Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.

Comparison of the effects of parecoxib and diclofenac in preemptive analgesia: A prospective, randomized, assessor-blind, single-dose, parallel-group study in patients undergoing elective general surgery.

BACKGROUND: Preoperative administration of analgesics may prevent or reducehyperalgesia, inhibit inflammation, and reduce pain by reducing the synthesis of prostaglandins in response to tissue damage caused by surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a potent, widely used class of analgesic agents; however, they may not be as effective as selective cyclooxygenase (COX)-2 inhibitors. OBJECTIVE: The aim of this study was to compare the efficacy and tolerabilityof the COX-2 inhibitor parecoxib sodium and the NSAID diclofenac sodium as preemptive analgesics in patients undergoing elective general surgery. METHODS: This was a prospective, randomized, assessor-blind, single-dose,parallel-group, comparative trial. Patients aged 18 to 65 years undergoing elective general surgery were enrolled. A single IM injection of parecoxib 40 mg or diclofenac 75 mg was administered 30 to 45 minutes before the induction of anesthesia. Surgery was performed as per standard protocol. The primary measures of efficacy were pain intensity score (measured on a visual analog scale [VAS]), pain relief score, duration of analgesia, and platelet aggregation response to adenosine diphosphate. Tolerability assessment included monitoring of treatment-emergent adverse events (AEs), physical examination, laboratory analysis, electrocardiography, and chest radiography. RESULTS: Eighty patients (56 men, 24 women; mean [SD] age, 45.96 [12.83] years) were enrolled in the study (40 patients per treatment group). All patients completed the trial. No pain was reported by any patient in the parecoxib group up to 12 hours; in the diclofenac group, no pain was reported up to 6 hours. At 12 hours, the mean (SD) VAS score was 2.33 (1.39) (moderate pain) in the diclofenac group and 0 (no pain) in the parecoxib group (P < 0.05). At 12 hours, total pain relief was reported by all 40 patients (100.0%) in the parecoxib group but by none (0.0%) in the diclofenac group, and 2 patients in the diclofenac group (5.0%) reported good pain relief (between-group difference for total + good pain relief, P < 0.05). Mean (SD) duration of analgesia was significantly longer in the parecoxib group than in the diclofenac group (19.48 [5.61] hours vs 8.32 [4.11 ] hours; P < 0.05). Platelet aggregation was significantly inhibited in the diclofenac group (change from baseline, 64.0%) but not in the parecoxib group (change from baseline, 12.0%) (P < 0.05). Both regimens were well tolerated, and no AEs were reported. CONCLUSIONS: In this study of patients undergoing elective general surgery,patients treated with the COX-2 specific inhibitor parecoxib experienced no pain at 12 hours, and the treatment was well tolerated. The results of this study suggest that good postoperative analgesia and minimal interference with platelet function may make parecoxib an alternative to the nonselective NSAID diclofenac in providing preemptive analgesia in patients undergoing general surgery.

Amlodipine/valsartan single-pill combination: a prospective, observational evaluation of the real-life safety and effectiveness in the routine treatment of hypertension.

INTRODUCTION: As several international guidelines on hypertension have now recommended, single-pill/fixed-dose combination antihypertensive therapies may be particularly beneficial as first-line therapy in high-risk patients, in whom more rapid and pronounced blood pressure (BP) control is desired. Upon the single-pill combination of amlodipine and valsartan becoming available, the authors conducted this international, observational study to evaluate its efficacy and safety in a real-life practice setting. METHODS: This prospective, open-label, postmarketing surveillance study enrolled adults with arterial hypertension (systolic BP >140 mmHg and/or diastolic BP >90 mmHg) who were prescribed antihypertensive therapy with single-pill combination amlodipine/valsartan 5/80, 5/160, or 10/160 mg once daily. Patients were observed over a 3-month period (12 weeks) with approximately monthly intervals between clinic visits. RESULTS: A total of 8336 patients completed all study visits and were included in the efficacy analysis. Mean age was 54.7 years and 83.4% of patients had received prior antihypertensive therapy. BP reductions were dose related. Overall, mean BP was reduced from 165.0/99.3 mmHg at baseline to 128.7/80.4 mmHg at 12 weeks (36.3/18.9 mmHg; P<0.0001). The magnitude of BP reduction rose with increasing severity of baseline BP. Control of BP (<140/90 mmHg) was achieved in 77.7% of patients. Efficacy was consistent in subgroups of patients with comorbidities and regardless of whether patients were previously treated with monotherapy or combination therapy. Adverse events were reported in 5.3% of patients. The incidence of edema declined from 10.4% at baseline to 8.5% at study end. CONCLUSION: Single-pill combination amlodipine/valsartan safely and effectively reduced BP across all hypertension grades and allowed the vast majority of patients to achieve BP goals.

Real-life safety and effectiveness of amlodipine/valsartan combination in the treatment of hypertension.

INTRODUCTION: The aim of our study was to evaluate the safety and effectiveness of the free combination of amlodipine/valsartan in patients with arterial hypertension in a real-life setting. METHODS: This was a multicenter, open-label, observational, noninterventional, postmarketing surveillance study conducted in 298 centers in China, Malaysia, Pakistan, Bangladesh, Egypt, and Russia. We evaluated changes in heart rate, systolic and diastolic office blood pressure (BP), as well as BP control rate (<140/90 mmHg) overall, and in clinically relevant subgroups of hypertensive patients (BP >140/90 mmHg) after 12 weeks of treatment with 5/10 mg amlodipine and 80/160 mg valsartan combination. RESULTS: Two thousand seven hundred and eighty-five patients with arterial hypertension were enrolled, 52 discontinued (eight due to adverse events), and four patients' data were missing. In total, 2729 patients completed the study: mean age 57.9 years, 54.5% men, 54.2% Asian, 44.6% Caucasian; 86.5% had prior hypertension treatment (which was discontinued), baseline BP was 163.1/96.2 mmHg. The significant reduction in BP (-33.2/-16.9 mmHg, P<0.0001) was achieved with amlodipine/valsartan treatment resulting in a final BP of 129.9/79.3 mmHg. A dose-dependent effect was observed with the least BP reduction for 5/80 mg (-29.2/-15.1 mmHg, P<0.0001) and the greatest for the 10/160 mg dose regimen (-43.6/-22.4 mmHg, P<0.0001). Treatment response increased with increasing initial severity of hypertension with the least BP reduction in patients with baseline grade 1 hypertension BP level (SBP 140-159 mmHg): -20.0/-13.4 mmHg, P<0.0001, and the greatest BP drops observed in grade 3 hypertensive patients with baseline systolic BP over 200 mmHg: -73.1/-26.3 mmHg, P<0.0001. Patients with isolated systolic hypertension had BP reductions of -24.2/-4.8 mmHg, P<0.0001. CONCLUSION: An optimal BP reduction was achieved for all hypertension grades as well as isolated systolic hypertension, providing evidence that most hypertensive patients may benefit from amlodipine/valsartan combination treatment.

Efficacy, safety, and tolerability of valsartan/hydrochlorothiazide in Asian patients with essential hypertension.

INTRODUCTION: Previous studies have demonstrated that hypertensive patients need concomitant therapy with one or more drugs from different classes of antihypertensive agents to achieve their blood pressure control targets. We performed the first multinational observational study of valsartan/hydrochlorothiazide (HCTZ) single pill combination in Asia to determine the efficacy, safety, and tolerability in hypertensive patients. The objective of this multinational, multicenter, 24-week follow-up observational study is to evaluate the efficacy, safety, and tolerability of valsartan/hydrochlorothiazide single pill combination in the treatment of essential hypertension in the Asia-Pacific region. METHODS: A total of 7567 Asian patients who were diagnosed with stage 1 or stage 2 essential hypertension and who took at least one dose of valsartan/hydrochlorothiazide single pill combination were included in the statistical analyses. A total of 59% were taking antihypertensive medication at the time of the study. Eligible patients received valsartan/hydrochlorothiazide single pill combination 80/12.5 mg tablets orally once daily at visit 1. The investigator could decide the subsequent dose of valsartan/hydrochlorothiazide single pill combination for their patients, and efficacy, safety, and tolerability data were collected at week 4, 12, and 24. RESULTS: Basal blood pressure was 155.9±13.3 mmHg (systolic) and 96.3±10.1 mmHg (diastolic). Response rates and control rates increased continuously from baseline to the study endpoint at week 24, when they reached 94.6% and 73.2%, respectively. Systolic and diastolic blood pressure reductions were -25.4±15.2 mmHg and -14.9±13.5 mmHg, respectively (P<0.001). Using a four-point global assessment scale, 96.8% of the patients and physicians reported good, very good, or excellent for both their subjective efficacy and tolerability assessments. CONCLUSION: In this multicenter, multicountry study including 7567 Asian patients with hypertension, valsartan/hydrochlorothiazide single pill combination was found efficacious, well tolerated, and devoid of any serious adverse effects.

Comparison of the efficacy, safety and tolerability of telmisartan with losartan in Indian patients with mild to moderate hypertension: a pilot study.

A prospective, randomised, double-blind, parallel group study was carried out to compare the efficacy, safety and tolerability of telmisartan 40 mg once daily with losartan 50 mg once daily in Indian patients with mild to moderate hypertension. It had a placebo run-in period of 2 weeks followed by drug treatment (telmisartan 40 mg, once daily or losartan 50 mg once daily) for 8 weeks. Supine BP was assessed at the end of every 2 weeks. Tolerability and safety was assessed by physical examination, laboratory parameters and evaluation of adverse events. Treatment with telmisartan resulted in a significant reduction of SBP of 10.3% and 13.7% as compared to 6.6% and 10.6% in losartan group at the end of 6th and 8th weeks respectively. At the end of 6th and 8th weeks, the reduction was 14.3% and 18.1% among telmisartan which was significantly more as compared to 8.8% and 14.3% in losartan group respectively. The laboratory values were within normal limits. Both drugs were well tolerated. Telmisartan monotherapy in a dose of 40 mg once daily has a clinically better therapeutic effect as compared to losartan 50 mg and a good tolerability profile in patients with mild to moderate hypertension.

Evaluation of the efficacy, safety and tolerability of valdecoxib gel (1%) in adult patients with painful inflammatory joint disease.

Valdecoxib, a COX-2 inhibitor, has recently been introduced as a gel formulation. The present study was conducted to evaluate the efficacy, safety and tolerability of valdecoxib gel in adult patients with painful inflammatory joint conditions. The present study was a 10-day prospective, open, multicentric (6 centres) trial. Patients with clinical and radiological diagnosis of painful inflammatory joint conditions were treated with valdecoxib gel (1%). Efficacy was assessed by visual analogue scale (VAS), patient's and physician's global assessment of pain relief. Grading of associated clinical manifestations such as stiffness, swelling, tenderness and restriction of mobility was done. Tolerability and safety was assessed by physical examination, laboratory parameters and evaluation of adverse events. There was a statistically significant decrease in the mean pain visual analogue score (p<0.05). Onset of pain relief was within 15 minutes. There was a reduction of 58.8%, 57.2%, 65.4% and 60.2% in mean scores of stiffness, swelling, tenderness and mobility respectively from the baseline which was statistically significant. The laboratory values were within normal limits. The drug was well tolerated. There was no report of any hypersensitivity reaction. This study confirms that valdecoxib gel (1%) is an effective and safe option for the management of painful inflammatory joint conditions.

Efficacy and safety of the first parenteral selective COX-2 inhibitor, parecoxib sodium, in adult patients with postoperative pain.

Parecoxib, a prodrug of valdecoxib, a selective COX-2 inhibitor, has been recently introduced for the treatment of moderate to severe postoperative pain. This prospective, open, multicentric study enrolled 260 patients undergoing orthopaedic, gynaecological, dental and general surgery. Postoperatively, patients were treated with parecoxib, 40 mg IM/IV. There was a statistically significant decrease in the mean pain intensity score (p<0.05). At the end of 24 hours, 89.6% of total cases had a very good to total relief of pain. The mean duration of analgesia was 19.26 hours and mean time of onset of analgesia was 16.25 minutes ranging from 11-20 minutes. The laboratory values were within normal limits. The drug was well tolerated. There was no report of any hypersensitivity reaction. This study suggests that parecoxib, in a dose of 40 mg IM/IV, is an effective and safe option for the management of postoperative pain.