Coadministration Of Hydrochlorothiazide Research Articles

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. ClinicalTrials.gov NCT06083116.

DESIGN AND DEVELOPMENT OF TOPICAL HYDROGEL FORMULATION OF IRBISARTAN

Objective: Irbesartan is an antihypertensive with limited bioavailability. The objective of the study was to develop controlled release matrix tablets of irbisartan drug.
 Methods: Tablets were prepared by wet granulation process. Result: In vitro drug release study revealed that HPMC causes initial burst release of drug hence combining HPMC sustained the action for 8 h (95.92±0.57% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism for drug release. Compared to conventional tablets, the release of model drug from these HPMC matrix tablets was prolonged, leading to achieve an effective therapy with a low dosage of the drug, to reduce the frequency of medication. The pharmacological and clinical properties of irbesartan, a noncompetitive angiotensin II receptor type 1 antagonist, successfully used for more than a decade in the treatment of essential hypertension.
 Results: Compatibility Studies In order to investigate the possible interactions between irbesartan and distinct polymers and/or diluents, FT-IR and DSC studies were carried out. FT-IR results proved that the drug was found to be compatible with excipients as wave numbers are almost similar for pure drug and also drug excipients mixture. In picture 1 and 2. DSC studies indicate that chosen excipients for the formulation were found to be compatible with the active ingredient as the melting endothermic peaks are in the range of 250-320 °C which is same as the melting point of irbisartan.
 Conclusion: Irbesartan exerts its antihypertensive effect through an inhibitory effect on the pressure response to angiotensin II. Irbesartan 150–300 mg once daily confers a lasting effect over 24 h, and its antihypertensive efficacy is further enhanced by the coadministration of hydrochlorothiazide.

Pharmacokinetic Interactions of Valsartan and Hydrochlorothiazide: An Open-Label, Randomized, 4-Period Crossover Study in Healthy Egyptian Male Volunteers

BackgroundCo-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. ObjectiveThis study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. MethodsThis study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. ResultsForty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. ConclusionsBoth VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.

Long-term use and tolerability of irbesartan for control of hypertension

In this review, we discuss the pharmacological and clinical properties of irbesartan, a noncompetitive angiotensin II receptor type 1 antagonist, successfully used for more than a decade in the treatment of essential hypertension. Irbesartan exerts its antihypertensive effect through an inhibitory effect on the pressure response to angiotensin II. Irbesartan 150–300 mg once daily confers a lasting effect over 24 hours, and its antihypertensive efficacy is further enhanced by the coadministration of hydrochlorothiazide. Additionally and partially beyond its blood pressure-lowering effect, irbesartan reduces left ventricular hypertrophy, favors right atrial remodeling in atrial fibrillation, and increases the likelihood of maintenance of sinus rhythm after cardioversion in atrial fibrillation. In addition, the renoprotective effects of irbesartan are well documented in the early and later stages of renal disease in type 2 diabetics. Furthermore, both the therapeutic effectiveness and the placebo-like side effect profile contribute to a high adherence rate to the drug. Currently, irbesartan in monotherapy or combination therapy with hydrochlorothiazide represent a rationale pharmacologic approach for arterial hypertension and early-stage and late-stage diabetic nephropathy in hypertensive type II diabetics.

Torasemide significantly reduces thiazide-induced potassium and magnesium loss despite supra-additive natriuresis

Resistance to high-dose loop diuretics can be overcome either by co-administration with thiazides or by treatment with medium-dose loop diuretics combined with thiazides. Combination therapy has been proven to be superior to high-dose loop diuretic monotherapy for cardiac and renal edema. However, such a strongly efficacious short-term regimen is often complicated by undesired effects, including circulatory collapse and electrolyte disturbances. The question of whether the loop diuretic/thiazide combinations are efficacious and safe when conventional doses are combined has not yet been answered. The effects of hydrochlorothiazide (HCT) and torasemide (TO) given alone on the excretion of Na+, Cl-, K+, Mg2+, and Ca2+ were compared with the effects of combined administration of the diuretics in 12 healthy volunteers. The co-administration of HCT (25 mg) with TO (5 or 10 mg) strongly increased Na+ excretion. However, the combination significantly reduced K+ and Mg2+ excretion. The K+-sparing effect of the HCT/TO combination was shown to be due to a significant reduction in the HCT-induced increase in fractional K+ excretion by the loop diuretic. Total excretion of Ca2+ relative to Na+ excretion was less with the HCT/TO combination than with TO given alone. The enhancement of desired NaCl excretion by the HCT/TO combination with significant reduction of undesired loss of K+ and Mg2+ meets clinical requirements but has to be validated in long-term clinical trials.

Effects of Valsartan and Hydrochlorothiazide Alone and in Combination on Blood Pressure and Heart Rate in Conscious-Telemetered Spontaneously Hypertensive Rats (SHR)

The purpose of this study was to examine the effectiveness of combined administration of the angiotensin AT 1 receptor antagonist valsartan, with the diuretic hydrochlorothiazide (HCTZ), on blood pressure in conscious spontaneously hypertensive rats (SHR). Both drugs were administered continuously via subcutaneously implanted osmotic minipumps alone or in combination for a period of 2 weeks. Mean arterial pressure and heart rate were monitored throughout the infusion interval by means of chronically-implanted radiotransmitters. Coadministration of a diuretic with valsartan potentiated the blood pressure lowering effect in conscious SHR. Responses varied in magnitude from additive (valsartan at 1 mg/kg/day + hydrochlorothiazide at 3 and 10 mg/kg/day) to synergistic (valsartan at 3 mg/kg/day + hydrochlorothiazide at 10 mg/kg/day). The greater blood pressure lowering seen in SHR receiving combination therapy was associated with only a transient increase in heart rate. A similar potentiation of the antihypertensive effect was seen during coadministration of hydrochlorothiazide (HCTZ) with the angiotensin converting enzyme inhibitor benazeprilat. Additivity was noted with benazeprilat at 1 mg/kg/day + hydrochlorothiazide at 3 mg/kg/day, whereas a higher dose of HCTZ resulted in a synergistic response. These findings suggest that the similar results obtained with angiotensin converting enzyme inhibitors and AT 1 receptor antagonists are due to the capacity to which diuretic-induced activation of the renin angiotensin system occurs.

Hemodynamic and Humoral Effects of the Angiotensin II Antagonist Losartan in Essential Hypertension

Losartan (DuP 753) is a novel orally active angiotensin II antagonist that lowers blood pressure. The present study evaluates the hemodynamic and humoral effects of losartan in essential hypertension. Fifteen patients (12 men, 3 women; mean age, 46 +/- 2 years; range, 33 to 64 years) with a diastolic blood pressure (DBP) between 95 and 115 mm Hg after 2 weeks of placebo participated in the study. Initially the patients were treated with losartan (50 mg) once daily for 1 month. Then, if the trough DBP was > or = 93 mm Hg, hydrochlorothiazide (HCTZ), 6.25 to 12.5 mg daily, and nifedipine, 30 to 60 mg daily, were added as needed. Ten patients completed 12 months of treatment. Trough blood pressure, heart rate, plasma creatinine, potassium, uric acid, cholesterol, renin activity (PRA), aldosterone, and norepinephrine were measured at baseline and after 1 and 12 months of treatment. Losartan lowered mean arterial pressure significantly from 119 +/- 2 mm Hg at baseline to 113 +/- 2 mm Hg (P < .05) after 1 month of treatment. Coadministration of HCTZ and nifedipine further decreased the mean arterial pressure to 103 +/- 2 mm Hg after 12 months of treatment. Plasma levels of creatinine, potassium, uric acid, cholesterol, and norepinephrine remained unchanged. PRA increased and plasma aldosterone decreased significantly (P < .05). The decrease in mean arterial pressure was related to baseline PRA (r = 0.53, P < .05). and to the change in PRA (r = 0.52, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of triamterene in geriatric patients — influence of piretanide and hydrochlorothiazide

Pharmacokinetics of triamterene (single oral dose of 50 mg) and its pharmacologically active metabolite (OH-TA-ester) were determined in 20 geriatric patients with multiple diseases. Mean peak concentration of triamterene was increased in the elderly patients compared with the data of young healthy volunteers. Coadministration of piretanide seems to lower the mean plasma concentration (AUC) and the mean concentration after 24 h of triamterene as compared with the coadministration of hydrochlorothiazide.

The Clinical Pharmacology of Lisinopril

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.