Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model.

Background: Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract. Objective: To study the effect of CYP450 modulation in galactosemic cataract. Materials and Methods: Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as µM NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated. Results: The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2. Conclusion: CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer.

[Imidazole-containig drugs and inhibition of cytochrome P450]

Nowadays, multi-medicament use is increasing in clinical practice, especially, in the treatment of elder patients. Therefore, the pharmacokinetic drug-drug interaction of medicaments, which are expected to be co administrated in clinical practice, seems to be significant. The present review provides an update for the relationship between type of chemical substitution [aliphatic or aromatic] of imdazole-containig drugs and their tendency to affect hepatic metabolizing enzyme cytochrome [CYP450s]. In the present review, examples of different therapeutically used imidazole-containing drugs are highlighted to support the first evidence regarding the relationship between CYP-inhibition and chemistry of imidazole ring system. The informations provided throughout this article are intended to improve the medicinal chemist's knowledge of imidazole-containig drugs that are therapeutically widely applied as agents including histamine H1 receptor antagonists [antiallergics], histamine H2 receptor antagonists [antiulcers], histamine H3 receptor antagonists [management of cognitive disorders and attention-deficit-hyperactivity-disorder], antivirals, antiHIV, antibacterials, antifungals, anethelmintics, antiemetics, and antihypertensives

Tyrosine phosphatase and cytochrome P450 activity are critical in regulating store-operated calcium channels in human fibroblasts

Diverse signaling pathways have been proposed to regulate store-operated calcium entry (SOCE) in a wide variety of cell types. However, it still needs to be determined if all of these known pathways operate in a single cell type. In this study, we examined involvement of various signaling molecules in SOCE using human fibroblast cells (HSWP). Bradykinin (BK)-stimulated Ca2+ entry, previously shown to be via SOCE, is enhanced by the addition of vanadate, an inhibitor of tyrosine phosphatases. Furthermore, SOCE is regulated by cytochrome P-450, as demonstrated by the fact that the products of cytochrome P-450 activity (14,15 EET) stimulated SOCE while econazole, an inhibitor of cytochrome P450, suppressed BK-stimulated Ca2+ entry. In contrast, Ca2+ entry was unaffected by the guanylate cyclase inhibitor LY83583, or the membrane permeant cyclic GMP analog 8-bromo-cyclic GMP (8-Br-cGMP). Neither nitric oxide donors nor phorbol esters affected BK-stimulated Ca2+ entry. SOCE in HSWP cells is primarily regulated by tyrosine phosphorylation and the cytochrome P-450 pathway, but not by cyclic GMP, nitric oxide, or protein kinase C. Thus, multiple pathways do operate in a single cell type leading to the activation of Ca2+ entry and some of these signaling pathways are more prominently involved in regulating calcium entry in different cell types.

Effect of dimethyl diphenyl bicarboxylate on normal and chemically-injured liver

This study evaluates the effect of DDB on normal and chemically-injured liver. When given to normal rats DDB had no significant effect on liver enzymes, but in chemically-injured rats there was a significant decrease in the elevated levels of liver enzymes. DDB produced a significant increase in reduced glutathione, glutathione peroxidase and glutathione reductase, and a significant decrease in malondialdehyde and glucose-6-phosphate dehydrogenase in both normal and chemically-injured liver. The histopathology examinations showed a slight improvement with DDB administration. DDB has a beneficial effect on liver enzymes and possesses significant antioxidant properties in normal and chemically-injured liver, and may therefore be clinically useful in treating chronic viral hepatitis B in humans

Fármacos de uso pediátrico, QT prolongado y trastornos del ritmo cardíaco / Medications of pediatric use, long QT and cardiac rhythm disturbances

En los últimos años se ha observado un progresivo aumento de publicaciones que describen alteraciones del ritmo cardíaco graves, e incluso muerte súbita, en pacientes pediátricos que reciben fármacos habituales de la terapéutica pediátrica. Entre los fármacos mencionados destacan cisaprida y otros de uso gastroenterológico, antibióticos macrólidos, antifúngicos, antihistamínicos y psicotrópicos. Estas complicaciones son poco frecuentes, ocurren en relación a sobredosis, uso combinado de ellos o en determinadas condiciones de mayor susceptibilidad de los pacientes. Estos fármacos pueden prolongar anormalmente el intervalo QT del electrocardiograma, lo que predispone a arritmias ventriculares graves y a muerte súbita. Se revisan algunos de estos fármacos, se describen los mecanismos a través de los cuales producen estas arritmias y se dan recomendaciones para su uso seguro en pediatría, especialmente en pacientes con mayor susceptibilidad, y así prevenir esta seria complicación de la farmacoterapia pediátrica

In vitro and in vivo inhibition of pulmonary cytochrome P450 activities by piperine, a major ingredient of piper species.

In vitro and in vivo modulation of drug metabolizing enzymes by piperine was investigated in microsomes of rats and guinea pigs. In vitro piperine caused concentration related inhibition (50% at 100 microM) of arylhydrocarbon hydroxylase (AHH) and 7-ethoxycourmarin deethylase (7ECDE) activities, which were comparable in control and 3-methylcholanthrene (3MC) treated rats. In guinea pig microsomes however, piperine caused strong inhibition at lower concentrations (35% at 10 microM) and relatively much lesser inhibition with further increase in piperine concentrations. A Dixon plot of the kinetic data of both AHH and 7ECDE indicated noncompetitive inhibition with a Ki of approx. 100 microM. In vivo, piperine given at a dose of 25 mg/kg body wt to rats caused a maximal inhibition at 1 hr of both the enzymes, while only AHH returned to normal value within 4 hr. Similarly, upon daily treatment of piperine (15 mg/kg body wt) to rats for 7 days, 7ECDE was consistently inhibited, while AHH showed faster recovery. Piperine thus appeared to cause differential inhibition of two forms of cytochrome P450 and thus would accordingly affect the steady-state level of those drugs metabolized by these pulmonary forms of cytochromes P450.

Circulating cortisol & related steroids following ketoconazole challenge in Cushing's disease.

Circulating levels of cortisol, 17 alpha hydroxy progesterone and delta 4 androstenedione were analysed by specific radioimmunoassays in 11 patients with Cushing's disease before and at 2, 4, 6, 12 and 24# h following an oral dose of 400 mg ketoconazole. A significant fall in cortisol (26 - 79.6%, 59.8 +/- 18.7 SEM), delta 4 androstenedione (21.5 - 63.3%, 47.8 +/- 4.87) with a concomitant rise in 17 alpha hydroxy progesterone (113 - 218%, 116 +/- 11.43) were noted, suggesting inhibition of 17, 20 desmolase and 11 beta-hydroxylase enzymes in cortisol biosynthetic pathway.