The Wonders of Phosphodiesterase-5 Inhibitors: A Majestic History.

The Nobel Prize winning discovery of nitric oxide (NO) in 1986 was the starting point for a new innovation in drug discovery. NO acting as a mediator at different physiological systems is believed to be involved in many physiological and pathological conditions through the formation of the second messenger cyclic guanosine monophosphate (cGMP). cGMP-dependent vasodilation effect of NO is important in regulating pulmonary and systemic pressures, maintaining penis erection, preventing atherosclerosis, preventing platelet aggregation, and protecting and controlling cardiac functions. The main enzyme involved in the termination of cGMP effects is phosphodiesterase enzyme 5 (PDE-5), which is overexpressed in ventricular hypertrophy and heart failure. A milestone in drug discovery was the selective inhibitors of PDE-5 that developed to be a multibillion dollar blockbuster in drug market. PDE-5 inhibitors are approved for the treatment of erectile dysfunctions (EDs), pulmonary hypertension, and benign prostatic hypertrophy. They are also under clinical trials for their cardiac protection against damage induced by ischemia or heart failure. This review article is an update about the pharmacotherapeutics of PDE-5 inhibitors and the majestic history that led to their discovery. The information reported in this review was obtained from the electronic sources of different databases such as PubMed Central, Google Scholar, and Scopus. Keywords used for search included cGMP (mechanisms and functions), EDs (drugs used), nitric oxide, and PDE-5 inhibitors (clinical applications). A total of 165 articles were studied, of which 45 articles were referred to in this review.

Cross-sectional pilot study about the health status of diabetic patients in city of Misurata, Libya.

BACKGROUND: Being a leading cause of death worldwide, epidemiological studies about diabetes mellitus have encouraged governments to initiate or improve local diabetes monitoring and prevention strategies. OBJECTIVE: The main objective of this study was to examine the profile of diabetic patients in the city of Misurata, the third largest city in Libya. METHODS: 260 diabetic cases of both gender randomly selected from the total number of patients admitted to the centre of diabetes and endocrine disorders, Misurata -Libya for the period between January to March 2008. Data collected from patients' files and by directly questioning the patients. SPSS software version 13 was used for the statistical analysis and presentation of the data. RESULTS: 87% of all patients were type 2 diabetics, while only 9.9% were type 1. 73% of all patients had family history of diabetes. 52% of all diabetic patients were obese, with more obesity in females (70% of females) than males (33.8% of males). Obesity was more pronounced in type 2 patients (56.8%) than in type 1 patients (11.5%). 38% of all patients were treated with insulin while 35.4% were treated with oral hypoglycemics. Meanwhile 32.6% of type 2 diabetic patients were treated with insulin. Only 9.2% of all patients had fasting blood sugar below 140 mg/dl, whereas 55% had levels in the range of 140-180 mg/dl, while 35.8% had levels above 180 mg/dl. Microvascular complications included retinopathy (16.2% of all patients), neuropathy (11.2%), nephropathy (1.5%) and combination of neuropathy and retinopathy (6.5%). CONCLUSION: High percentage of risk factors including obesity, family history of diabetes, hypertension and microvascular complications requires a Libyan national policy for the surveillance, prevention and control of diabetes and its complications.

Behavioral effects of acute and chronic triazolam treatments in albino rats.

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.

Brain glycine levels in triazolam-treated albino rats.

The present study investigates the effects of acute and chronic administration of triazolam in albino rats on glycine levels in different brain areas. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of triazolam (0.25 mg/kg-4.0 mg/kg i.p.). In the second experiment, rats were treated chronically by a single daily dose of triazolam (started by 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically three daily doses of triazolam (started by 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, simulating a form of drug abuse. Brain levels of glycine and plasma levels of triazolam were measured using HPLC technique. The acute triazolam administration produced an increase in glycine levels in almost all brain areas studied. The chronic administration of single daily dose of triazolam produced normal glycine levels in most of the brain areas; this indicates the development of tolerance to glycine content increasing action of triazolam. The chronic administration of three daily doses of triazolam produced a decrease in glycine levels in almost all brain regions studied, which might be a prerequisite for oncoming withdrawal syndrome.

Pharmacodynamic and pharmacokinetic interactions between alpha-methylparatyrosine and phenobarbitone.

The hypnosis and hypothermia induced by phenobarbitone (100 mg/kg i.p.) were greatly potentiated by combined treatment with alpha-methylparatyrosine (alpha-MPT, 250 mg/kg i.p.). alpha-MPT per se produced sedation and hypothermia. Measurement of blood and brain levels of phenobarbitone in rats treated with phenobarbitone alone or phenobarbitone plus alpha-MPT revealed that the latter delayed the disappearance rates of phenobarbitone from both brain and plasma. These results suggest an interaction at the site of distribution, metabolism and/or excretion of phenobarbitone. The possibility of a pharmacodynamic interaction involving neurotransmitters is also discussed.