The effect of alcohol on ionizing and non-ionizing drug release from hydrophilic,lipophilic and dual matrix tablets

The aim of this work was to investigate and quantitatively evaluate the effect of presence of alcohol on in vitro release of ionizing and non-ionizing drug from hydrophilic, lipophilic and hydrophilic-lipophilic matrix tablets. The Food and Drug Administration (FDA) recommends in vitro dissolution testing of extended release formulations in ethanolic media up to 40% because of possible alcohol-induced dose dumping effect. This study is focused on comparison of the dissolution behavior of matrix tablets (based on hypromellose and/or glyceryl behenate as retarding agent) of the same composition containing different type of drug – ionizing tramadol hydrochloride (TH) and non-ionizing pentoxifylline (PTX). The dissolution tests were performed in acidic medium (pH 1.2) and in alcoholic medim (20%, 40% of ethanol) and the changes of tablets were observed also photographically.It was found that the alcohol resistence of the hydrophilic-lipophilic formulations with TH and the hydrophilic-lipophilic formulations with PTX containing a higher amount of hypromellose does not reflect the alcohol resistence of the formulations with pure hypromellose or glyceryl behenate. Both hydrophilic-lipophilic formulation with TH and more lipophilic formulation with PTX show significant alcohol dose dumping effect.     

PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor

Objective

To investigate if PACAP and VIP have an effect on CGRP release or NOS activity in the trigeminal ganglion and trigeminal nucleus caudalis and if there can be a difference in effect between PACAP and VIP on these two systems. Furthermore, we investigate if PACAP co-localize with CGRP and/or nNOS in the two tissues.

Background

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide-38 (PACAP-38) partially share receptors and are both potent vasodilators. However, PACAP-38 but not VIP is an efficient inducer of migraine attacks in migraineurs. Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are two signaling molecules known to be involved in migraine.

Methods

Rat tissue was used for all experiments. Release of CGRP induced by VIP and PACAP in dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) was quantified by EIA. Regulation of NOS-enzymes caused by VIP and PACAP was investigated in dura mater, TG and TNC by measuring the conversion of l-[³H]arginine to l-[³H]citrulline. Co-expression of PACAP, neuronal nitric oxide synthase (nNOS) and CGRP was explored by immunohistochemistry in TG and TNC. mRNA expression studies of VPAC₁, VPAC₂ and PAC₁-receptors were performed by qRT-PCR.

Results

PACAP-38 administered in increasing concentrations caused a concentration-dependent CGRP-release in the TNC, but not in TG. VIP was without effect in both tissues examined. The PAC₁ receptor agonist maxadilan had no effect on CGRP release and the PAC₁ antagonist M65 did not inhibit PACAP-38 induced CGRP release. PACAP-38 or VIP did not affect NOS activity in homogenates of TG and TNC. Quantitative PCR demonstrated the presence of VPAC₁, VPAC₂ and PAC₁ receptors in TG and TNC. Immunohistochemistry of PACAP and CGRP showed co-expression in TG and TNC. PACAP and nNOS were co-localized in TG, but not in TNC. PACAP was found to co-localize with glutamine synthetase in TG satellite glial cells.

Conclusion

PACAP-38 cause release of CGRP from TNC but not from TG. We suggest that the release is not caused via activation of PAC₁, VPAC₁ or VPAC₂ receptors. PACAP has no effect on NOS activity in TG or TNC. In TG PACAP was found in neuronal cells and in satellite glial cells. It co-localized with CGRP and nNOS in the neuronal cells. In TNC PACAP was co-localized with CGRP but not with nNOS.     

Ambulatory blood pressure,left ventricular mass,and conduit artery function late after successful repair of coarctation of the aorta

OBJECTIVES: We sought to evaluate the determinants of hypertension during daily life and left ventricular (LV) hypertrophy in patients with successfully repaired coarctation of the aorta (CoA), as well as their relationship to abnormalities of arterial function. BACKGROUND: Arterial hypertension may recur late after repair of CoA, which is related to a more adverse outcome. Furthermore, patients with normal resting blood pressure (BP) may have hypertension during daily life and LV hypertrophy. The determinants of these two adverse prognostic factors have not been investigated. METHODS: We studied 72 patients (9 to 58 years of age) who underwent coarctation repair at age 0.1 to 480 months (42 [60%] at <1 year) and had been followed up for 155 +/- 76 months. They underwent ambulatory BP monitoring, echocardiography for LV mass, studies of brachial artery responses to flow (i.e., flow-mediated dilation [FMD]) and glyceryl trinitrate (GTN), and determination of pulse wave velocity (PWV) and measures of arterial reactivity and stiffness. Findings were compared with those of 53 healthy volunteers. RESULTS: Patients had higher 24-h systolic BP and LV mass than controls. Both endothelium-dependent FMD and the response to the smooth muscle dilator GTN were reduced, and PWV was increased. There was a negative independent correlation between GTN response and 24-h systolic BP in both patients and control subjects. Systolic BP at 24 h was an independent predictor of LV mass, having an accentuated impact in coarctation subjects as compared with controls. CONCLUSIONS: In patients with repaired coarctation, reduced vascular reactivity is associated with hypertension during daily life and with increased LV mass, both of which are important predictors for late morbidity and mortality.     

Early vascular abnormalities and de novo nitrate tolerance in diabetes mellitus

Objective: The haemodynamic consequence of altered mechanical wall properties in diabetes can impair the compliance characteristics or pulsatile function of arteries before changes in calibre or peripheral resistance become evident. We studied the sensitivity of pulsatile and steady-state haemodynamic variables in identifying vascular abnormalities and assessing arterial responsiveness to glyceryl trinitrate (GTN) in patients with diabetes, free from clinical complications of the disease.
Methods: Radial artery pressure waveforms were recorded in 22 patients with diabetes and 22 age- and sex-matched control subjects, using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was used to quantify changes in arterial waveform morphology in terms of pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. Pressure pulse waveforms were recorded before and 3, 6 and 9 min after the administration of 300 µg of GTN.
Results: Of the pulsatile and steady-state impedance parameters, only small artery compliance was significantly different in patients, 4.7 ml/mmHg (95% CI 3.8–5.8), compared with control subjects 7.1 ml/mmHg (95% CI 5.4–8.7); (p < 0.05). In response to GTN small artery compliance increased, and systemic vascular resistance decreased significantly in control subjects; (p < 0.05) but remained unchanged in patients with diabetes.
Conclusions: Arterial waveform analysis proved more sensitive in detecting early vascular abnormalities and tracking the haemodynamic effects of GTN in patients with diabetes than changes in total peripheral resistance. The diminished responsiveness of the arterial vasculature to organic nitrates may have therapeutic implications for the treatment of cardiovascular disease in diabetes mellitus.     

Effects of Sublingual Glyceryl Trinitrate Administration on the Quality of Preprocedure CT Angiography Performed to Plan Prostate Artery Embolization

Purpose

To determine the effects of sublingual glyceryl trinitrate (GTN) on the quality of planning computed tomography (CT) angiography performed prior to prostate artery embolization (PAE).

硝酸甘油、硝苯吡啶治疗慢性肛裂127例

目的:探讨硝酸甘油、硝苯吡啶联合用药治疗慢性肛裂的疗效。方法:对采用硝酸甘油、硝苯吡啶联合用药治疗慢性肛裂127例和采用内扩约肌切断术治疗慢性肛裂81例的临床资料进行对比分析。结果:采用药物治疗的治愈率达91.35％,复发率10.2％。采用手术治疗的治愈率91.5％,复发率8.64％。两组的治愈率和复发率无显著差异(P>0.05)结论:硝酸甘油、硝苯吡啶联合用药治疗慢性肛裂与采用内扩约肌切断术治疗的治愈率、复发率无显著差异。且药物治疗可明显减少患者的痛苦,没有肛门失禁的危险。所以该药物治疗方法可用以治疗初发慢性肛裂。     

Nociceptive-specific blink reflex and glyceryl trinitrate infusion in healthy volunteers

Glyceryl trinitrate (GTN) is known to induce early headache in healthy humans after intravenous infusion. Moreover, in animal models subcutaneous administration produces an increase in Fos expression in brainstem areas that are involved in trigeminal pain processing. In a double-blind crossover study, we tested the blink reflex before, during and immediately after GTN and placebo intravenous infusion in eight healthy volunteers using a new stimulation electrode that preferentially activates A-delta nociceptive afferent fibres. The initial hypothesis that GTN could induce an increase in the magnitude of the nociceptive blink reflex R2 component by stimulating activity of trigeminal nucleus caudalis wide dynamic range interneurones was not confirmed. Although mild headache was induced in six subjects, there was no significant change between the R2 area under the curve before and after drug vs. placebo.     

硝酸甘油消化道吸收后在动物体内的代谢研究

目的　观察硝酸甘油 (glyceryltrinitrate ,GTN)经消化道吸收后的分解代谢机理。方法　以实验兔为动物模型 ,应用电生理监测仪动态检测血压 ,血气分析仪检测高铁血红蛋白 (MetHb) ,全自动生化分析仪检测丙氨酸氨基转移酶 (ALT) ,比色法检测硝酸盐、亚硝酸盐、还原型谷胱甘肽 (GSH)。结果　GTN经消化道吸收后代谢产生亚硝酸盐 ,实验动物血压、红细胞GSH降低 ,MetHb、ALT未见明显变化。结论　机体内GTN分解代谢过程中可消耗还原性巯基和产生亚硝酸盐 ,对血红蛋白和肝脏功能无明显影响。