Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize permeability of captopril oral films.

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.

Comparing different treatment schedules of Zomen (zofenopril).

BACKGROUND: Chronotherapy of hypertension became, during the last years, a main target in optimal BP values control, during 24 hours. Many clinical studies have demonstrated a different effect on blood pressure of the majority of angiotensin-converting enzyme inhibitors (ACEIs), studied as function of the moment of their administration. Until now, the majority of clinical proofs sustain the greater benefit offered by bedtime administration of ACEIs, concerning especially a significantly greater efficacy in reducing BP during the asleep period, thus increasing the prevalence of "dippers", the circadian profile considered to offer the best cardio-vascular prognosis, compared to at awakening administration. MATERIALS AND METHODS: This study investigated time-dependent effects of zofenopril (Zomen, 30 mg, Berlin-Chemie, Menarini Group, Romania) administration on ambulatory blood pressure values. We studied 33 consecutive untreated hypertensive patients (19 men, 14 women), 56 +/- 12.7 years old, with grade 1 or 2 uncomplicated essential hypertension (according to the European Society of Hypertension-European Society of Cardiology guidelines) (diagnostic formulated by casual determination and confirmed by an ABPM session at baseline), using zofenopril as monotherapy. The drug was initially administered in a single dose, at bedtime, during one month; after that period, we performed for all of them a new ABPM session, and, after that, for another month we administered the same drug, in single dose, at awakening. Blood pressure was measured for 48 hours before and after one month of treatment. RESULTS: The blood pressure reduction during diurnal activity was similar for both treatment schedules. Bedtime administration of zofenopril, however, was significantly more efficient than at awakening administration in reducing asleep blood pressure. The awake:asleep blood pressure ratio was decreased after zofenopril on awakening but significantly increased towards a more dipping pattern, (from 60.60% to 90.90%) after at bedtime administration. The proportion of patients with controlled ambulatory BP increased from 51.51% to 84.84% (p < 0.001) by bedtime administration. CONCLUSIONS: Nocturnal blood pressure regulation is significantly better achieved at bedtime as compared with at awakening administration of zofenopril, without any loss in efficacy during diurnal active hours; this might be clinically important, because nighttime blood pressure has been shown to be a more relevant marker of cardiovascular risks than diurnal mean values. The change in the dose-response curve, the increased proportion of controlled patients, and improved efficacy on nighttime BP values by bedtime administration of zofenopril should be taken into account when prescribing this ACEI for treatment of essential hypertension.

Curso de Atualização em emergências médicas: aula 2: Urgências e emregências hipertensivas / Medical emergencies actualization course: class 2: hypertensive urgencies and emergencies

A hipertensão arterial é uma condição clínica com alta prevalência em todo o mundo, sendo fundamental estar atento às suas possíveis complicações. As emergências hipertensivas são condições associadas a risco iminente de vida, associadas à perda rápida da função de órgãos-alvo. Nesses casos a redução da pressão arterial deve ser imediata, em horas ou minutos. Nas urgências hipertensivas esse risco também existe, mas a redução da pressão arterial pode ser mais gradual, em cerca de 24 horas.

Quantum dot as a drug tracer in vivo.

Quantum dots (QDs) have been applied to a wide range of biological studies by taking advantage of their fluorescence properties. There is almost no method to trace small molecules including medicine. Here, we used QDs for fluorescent tracers for medicine and analyzed their kinetics and dynamics. We conjugated QDs with captopril, anti-hypertensive medicine, by an exchange reaction while retaining the medicinal properties. We investigated the medicinal effect of QD-conjugated captopril (QD-cap) in vitro and in vivo. We also evaluated the concentration and the distribution of the QD-cap in the blood and the organs with their fluorescence. We demonstrate that the QD-cap inhibits the activity of ACE in vitro. The QD-cap reduced the blood pressure of hypertensive model rats. The concentration of the QD-cap in the blood was measured by using the standard curve of the fluorescence intensity. The blood concentration of the QD-cap decrease exponentially and QD-cap has approximately the same half-life as that of captopril. In addition, the fluorescence of the QDs revealed that QD-cap accumulates in the liver, lungs, and spleen. We succeeded in analyzing the dynamics and kinetics of small molecules using fluorescence of QDs.

Effect of chronic exercise and Angiotensin-converting enzyme inhibition on rodent thoracic aorta.

Vascular reactivity can be modulated by local physical factors as well as pharmacologic manipulations. The aim of this study was to evaluate the effects of chronic exercise (EX) with or without the ACEI captopril (CAP) on vascular reactivity. Sixty-four Sprague-Dawley male rats were randomized into 4 groups (n = 16): group 1, control; group 2, captopril; group 3, exercise; and group 4, exercise and captopril. After 10 weeks of treatment, rats were killed, and their thoracic aortas harvested. Vascular reactivity was studied in an organ chamber (n = 12). Aortic endothelium constitutive nitric oxyde synthase (NOS3) expression was determined by Western blot analysis (n = 4). Endothelial-dependent relaxation was increased in both CAP and EX rats relative to the control group. Maximal aortic relaxations were enhanced in the CAP group, and potencies of these mediators were enhanced in the EX group (P < 0.05 versus control). Combined treatment did not result in a synergistic effect. NOS3 relative expressions were: group 1, 100%; group 2, 241%; group 3, 64%; and group 4, 108%. Exercise enhanced both potencies and efficacies of the mediators studied, whereas CAP increased mainly their efficacies. NOS3 protein expression was up-regulated in CAP-treated rats but not in exercised rats. These findings suggest different mechanisms for the observed increased vascular reactivity.

Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers.

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo, propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85-100 degrees C, relative humidity 25-35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng.ml-1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0-5h (119 vs 71 micrograms.h.l-1) of propranolol from 0 to 5 hours tmax, t1/2 beta and AUC0-24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase.(ABSTRACT TRUNCATED AT 250 WORDS)