Animals ; Epilepsy ; genetics ; metabolism ; Genes, MDR ; Hippocampus ; drug effects ; metabolism ; Male ; Rats ; Rats, Wistar ; Triazines ; pharmacology

The remarkable therapeutic success of PDE5 inhibitors in the treatment of male erectile dysfunction has focused the attention of the researchers on better defining the properties of the individual inhibitors and PDE5 that contribute to the high affinity of these inhibitors for interaction with the PDE5 catalytic site. Recent molecular studies have demonstrated that vardenafil has high affinity for PDE5 and low dissociation rate from PDE5, which serves to explain why vardenafil works with low dosage, onsets quickly and has curative action in clinical practice. Moreover, the potency of vardenafil depends on its ring structure that resembles the purine moiety in cGMP.
Drug Interactions ; Erectile Dysfunction ; drug therapy ; Humans ; Imidazoles ; chemistry ; pharmacology ; Male ; Molecular Structure ; Phosphodiesterase Inhibitors ; chemistry ; pharmacology ; Piperazines ; chemistry ; pharmacology ; Sulfones ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology ; Vardenafil Dihydrochloride

Melamine in combination with cyanuric acid has been considered to be more toxic than either melamine or cyanuric acid alone. The objective of this study was designed to evaluate the combined genotoxicity and cytotoxicity of melamine (M) and cyanuric acid (C) at three mass ratios (1:1, 1:2, 2:1). MC (1:1), MC (1:2), and MC (2:1) were evaluated for their potential genotoxic risk, at gene level by Ames test, and at chromosomal level by micronucleus test. In order to evaluate cytotoxicity in HEK-293 cells, the MTT assay was included. Western blot was also employed to investigate the renal injury molecule-1 (Kim-1) expression in HEK-293 cells exposed to MC. Neither genotoxicity at gene level nor at chromosomal level was observed for MC (1:1), MC (1:2), and MC (2:1). Based on MTT assay, three ratios of MC at 82.5 and 165 µg/mL slightly inhibited viability of HEK-293 cells (P<0.05). MC (1:1) at 41.25 and 82.50 µg/mL could elevate the Kim-1 expression in HEK-293 cells.
Cell Survival ; drug effects ; HEK293 Cells ; Hepatitis A Virus Cellular Receptor 1 ; Humans ; Membrane Glycoproteins ; metabolism ; Receptors, Virus ; metabolism ; Triazines ; pharmacology

Vardenafil is a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor with a potency about 10-fold higher than sildenafil. Vardenafil can significantly improve erectile function and works rapidly. Vardenafil is a PDE5 inhibitor with the fastest onset of action among its kind so far found and works as early as 10 minutes after oral administration, providing patients with penile erection sufficient to complete an intercourse. The absolute oral bioavailability is about 15%. Vardenafil is rapidly absorbed with a median tmax of 0.7 h and a terminal half-life (t1/2) of more than 4 h. The observed pharmacodynamic properties, pharmacokinetic characteristics and good safety and tolerability profile showed that vardenafil treatment provides an effective and generally well tolerated treatment for ED.
Adolescent ; Adult ; Aged ; Animals ; Erectile Dysfunction ; drug therapy ; Half-Life ; Humans ; Imidazoles ; pharmacokinetics ; pharmacology ; Male ; Middle Aged ; Phosphodiesterase Inhibitors ; pharmacokinetics ; pharmacology ; Piperazines ; pharmacokinetics ; pharmacology ; Purines ; pharmacokinetics ; pharmacology ; Rabbits ; Sildenafil Citrate ; Sulfones ; pharmacokinetics ; pharmacology ; Triazines ; pharmacokinetics ; pharmacology ; Vardenafil Dihydrochloride

This study was conducted to evaluate the effects of vardenafil (Levitra), a phosphodiesterase-5 (PDE-5) inhibitor, on cell proliferation in the hippocampal dentate gyrus and on 5-hyroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the rat dorsal raphe nucleus. Male Sprague-Dawley rats were divided into 6 groups (n=5 in each group): a control group, a 0.5 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-1 day vardenafil-treated group, a 2 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-3 day vardenafil-treated group, and a 1 mg/kg-7 day vardenafil-treated group. 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was then performed to evaluate cell proliferation in the dentate gyrus. In addition, 5-HT and TPH immunohistochemistry was conducted to evaluate serotonin expression in the dorsal raphe. The results revealed that treatment with vardenafil increased cell proliferation in the dentate gyrus and enhanced 5-HT synthesis and TPH expression in the dorsal raphe in a dose- and duration-dependent manner. The findings demonstrate that the increasing effect of vardenafil on cell proliferation is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions.
Animals ; Cell Proliferation/*drug effects ; *Dentate Gyrus/cytology/drug effects/metabolism ; Imidazoles/*pharmacology ; Male ; Phosphodiesterase Inhibitors/*pharmacology ; Piperazines/*pharmacology ; *Raphe Nuclei/cytology/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Serotonin/*biosynthesis ; Sulfones/pharmacology ; Triazines/pharmacology ; Tryptophan Hydroxylase/metabolism

The use of antiepileptic drugs in pregnancy always presents challenges to doctors and their patients as it may have deleterious effects on the developing embryo. Lamotrigine is most commonly-prescribed drug among the newer antiepileptic drugs; hence, it has been selected for the present review. A number of studies pertaining to the safety of lamotrigine use during pregnancy have been reported, with differing results. Contradictory results have been reported in animals regarding lamotrigine teratogenicity, and human studies have also proven inconclusive. In many countries, human pregnancy registries are maintained to establish the safety of antiepileptic drugs during pregnancy, as all the different suggestions favour some over others, with specific antiepileptic combinations still being questioned. It is our hope that the present work may integrate the available disparate relevant facts into a directed effort towards minimising the risk of foetal compromise.
Abnormalities, Drug-Induced ; Animals ; Anticonvulsants ; adverse effects ; therapeutic use ; Epilepsy ; drug therapy ; Female ; Folic Acid Deficiency ; chemically induced ; Humans ; Pregnancy ; Teratogens ; pharmacokinetics ; pharmacology ; Triazines ; adverse effects ; therapeutic use

Eight new diaryltriazine derivatives containing 4-allylamino and 4-azido substitutes guided by molecular docking have been designed and synthesized based on our previous work. The evaluation of HIV inhibitory activity demonstrated that all compounds were potent against HIV-1 replication. The most active compound 7c exhibited activity against HIV-1 (IC50 = 0.034 micromol x L(-1), SI = 6,475) and the double mutant strain (IC50 = 9.39 micromol x L(-1)) in the micromolar range, which was more potent than nevirapine.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Catalytic Domain ; HIV-1 ; drug effects ; Inhibitory Concentration 50 ; Molecular Structure ; Reverse Transcriptase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Triazines ; chemical synthesis ; chemistry ; pharmacology

Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 microg) was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 microg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity, indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.
Analgesics/*pharmacology ; Animals ; Antigens, CD11b/metabolism ; Astrocytes/cytology ; Drug Tolerance ; Immunohistochemistry ; Male ; Microglia/cytology ; Morphine/*pharmacology ; Nerve Tissue Proteins/metabolism ; Neuroglia/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*cytology ; Triazines/*pharmacology

Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Anthraquinones ; chemistry ; pharmacology ; Antineoplastic Agents ; chemistry ; pharmacology ; Aziridines ; chemistry ; pharmacology ; Cell Hypoxia ; drug effects ; Humans ; Indolequinones ; chemistry ; pharmacology ; Molecular Structure ; NAD(P)H Dehydrogenase (Quinone) ; chemistry ; pharmacology ; Neoplasms ; drug therapy ; pathology ; Nitrogen Mustard Compounds ; chemistry ; pharmacology ; Nitroimidazoles ; chemistry ; pharmacology ; Phosphoramide Mustards ; chemistry ; pharmacology ; Prodrugs ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology

No abstract available.
Acetic Acids/adverse effects/pharmacology ; Anticonvulsants/adverse effects/*pharmacology ; Carbamazepine/adverse effects/analogs & derivatives/pharmacology ; Clinical Trials ; Forecasting ; Fructose/adverse effects/analogs & derivatives/pharmacology ; Human ; Isoxazoles/adverse effects/pharmacology ; Propylene Glycols/adverse effects/pharmacology ; Triazines/adverse effects/pharmacology ; Vigabatrin ; gamma-Aminobutyric Acid/adverse effects/analogs & derivatives/pharmacology