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.Keywords: Cyclic guanosine monophosphate, Nitric oxide, Phosphodiesterase enzyme 5 inhibitor

The effect of GABAmimetics on the duration of immobility in the forced swim test in albino mice

Objectives: Studies regarding the role of gamma aminobutyric acid (GABA) in depression are conflicting. Therefore, it was decided to examine the effect of different drugs that enhance the GABA system on the time of immobility induced by the forced swim test (FST).Materials and methods: Adult albino mice were divided into several groups of six animals. Each group received an intraperitoneal injection of either imipramine (10, 20, or 30 mg/kg), diazepam (0.5, 1, or 2 mg/kg), vigabatrin (100, 200, or 300 mg/kg), zolpidem (2.5, 5, or 10 mg/kg), or alprazolam (1, 2.5, or 5 mg/kg). Control groups received the appropriate vehicle. One hour after injection, the duration of immobility was measured for 5 min in the FST. The percentage change in the duration of immobility from the control was calculated for each group. The statistical test of the difference between the treated and the control groups was calculated using unpaired Student’s t-test.Results: Imipramine produced a significant dose-dependent decrease in the duration of immobility (78, 74, and 56%, respectively). Different doses of diazepam, vigabatrin, and zolpidem produced a significant increase in the duration of immobility (119, 126, and 128%), (116, 124, and 128%), and (108, 109, and 119%), respectively. The two low doses of alprazolam produced a significant increase (115 and 120%), while the high dose produced a significant decrease in the duration of immobility (74%).Conclusion: Increasing central GABAergic activity by different mechanisms has resulted in a depressant-like activity measured as an increase in the duration of immobility in the FST model of depression.Keywords: GABAmimetics; forced swim test; diazepam; vigabatrin; zolpidem; alprazola

The analgesic effect of different antidepressants combined with aspirin on thermally induced pain in Albino mice

Background:Combination analgesics provide more effective pain relief for a broader spectrum of pain. This research examines the possible potentiation of the analgesic effect of different classes of antidepressants when combined with aspirin in thermal model of pain using Albino mice.Methods:Different groups of six animals each were injected intraperitoneally by different doses of aspirin (50, 100, or 200 mg/kg), imipramine (2.5, 7.5, 15 or 30 mg/kg), fluoxetine (1.25, 2.5, 5 or 7.5 mg/kg), mirtazapine (1.25, 2.5, or 5 mg/kg) and a combination of a fixed dose of aspirin (100 mg/kg) with the different doses of the three antidepressants. One hour later the analgesic effect of these treatments were evaluated against thermally induced pain. All data were subjected to statistical analysis using unpaired Student's t-test.Results:Aspirin had no analgesic effect in thermally induced pain. The three selected antidepressants produced dose dependent analgesia. The addition of a fixed dose of aspirin to imipramine significantly increased the reaction time (RT) of the lowest dose (by 23%) and the highest dose (by 20%). The addition of the fixed dose of aspirin to fluoxetine significantly increased RT by 13% of the dose 2.5 mg/Kg. Finally, the addition of the fixed dose of aspirin significantly potentiated the antinociceptive effect of the different doses of mirtazapine (RT was increased by 24, 54 and 38% respectively).Conclusion:Combination of aspirin with an antidepressant might produce better analgesia, increasing the efficacy of pain management and reduces side effects by using smaller doses of each drug

Neurochemical studies into the mode of action of anticonvulsant drugs

Single doses of phenobarbitone decreased the turnover rate of dopamine (DA) and noradrenaline (NA) and increased the whole brain levels of 5- hydroxytryptamine (5-RT) and gamma-aminobutyric acid (GABA) . Habituation to phenobarbitone increased the levels of DA in striata and midbrain and decreased that of cerebral hemispheres, leaving the total amount unchanged. Habituation resisted the depletion otherwise caused by alpha-methyl-p-tyrosine (alpha-m.p.t.) in the striata for DA and in the cerebral hemispheres for both DA and NA. Withdrawal of phenobarbitone decreased the levels of DA in the striata and both catecholamines in the cerebral hemispheres. Withdrawal increased the depletion of DA in the striata and cerebral hemispheres and that of NA in the cerebral hemispheres and midbrain caused by alpha-m.p.t. Withdrawal convulsions increased the levels of DA in the striata and decreased it in the cerebral hemispheres, leaving the total amount unchanged. NA was less in this group than it was in controls. Alpha-m.p.t. protected animals from convulsions. This group showed less DA in the striata and in the cerebral hemispheres and less NA in midbrain. Habituation to phenobarbitone increased the levels of 5-HT and 5-HIAA. Withdraiwal returned both levels to control values. While withdrawal convulsions decreased the levels of 5-HT, 5-HIAA levels were increased. Single doses of phenytoin increased the levels of DA in striata and NA in midbrain. It also increased the l levels of 5-HIAA in whole brain and decreased the depletion of 5-HIAA caused by p-chlorophenylalanine (p-c.p.a.) or pargyline. Long term administration of phenytoin increa sed the levels of dopamine in the striata and the midbrain and decreased that of the cerebral hemispheres. It also produced an increase in the level s of NA in the cerebral hemispheres. Similar effects were observed after alpha-m.p.t. Whole brain levels of 5-HT and 5- HIAA were increased after long term treatment with phentoin. Single doses of carbamazepine increased the levels of NA in the midbrain and decreased the depletion of 5-HIAA after p-c.p.a. and pargyline. The long term treatment with carbamazepine increased the total brain levels of 5- HT and 5-HIAA and those of DA in the striata and cerebral hemispheres and for NA in the cerebral hemispheres and midbrain. The same effect was seen after alpha-m.p.t. While NA and GABA levels were decreased in the primary focal area oneweek after cobalt implantation, 5-HIAA levels were increased. The same effect was seen for NA and 5-HIAA levels two weeks after cobalt implantation

Neurochemical studies into the mode of action of anticonvulsant drugs

Single doses of phenobarbitone decreased the turnover rate of dopamine (DA) and noradrenaline (NA) and increased the whole brain levels of 5- hydroxytryptamine (5-RT) and gamma-aminobutyric acid (GABA) . Habituation to phenobarbitone increased the levels of DA in striata and midbrain and decreased that of cerebral hemispheres, leaving the total amount unchanged. Habituation resisted the depletion otherwise caused by alpha-methyl-p-tyrosine (alpha-m.p.t.) in the striata for DA and in the cerebral hemispheres for both DA and NA. Withdrawal of phenobarbitone decreased the levels of DA in the striata and both catecholamines in the cerebral hemispheres. Withdrawal increased the depletion of DA in the striata and cerebral hemispheres and that of NA in the cerebral hemispheres and midbrain caused by alpha-m.p.t. Withdrawal convulsions increased the levels of DA in the striata and decreased it in the cerebral hemispheres, leaving the total amount unchanged. NA was less in this group than it was in controls. Alpha-m.p.t. protected animals from convulsions. This group showed less DA in the striata and in the cerebral hemispheres and less NA in midbrain. Habituation to phenobarbitone increased the levels of 5-HT and 5-HIAA. Withdraiwal returned both levels to control values. While withdrawal convulsions decreased the levels of 5-HT, 5-HIAA levels were increased. Single doses of phenytoin increased the levels of DA in striata and NA in midbrain. It also increased the l levels of 5-HIAA in whole brain and decreased the depletion of 5-HIAA caused by p-chlorophenylalanine (p-c.p.a.) or pargyline. Long term administration of phenytoin increa sed the levels of dopamine in the striata and the midbrain and decreased that of the cerebral hemispheres. It also produced an increase in the level s of NA in the cerebral hemispheres. Similar effects were observed after alpha-m.p.t. Whole brain levels of 5-HT and 5- HIAA were increased after long term treatment with phentoin. Single doses of carbamazepine increased the levels of NA in the midbrain and decreased the depletion of 5-HIAA after p-c.p.a. and pargyline. The long term treatment with carbamazepine increased the total brain levels of 5- HT and 5-HIAA and those of DA in the striata and cerebral hemispheres and for NA in the cerebral hemispheres and midbrain. The same effect was seen after alpha-m.p.t. While NA and GABA levels were decreased in the primary focal area oneweek after cobalt implantation, 5-HIAA levels were increased. The same effect was seen for NA and 5-HIAA levels two weeks after cobalt implantation

Single- and multi-photon excited fluorescence from serotonin complexed with B-cyclodextrin

The fluorescence of serotonin on binding with B-cyclodextrin has been studied using both steady-state and time-resolved methods. Steady state fluorescence intensity of serotonin at 340 nm showed ~ 30% increase in intensity on binding with Ka ~ 60 dm3 mol 1 and the fluorescence lifetimes showed a corresponding increase. In contrast, the characteristic green fluorescence (‘hyperluminescence’) of serotonin observed upon multiphoton near-infrared excitation with sub-picosecond pulses was resolved into two lifetime components assigned to free and bound serotonin. The results are of interest in relation to selective imaging and detection of serotonin using the unusual hyperluminescence emission and in respect to recent determinations of serotonin by capillary electrophoresis in the presence of cyclodextrin. The results also suggest that hyperluminescence occurs from multiphoton excitation of a single isolated serotonin molecule

Antinociceptive and anti-inflammatory activity of ferula hermonis root oil in experimental animals

Ferula hermonis (Apiaceae) is a well known Middle-Eastern medicinal plant. It has long been used traditionally as an aphrodisiac agent. The antinociceptive and anti-inflammatory activities of the root oil of F. hermonis were evaluated by the hot-plate test, the acetic acid-induced writhing test and the carragennan-induced rat paw edema test. In the hot-plate test, the root oil in oral doses of 400 and 800 mg/kg significantly increased the reaction time of animals to thermal pain, and in the acetic acid-induced writhing test, in similar oral doses it showed a considerable inhibition of acetic acid-induced writhing in mice in a dose-dependant manner. In the carrageenan induced paw oedema model, the oral administration of 50 and 100 mg/kg of F. hermonis root oil to adult Wister rats showed a statistically significant decrease in rat paw o induced by carrageenan 1 and 2 h after carrageenan injection.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Monoamine involvement in the antidepressant-like effect induced by P2 blockade

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