Pharmacokinetics and Bioequivalence of Two Formulations of Rosuvastatin Following Single-dose Administration in Healthy Chinese Subjects Under Fasted and Fed Conditions.

The main objective of the study was to evaluate the bioequivalence of two rosuvastatin calcium tablets in healthy Chinese subjects under fasted and fed conditions. The study was carried out using a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design, with a washout period of 7 days. Both the fasted study and fed study enrolled 28 subjects. In each study period, the subjects were administrated a single oral dose of the test product or reference product of rosuvastatin 10 mg. Blood samples were collected from pre-dose to 72 hours after administration with 16 time points in total. Bioequivalence evaluation was performed using ln-transformed pharmacokinetic parameters of rosuvastatin, including Cmax , AUC0-t , and AUC0-∞ . In the present study, 95% confidence intervals (CIs) of test/reference geometric mean ratios (GMRs) of Cmax , AUC0-t , and AUC0-∞ under the fasted and fed conditions were all within the acceptance range of 80%-125%. Additionally, only one subject experienced one adverse event (AE). High-fat meals reduced the Cmax , AUC0-t , and AUC0-∞ , but had no significant effects on the λz, t1/2 , or Tmax of rosuvastatin. In the current study, the test product was bioequivalent to the reference product, and a single dose of rosuvastatin (10 mg) was well-tolerated. Food decreased the systemic exposure of rosuvastatin without the effects on the Tmax or elimination rate.

Pharmacokinetics and bioequivalence study of two ciprofloxacin hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover study.

OBJECTIVE: The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under fasting and fed conditions. MATERIALS AND METHODS: The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg ciprofloxacin hydrochloride. Blood samples were collected from 1 hour before dosing to 36 hours after administration with 16 timepoints in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 48 subjects were enrolled in the fasting and fed studies, and 1 of the subjects was excluded before drug administration. In the fasting study, the 90% CIs for the test/reference geometric mean ratios (GMRs) of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 85.41 - 100.97%, 95.40 - 100.27%, and 95.48 - 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 90.15 - 113.75%, 99.10 - 103.77%, and 99.11 - 103.80%, respectively. These values all fell within the standard acceptance range of 80 - 125%. CONCLUSION: In the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after single-, oral-dose administration under fasting and fed conditions.

Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension.

BACKGROUND: Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown. OBJECTIVES: To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension. SEARCH METHODS: The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis. MAIN RESULTS: We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non-diabetic patients, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear. OBJECTIVES: To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies with at least six months follow-up in people with primary elevated blood pressure (≥130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. Patients with proven secondary hypertension were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis. MAIN RESULTS: We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were all-cause death, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), fatal and non-fatal congestive heart failure (CHF) requiring hospitalization, total cardiovascular (CV) events (consisted of fatal and non-fatal stroke, fatal and non-fatal MI and fatal and non-fatal CHF requiring hospitalizations), and ESRF. Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).Compared with first-line calcium channel blockers (CCBs), we found moderate quality evidence that first-line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, RR 0.83, 95% CI 0.77 to 0.90, ARR 1.2%), and moderate quality evidence that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, ARI 0.7%). They had similar effects on all-cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09; moderate quality evidence), total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02; moderate quality evidence), total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09; moderate quality evidence). The results for ESRF do not exclude potentially important differences (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05; low quality evidence).Compared with first-line thiazides, we found moderate quality evidence that first-line RAS inhibitors increased HF (24,309 participants in 1 RCT, RR 1.19, 95% CI 1.07 to 1.31, ARI 1.0%), and increased stroke (24,309 participants in 1 RCT, RR 1.14, 95% CI 1.02 to 1.28, ARI 0.6%). They had similar effects on all-cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07; moderate quality evidence), total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11; moderate quality evidence), and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01; moderate quality evidence). Results for ESRF do not exclude potentially important differences (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37; low quality evidence).Compared with first-line beta-blockers, we found low quality evidence that first-line RAS inhibitors decreased total CV events (9239 participants in 2 RCTs, RR 0.88, 95% CI 0.80 to 0.98, ARR 1.7%), and low quality evidence that they decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Our analyses do not exclude potentially important differences between first-line RAS inhibitors and beta-blockers on all-cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01; low quality evidence), HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18; low quality evidence), and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27; low quality evidence).Blood pressure comparisons between RAS inhibitors and other classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.In the protocol, we identified non-fatal serious adverse events (SAE) as a primary outcome. However, when we extracted the data from included studies, none of them reported total SAE in a manner that could be used in the review. Therefore, there is no information about SAE in the review. AUTHORS' CONCLUSIONS: We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents. First-line thiazides caused less HF and stroke than first-line RAS inhibitors. The quality of the evidence comparing first-line beta-blockers and first-line RAS inhibitors was low and the lower risk of total CV events and stroke seen with RAS inhibitors may change with the publication of additional trials. Compared with first-line CCBs, first-line RAS inhibitors reduced HF but increased stroke. The magnitude of the reduction in HF exceeded the increase in stroke. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes.