Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032).

BACKGROUND: Pancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without cobimetinib in advanced/metastatic solid tumors, including pancreatic cancer. METHODS: In the original pancreatic cancer cohort, previously treated patients (≥1 prior regimen) with advanced/metastatic pancreatic adenocarcinoma were assigned to nivolumab 3 mg/kg every 2 weeks (monotherapy arm) or nivolumab 1 mg/kg and ipilimumab 1 mg/kg or 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks (combination arm). A subsequent modified pancreatic cohort (one or two prior regimens) received nivolumab 3 mg/kg every 2 weeks, ipilimumab 1 mg/kg every 6 weeks, and cobimetinib 60 mg orally once daily for 21 days on and 7 days off (triplet arm). The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were investigator-assessed progression-free survival (PFS), PFS rate, overall survival (OS), OS rate, safety, and tolerability. Additionally, ORR, PFS, and duration of response were assessed by blinded independent central review (BICR) in the triplet arm. RESULTS: 18 patients received nivolumab monotherapy, 21 received nivolumab plus ipilimumab, and 30 received nivolumab plus ipilimumab plus cobimetinib. In the triplet arm, partial responses were observed in two patients per investigator (ORR 6.7% (95% CI 0.8% to 22.1%)) and in three patients per BICR (ORR 10% (95% CI 2.1% to 26.5%)); no responses were observed in the other arms. Median (95% CI) PFS per investigator was 1.4 (1.3 to 2.0), 1.4 (1.2 to 2.7), and 3.0 (1.5 to 4.1) months for the monotherapy, nivolumab plus ipilimumab, and triplet arms, respectively. Median (95% CI) OS was 5.1 (2.0 to 9.0) months, 4.0 (1.9 to 5.6) months, and 6.2 (3.9 to 11.4) months, respectively. Most treatment-related adverse events were grade 2 or less. CONCLUSIONS: Nivolumab with or without ipilimumab did not elicit objective responses in previously treated patients with advanced pancreatic adenocarcinoma, although three confirmed partial responses and manageable safety were observed with cobimetinib-containing triplet therapy. The small sample size and differences in baseline disease-specific characteristics between arms limit interpretation of these results.

Exposure-response analysis for nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma (CheckMate 040).

This analysis was conducted to inform dose selection of a combination of nivolumab plus ipilimumab for the treatment of sorafenib-experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open-label, multicohort, phase I/II trial in adults with advanced HCC that evaluated nivolumab monotherapy (0.1-10 mg/kg once every 2 weeks [q2w]) and the following three combinations of nivolumab plus ipilimumab: (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); and (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks continuously (arm C). Exposure-response relationships (efficacy and safety) were characterized using nivolumab and ipilimumab concentrations after the first dose (Cavg1) as the exposure measure. Objective tumor response (OTR) and overall survival (OS) improvements were associated with increased ipilimumab exposure (OTR: odds ratio 1.45, 95% confidence interval [CI], 1.13-1.86; OS: hazard ratio 0.86, 95% CI 0.75-0.98), but not nivolumab exposure (OTR: odds ratio 0.99, 95% CI 0.97-1.02; OS: hazard ratio 1.08, 95% CI 0.89-1.32). Hepatic treatment-related and immune-mediated adverse events were more common in arm A than in arms B or C. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w had the most favorable benefit:risk profile in patients with advanced HCC.

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial.

PURPOSE: To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma. METHODS: In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival. RESULTS: Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm. CONCLUSION: Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.

BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER: NCT01658878.

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER: NCT01658878.

Nivolumab in Advanced Hepatocellular Carcinoma: Safety Profile and Select Treatment-Related Adverse Events From the CheckMate 040 Study.

BACKGROUND: CheckMate 040 assessed the efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma (HCC). Understanding the safety profile of nivolumab is needed to support the management of treatment-related adverse events (TRAEs). This analysis assessed the safety of nivolumab monotherapy in the phase I/II, open-label CheckMate 040 study. MATERIALS AND METHODS: Select TRAEs (sTRAEs; TRAEs with potential immunologic etiology requiring more frequent monitoring) occurring between first dose and 30 days after last dose were analyzed in patients in the dose-escalation and -expansion phases. Time to onset (TTO), time to resolution (TTR), and recurrence of sTRAEs were assessed, and the outcome of treatment with immune-modulating medication (IMM) was evaluated. RESULTS: The analysis included 262 patients. The most common sTRAE was skin (35.5%), followed by gastrointestinal (14.5%) and hepatic (14.1%) events; the majority were grade 1/2, with 10.7% of patients experiencing grade 3/4 events. One patient had grade 5 pneumonitis. Median (range) TTO ranged from 3.6 (0.1-59.9) weeks for skin sTRAEs to 47.6 (47.1-48.0) weeks for renal sTRAEs. Overall, 68% of sTRAEs resolved, with median (range) TTR ranging from 3.7 (0.1-123.3+) weeks for gastrointestinal sTRAEs to 28.4 (0.1-79.1) weeks for endocrine sTRAEs. Most gastrointestinal and all hepatic events resolved with treatment in accordance with established toxicity management algorithms. In 57 patients (40%), sTRAEs were managed with IMM. Reoccurrence of sTRAEs was uncommon following rechallenge with nivolumab. CONCLUSION: Nivolumab demonstrated a manageable safety profile in this analysis of patients with advanced HCC. A majority of sTRAEs resolved with treatment. IMPLICATIONS FOR PRACTICE: Nivolumab is a viable treatment option for patients with previously treated advanced hepatocellular carcinoma as it has demonstrated durable tumor responses and promising survival. Nivolumab has a manageable safety profile. The most common select treatment-related adverse events (sTRAEs) in this analysis were skin related (35%). Gastrointestinal and hepatic sTRAEs were observed in approximately 14% of patients. The majority of sTRAEs resolved (68%). Safety events are easier to manage if addressed early. Patient education on signs and symptoms to watch out for and the importance of early reporting and consultation should be emphasized.

CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer.

PURPOSE: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. RESULTS: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. CONCLUSION: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.

Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.

BACKGROUND: Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. METHODS: In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. FINDINGS: Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9-16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3-35·4) of 78 patients. Grade 3-4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. INTERPRETATION: Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. FUNDING: Bristol-Myers Squibb.

Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.

PURPOSE: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. PATIENTS AND METHODS: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. RESULTS: The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. CONCLUSION: The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.

Sodium valproate stimulates potassium and chloride urinary excretion in rats: gender differences.

BACKGROUND: The diuretic effect of valproates and its relation to urinary potassium (K+) and chloride (Cl-) excretion have not yet been investigated, so the aim of this study was to evaluate the influence of a single dose of sodium valproate (NaVPA) on 24-h urinary K+ and Cl- excretion in young adult Wistar rats of both genders. For measurement of K+ in urine, the same animals and samples as in our earlier publication were used (Pharmacology 2005 Nov, 75:111-115). The authors propose a new approach to the pathophysiological mechanisms of NaVPA effect on K+ and Cl- metabolism. Twenty six Wistar rats were examined after a single intragastric administration of 300 mg/kg NaVPA (13 NaVPA-male and 13 NaVPA-female), 28 control intact Wistar rats (14 males and 14 females) were studied as a control group. The 24-h urinary K+, Cl-, creatinine and pH levels were measured. RESULTS: Total 24-h diuresis and 24-h diuresis per 100 g of body weight were found to be significantly higher in NaVPA-rats of both genders than in rats of the control group (p < 0.05). The data showed NaVPA to enhance 24-h K+ excretion in NaVPA-males and NaVPA-females with significant gender-related differences: 24-h K+ excretion in NaVPA-male rats was significantly higher than in control males (p = 0.003) and NaVPA-female rats (p < 0.001). Regarding the 24-h K+ excretion, NaVPA-female rats did not show a statistically significant difference versus females of the control group (p > 0.05). 24-h urinary K+ excretion per 100 g of body weight in NaVPA-male rats was significantly higher than in control males (p = 0.025). NaVPA enhanced Cl- urinary excretion: 24-h Cl- urinary excretion, 24-h urinary Cl- excretion per 100 g of body weight and the Cl-/creatinine ratio were significantly higher in NaVPA-male and NaVPA-female rats than in gender-matched controls (p < 0.05). 24-h chloriduretic response to NaVPA in male rats was significantly higher than in female rats (p < 0.05). CONCLUSION: NaVPA causes kaliuretic and chloriduretic effects with gender-related differences in rats. Further investigations are necessary to elucidate the mechanism of such pharmacological effects of NaVPA.

Influence of sodium valproate on sodium and chloride urinary excretion in rats, gender differences.

Evidence exists indicating that sodium valproate (VPA) increases diuresis in rats. The chloriuretic and natriuretic effect of VPA has not previously been investigated, so the aim of the present study was to define the peculiarities of 24-hour urinary sodium (Na) and chloride (Cl) excretion in young adult Wistar rats of both genders, and to evaluate the effects of VPA. 24-hour urinary Na, Cl, creatinine and pH levels were measured in 28 control intact Wistar rats and 26 Wistar rats after a single intragastric administration of 300 mg/kg VPA. After VPA administration, 24-hour diuresis and 24-hour diuresis per 100 g of body weight were significantly higher in VPA rats of both genders. 24-hour urine Na and Cl excretion were significantly higher in VPA male and VPA female rats than in gender-matched controls. The 24-hour urinary Cl excretion was found to be significantly higher in VPA male than in VPA female rats. The study data show that VPA, alongside the diuretic effect, enhances Na and Cl excretion with urine. The 24-hour chloriuretic response to VPA in male rats was significantly higher than in female rats. The mechanism of such a gender-related effect is not yet clear.

Possible association between cell membrane band 3 impairment function and renal tubular acidosis (liver diseases, malignancies and adverse drug reactions).

Renal tubular acidosis (RTA) more frequently develops in case of chronic diseases of inflammatory-immunological origin. RTA is well known to be associated with chronic liver disease (CLD), with nephrolithiasis, common cases of RTA occur among cancer patients. Abnormalities in the expression or function of band 3 in cell membrane may play a role in the pathogenesis of RTA. Cl-/HCO3- anion exchanger (AE2) is an isoform of band 3 protein, which is expressed in cell membranes of organs such as liver cells and kidney endothelium. There are reports on downregulated AE2 immunoreactivity in the liver of patients with chronic liver diseases and in the kidney tubular tissue of patients with RTA. The proteolytic damage of cell membrane band 3 in tissues could be related to inflammatory-immunological processes. Another important factor able to disturb the band 3 function is medicinal products used in the treatment of certain pathologies. The active substance of a drug itself may have a direct effect on this protein or trigger a pathological process. In such cases ADR can take place and may be evaluated as such. Acid-base disturbances, notably metabolic acidosis, are a serious complication of drug treatment. Reduced AE2 expression or its changed activity (congenital or acquired) could be related with alterations of intracellular pH. This could lead to antigenic changes and autoimmunity. The derangement of band 3 function in organ cell membrane could act as a factor which creates an "acidotic environment" for organ cells. Such circumstances could be the reason for unsuccessful treatment or determine resistance of tumor treatment. The understanding of the mechanisms of RTA development, early diagnostics, and knowledge of the drugs that can cause RTA, are of particular practical significance.