTIVE: Research has examined the association of folate-dependent gene polymorphisms with methotrexate (MTX) toxicity in racially homogenous patients with rheumatoid arthritis (RA). We examined the influence of MTX transporter gene polymorphisms on MTX toxicity in 2 racial groups of patients with RA. METHODS: Using a retrospective cross-validation approach, the association of polymorphisms in 6 genes in the MTX cellular pathway with MTX toxicity was examined in training and validation cohorts. The genes analyzed were ATP-binding cassette transporter B1 (ABCB1), C1 (ABCC1), C2 (ABCC2), folylpolyglutamyl synthase (FPGS), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS). Both cohorts included Caucasian Americans and African Americans. Statistical analyses consisted of Fisher exact tests, multivariable logistic regression models, and survival analyses. RESULTS: Four of 25 variants displayed significant associations with MTX toxicity in the training cohort. The intronic single-nucleotide polymorphism (SNP) ABCC2 IVS 23+56 T --&gt; C was associated with alopecia in Caucasians (p = 0.035). ABCB1 1236 C --&gt; T was associated with overall toxicity (p = 0.013); ABCC2 1249 G --&gt; A with gastrointestinal toxicity (p = 0.009); and ABCC2 1058 G --&gt; A with hepatotoxicity (p = 0.04) in African Americans. These 4 SNP and the MTHFR 677 C --&gt; T variant were assessed in the validation cohort. Of these, only the MTHFR 677 C --&gt; T SNP was associated with alopecia, and only in African Americans (p = 0.032). The ABCC2 IVS 23+56 T --&gt; C genotype influenced toxicity-related time to discontinuation or dose decrease in the Caucasian validation cohort (p &lt; 0.0001). CONCLUSION: In addition to SNP in folate-dependent genes, MTX transporter gene SNP may be important markers of MTX toxicity in RA. Such pharmacogenetic associations are race-specific.
[Drug-Disease]: MTX - RA
[Title]: Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus.
[Abstract]: Rosiglitazone (RSG) is known to be an agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) and promotes differentiation of pre-adipocytes into adipocytes. Leptin is highly correlated with adiposity, while the activation of PPARgamma is known to inhibit Lep gene expression and leptin release. This study was performed to evaluate the relationship between changes in circulating leptin levels, insulin sensitivity and regional adiposity after RSG treatment. Two hundred fifty-one type 2 diabetic patients (176 men and 75 women) who had been treated with sulfonylurea and/or metformin received 4 mg of RSG daily, in addition to the previous medications. Before and after RSG treatment (average duration 5.6+/-0.9 months), indices of insulin resistance, metabolic parameters, and serum leptin and adiponectin levels were measured. Abdominal subcutaneous fat thickness (SFT(max)) and visceral fat thickness were measured by sonography. After RSG treatment, HOMA-IR index decreased significantly (2.82+/-1.94 vs. 2.01+/-1.58), while BMI and SFT(max) increased, and leptin (4.72+/-3.77 vs. 5.69+/-4.30 ng/ml) and adiponectin levels (7.54+/-10.20 vs. 12.89+/-10.13 microg/ml) increased. The increase in serum leptin correlated with an increase in SFT(max) (r=0.511, p&lt;0.001) and with a reduction in HOMA-IR (r=-0.368, p&lt;0.001). The correlation of Delta leptin with Delta HOMA-IR and with Delta SFT(max) was higher in females and among insulin-resistant subjects. In conclusion, RSG improves the insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus, which is related to an increase in subcutaneous adiposity.
[Drug-Disease]: RSG - diabetes mellitus
[Title]: The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial.
[Abstract]: BACKGROUND: The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms. METHODS: Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 +/- 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing. RESULTS: Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes. CONCLUSIONS: There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration-response relationship of an antihypertensive drug may be genotype dependent.
[Drug-Disease]: irbesartan - hypertensive
[Title]: CPT-11 for recurrent temozolomide-refractory 1p19q co-deleted anaplastic oligodendroglioma.
[Abstract]: OBJECTIVE: A Phase II study of CPT-11 in adults with recurrent, temozolomide (TMZ)-refractory, 1p19q co-deleted, anaplastic oligodendroglioma (AO) with a primary objective of determining 6-month progression free survival (PFS). BACKGROUND: There is no standard therapy for alkylator-resistant AO. METHODS: Twenty-two patients (11 men; 11 women) ages 26-65 (median 40), with radiographically recurrent AO were enrolled. All patients had previously been treated with surgery, involved-field radiotherapy, and adjuvant chemotherapy (TMZ in 15; BCNU in 6). Fifteen patients were treated at first recurrence with an alternative chemotherapy. 13 patients underwent repeat surgery. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks. Neurological and neuroradiographic evaluations were performed every 8-9 weeks. RESULTS: All patients were evaluable for toxicity and response. A total of 141 cycles of CPT-11 (median 3 cycles; range 3-18) were administered. CPT-11 related toxicity included diarrhea (14 patients; 4 grade 3), neutropenia (8; 4 grade 3), fatigue (12; 3 grade 3), and delayed nausea/vomiting (12; 3 grade 3). 5 patients (23%) demonstrated a partial radiographic response, 8 (36%) demonstrated stable disease and 9 (41%) had progressive disease following three cycles of CPT-11. Time to tumor progression ranged from 2 to 13.5 months (median: 4.5 months). Survival ranged from 3 to 21 months (median: 5.5 months). Six-month and 12-month PFS were 33% and 4.5% respectively. CONCLUSIONS: CPT-11 demonstrated modest efficacy (similar to other salvage glioma regimens) with acceptable toxicity in this cohort of adults with recurrent, 1p19q co-deleted AO all of whom had failed prior TMZ chemotherapy.
[Drug-Disease]: CPT-11 - oligodendroglioma
[Title]: [Dutasteride in the treatment of hormone refractory prostate cancer].
[Abstract]: AIM: Most patients with advanced prostate cancer respond to androgen inhibition with or without antiandrogens. Progression to androgen-independent prostate cancer takes 5-7 years and is characterized by biochemical or diagnostic changes, despite testosteronemia levels similar to those after castration. Dutasteride, a 5-alfa-reductase types 1 and 2 inhibitor, is used in the treatment of benign prostatic hyperplasia (BPH). In prostate cancer, 5-alfa-reductase type 1 expression is greater than in BPH, but no differences in 5-alfa-reductase type 2 expression have been observed between metastatic prostate cancer and BPH. The higher levels of the two isozymes in metastatic and in recurrent prostate cancer after androgen withdrawal may reflect a selective adaptive mechanism to the amplification of remaining androgen signals. The aim of this prospective study was to evaluate the clinical utility of dutasteride in the treatment of hormone refractory prostate cancer. METHODS: Between March 2005 and December 2007, 8 patients with hormone refractory prostate cancer were evaluated prospectively. Following antiandrogen withdrawal and subsequent increase in PSA, 5 patients received docetaxel plus prednisone and 3 received ketoconazole plus hydrocortisone. The regimen was a single administration of 2 tablets of 0.5 mg dutasteride/die. Therapeutic response was defined as a &gt;50% reduction in PSA or a 75% reduction at 4 weeks after the start of therapy. RESULTS: The mean duration of follow-up was 9 months (range, 21-24 months). A reduction &gt;50% or &gt;75% in PSA was noted in 4 and 6 patients, respectively. Bone scintigraphy detected no normalization of bone lesions; computed tomography scanning showed no partial response to treatment. The mean duration of response was 6.9 months (range, 0-21 months). Two (25%) of the 8 patients died at 6 and 10 months, respectively, neither of which had responded to dutasteride treatment. Only 1/8 patients reported experiencing dyspepsia during the study period. CONCLUSION: The activity of 5-alfa-reductase types 1 and 2 is expressed in the epithelial cells of the prostate, the stroma, and the prostate tumor. The genetic expression of fatty acid synthesis is influenced by dutasteride, which inhibits it by blocking the pathway that regulates sterol protein binding which, in turn, regulates androgen stimulation. The addition of a dual inhibitor of 5-a-reductase types 1 and 2 to antiandrogen therapy may further inhibit tumor growth, thus reducing the concentration of intracellular dihydrotestosterone, which is the primary androgen mediator of PSA gene expression in prostate tumor cell lines. These data support the rationale for the use of dutasteride in the treatment of hormone refractory prostate cancer. The study findings show that dutasteride is useful in the treatment of hormone refractory prostate cancer.
[Drug-Disease]: dutasteride - benign prostatic hyperplasia