Development and validation of alternative methods by non-aqueous acid-base titration and derivative ultraviolet spectrophotometry for quantification of sildenafil in raw material and tablets

Sildenafil citrate (SILC) is a potent phosphodiesterase-5 inhibitor used for erectile dysfunction and pulmonary hypertension. This study shows two simple, fast and alternative analytical methods for SILC determination by non-aqueous titration and by derivative ultraviolet spectrophotometry (DUS) in active pharmaceutical ingredient and/or dosage forms. The quantitation method of SILC active pharmaceutical ingredient by non-aqueous acid-base titration was developed using methanol as solvent and 0.1 mol/L of perchloric acid in acetic acid as titrant. The endpoint was potentiometrically detected. The non-aqueous titration method shows satisfactory repeatability and intermediate precision (RSD 0.70-1.09%). The neutralization reaction occurred in the stoichiometric ratio 1:1 in methanol. The determination of SILC active pharmaceutical ingredient or dosage forms by DUS was developed in the linear range from 10 to 40 µg/mL, in 0.01 mol/L HCl, using the first order zero-peak method at λ 256 nm. The DUS method shows selectivity toward tablets excipients, appropriate linearity (R2 0.9996), trueness (recovery range 98.86-99.30%), repeatability and intermediate precision in three concentration levels (RSD 1.17-1.28%; 1.29-1.71%, respectively). Therefore, the methods developed are excellent alternatives to sophisticated instrumental methods and can be easily applied in any pharmaceutical laboratory routine due to simple and fast executions.

Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide.

Inhaled nitric oxide (iNO) is approved for use in persistent pulmonary hypertension of the newborn (PPHN) but does not lead to sustained improvement in oxygenation in one-third of patients with PPHN. Inhaled NO is less effective in the management of PPHN secondary to congenital diaphragmatic hernia (CDH), extreme prematurity, and bronchopulmonary dysplasia (BPD). Intravenous pulmonary vasodilators such as prostacyclin, alprostadil, sildenafil, and milrinone have been successfully used in PPHN resistant to iNO. Oral pulmonary vasodilators such as endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are used both during acute and chronic phases of PPHN. In the absence of infection, glucocorticoids may also be effective in PPHN. Many of these pharmacologic agents are not approved for use in PPHN and our knowledge is based on case reports and small trials. Large multicenter randomized controlled trials with long-term follow-up are required to evaluate alternate pharmacologic strategies in PPHN.

HDL particle subpopulations: Focus on biological function.

Low levels of high-density lipoprotein-cholesterol (HDL-C) constitute an independent biomarker of cardiovascular morbi-mortality. However, recent advances have drastically modified the classical and limited view of HDL as a carrier of 'good cholesterol', and have revealed unexpected levels of complexity in the circulating HDL particle pool. HDL particles are indeed highly heterogeneous in structure, intravascular metabolism and biological activity. This review describes recent progress in our understanding of HDL subpopulations and their biological activities, and focuses on relationships between the structural, compositional and functional heterogeneity of HDL particles.

Vasodilator effects of red wines in subcutaneous small resistance artery of patients with essential hypertension.

BACKGROUND: It has been suggested that in animal models, red wine may have a protective effect on the vascular endothelium. However, it is not known whether this effect is also present in human small vessels and whether it is specific for certain wines. The objective of this study is to compare the vasodilator effects in subcutaneous small resistance arteries of wines with different flavonoid content as well as of ethanol vs. wines in normotensive (NT) subjects and in patients with essential hypertension (EH). METHODS: Twenty-six EH and 27 NT were included in the study. Subcutaneous small resistance arteries were dissected and mounted on a micromyograph. Then we evaluated vasodilator responses as concentration-response curves (20, 30, and 50 microl) to the following items: (i) a red wine produced in small oak barrels ("en barrique": EB) (Barolo Oberto 1994), (ii) a red wine produced in large wood barrels (LB) (Barolo Scarzello 1989), (iii) a red wine produced in steel tanks (Albarello Rosso del Salento 1997), and (iv) a white wine produced in steel tanks in the presence or absence of an inhibitor of the nitric oxide (NO) synthase (L-NMMA 100 micromol/l). RESULTS: A dose-dependent vasodilator effect of red wines (particularly EB and LB) was detected in both NT and HT. The observed response was not reduced after preincubation with L-NMMA. CONCLUSIONS: Our results suggest red wines are more potent vasodilator than ethanol alone, possibly depending on the content of polyphenols or tannic acid. HT show similar responses compared with NT, indicating that red wine is not harmful in this population.

[Third generation beta-blockers: current state of research on vasodilating beta-blockers]. / Betablocker der 3. Generation: Stand der Forschung zu den Betablockern mit vasodilatierenden Zusatzeigenschaften.

Nebivolol (Nomexor) is a third generation, vasodilating beta-blocker with a high beta(1)-adrenoceptor selectivity. Nebivolol acts as an agonist at the beta(3) adrenoceptor as well as the estrogen receptor thereby releasing nitric oxide in blood vessels via eNOS. Pleiotropic effects of nebivolol furthermore include a positive influence on cholesterol and triglycerides and a decrease in thrombocyte activity. Nebivolol is recommended in the guidelines of the European cardiac society (ESC) for patients with metabolic syndrome. Nebivolol's main properties in combination with its broad range of beneficial pleiotropic effects allow it to be clearly distinguished from other second and third generation beta-blockers.

[Drugs for veno-lymphatic insufficiency]. / Médicaments de l'insuffisance veinolymphatique.

Treatment of venous and lymphatic insufficiency of the lower limbs is based on 3 components: elastic support, venotonic drugs and radical treatments (surgery or sclerotherapy) of insufficient veins. Venotonic drugs have specific indications limited to functional impairment: heavy feeling in the legs, pain and impatience in the evening. There are different categories of venolymphatic drugs. Flavonoids have various pharmacological actions, most notably an increase in venous tone, reduction of capillary permeability and increase of capillary resistance. Choice of a venotonic drug is funded on knowledge of pharmacodynamics and pharmacokinetics of the molecule, critical evaluation of clinical studies, physician's personal experience and drug cost. Venotonic drugs are useful when venous insufficiency leads to functional manifestations. They are especially the treatment of heavy leg syndromes during warm seasons when elastic support is uncomfortable.

Pituitary adenylate cyclase-activating polypeptide- and VIP-induced activation of adenylate cyclase in the porcine non-pigmented ciliary epithelium: effects of antagonists.

Vasoactive intestinal polypeptide (VIP) and two pituitary adenylate cyclase-activating polypeptides (PACAP-38 and PACAP-27) were investigated for their ability to activate the adenylate cyclase system in membrane preparations from the porcine non-pigmented ciliary epithelium (NPE). The NPE was dissociated from the adjacent pigmented ciliary epithelium of the iris-ciliary body (ICB) by incubation in low Ca2+ Ringer's solution. All three peptides caused a dose-dependent increase in cAMP formation in the NPE and the remaining part of the ICB. A VIP antagonist had a small effect on the dose-response curve for VIP, while the two PACAP fragments, PACAP(6-38) and PACAP(6-3 1), caused a rightward shift of the concentration response curves for PACAP-38, PACAP-27 and VIP. The results of the present study indicate that the non-pigmented ciliary epithelium of the porcine eye contain receptors for PACAP- and VIP-coupled to adenylate cyclase activation.

Variation in the salivary peptide, maxadilan, from species in the Lutzomyia longipalpis complex.

Maxadilan is an approximately 7kDa peptide that occurs in the saliva of the sand fly Lutzomyia longipalpis. This peptide is a potent vasodilator and may also have immunomodulatory effects related to the pathogenesis of leishmanial infections. Variation in the primary DNA and inferred amino acid sequence of maxadilan is reported. Differences were found within and among natural field populations as well as among sibling species. Extensive amino acid sequence differentiation, up to 23%, was observed among maxadilan from different populations. This is a remarkable degree of polymorphism considering the small size of this peptide. The vasodilatory activity of maxadilan was equivalent among recombinant maxadilan variants. All maxadilan variants induce interleukin-6. Predicted secondary structure and hydrophobicity plots suggest that these characteristics are conserved among variant peptides. However, profiles based on the antigenic index do differ among peptides.

Vasodilatadores orales en la insuficiencia cardíaca / Oral vasodilators in heart failure

Oral vasodilators have proved to be valuable drugs in the management of systolic or diastolic heart failure. They produce a clinical and hemodynamic relief of preload, afterload or both during the resting state or exercise. Although left ventricular hypertrophy is an adaptative response to myocardial stress, in the long run it becomes an independent risk factor leading to diastolic dysfunction. At present, pharmacological regression of ventricular hypertrophy has a prognostic importance. Of the large number of available vasodilators, angiotensin converting enzyme inhibitors have proved to be the most succesful drugs. They behave as afterload relievers, counteracting both the renin-angiotensin and adrenergic systems, but also are powerful inhibitors of cardiomyocite enlargement and interstitial connective tissue proliferation. This last structural change may revert the compromised diastolic function of the heart

Psychotropic and medical drug interactions.

In a number of situations, drugs used to treat psychiatric and physical illnesses are coadministered to patients suffering primarily from a psychiatric illness. Hence, coadministration of medical and psychiatric drugs is not uncommon. With increasing use of multiple drugs, our ability to treat a number of disorders has increased, but simultaneously, the problem of drug interactions has also assumed importance. A number of factors contribute to such drug interactions in psychiatric patients. All these interactions are both pharmacologically and genetically determined. Genetic susceptibility is not practical to determine. It is therefore essential for the physician to employ drug combinations only when necessary, be aware of the known clinically significant interactions, anticipate and watch for them, avoid dangerous combinations, and monitor the patients receiving combination of drugs with vigilance.