12-hydroxy nevirapine as a possible cause of nevirapine induced skin rashes

Nevirapine [NVP] is the first non-nucleoside reverse transcriptase inhibitor approved by the U.S. Food and Drug Administration [FDA] for use in combination therapy of HIV-1 infection. The favorable pharmacokinetic profile of NVP permits a simplified dosage and inexpensive regimen to prevent perinatal transmission, more especially in developing countries. Greater than 80% of administered NVP dose is transformed to glucuronidated conjugates of hydroxylated metabolites that are excreted in urine and only a small fraction of the dose [2.7%] was urinary excreted as the parent compound NVP. Adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have emerged from NVP and hampered its use. Maculopapular rash and several cases of Stevens-Johnson syndrome have been reported in 17% of patients treated with NVP. 12-hydroxynevirapine has been proposed as a factor in nevirapine hepatocarcinogenicity and skin rashes. This work was conducted to explore the proposition that 12-hydroxy-NVP is the ultimate toxic metabolite responsible for the NVP induced side effects. Primary culture of skin fibroblasts of small female Brown Norway rats was utilized in this study, where the third and the fourth passaged cells were used. NVP, 12-hydroxy-NVP as well as 12-chloro-NVP [as surrogate for 12-hydroxy-NVP] were utilized for exploring the expression profiles of some genes as well as the cytotoxic potential of each of them. Also, the stability of 12-hydroxy and 12-chloro NVP in vitro was determined. Results showed that both of NVP and 12-hydroxy-NVP are free from any cytotoxic potential while 12-chloro-NVP exhibited cytotoxic effect in the third and the fourth passaged population. Each of NVP, 12-hydroxy-NVP or 12chloro-NVP caused some what similar gene expression profile. The stability study showed clear transformation of 12-chloro-NVP to more stable metabolite which is 12-hydroxy-NVP. As a conclusion obtained from the present work is that the main metabolite of NVP which is 12-hydroxy-NVP may not be the ultimate toxic metabolite responsible for NVP induced side effect. It is possible to propose that; 12-hydroxy-NVP may be further converted to ultra short lived ultimate toxic metabolite responsible for the adverse side effects. This suggested proposal need to be verified by more extensive and advanced works

Study on the psychotherapeutic potential of marjoram oil on clonidine-induced depressed rats

Depression is a strong mood involving sadness, discouragement, despair, or hopelessness that lasts for weeks, months, or even longer. It interferes with a person's ability to participate in normal activities. Depression affects a person's thoughts and behavior as well as mood. The use of herbal medicine in psychiatry practice has increased tremendously in the past decade due to its fewer side effects and it can enhance the effects of conventional agents or be an alternative treatment. Marjoram is considered one of the most common herbs of Lamiaceae family. The therapeutic properties of marjoram oil are analgesic, antioxidant, calms nerves, anti-spasmodic, expectorant, hypotensive and sedative. This work aims to investigate the effect of marjoram oil on the brain neurotransmitters of clonidine-induced depressed rats as well as their behavioral responses using open field and forced swimming tests. The results show that marjoram oil treatment normalized the brain neurotransmitters content, the latency period and ambulation frequency in clonidine depressed rats. A decrease in the immobility time and an increase in the struggling time were observed in the forced swimming test. Treatment with fluoxetine or marjoram oil of the depressed rats decrease malondialdehyde content and increase the reduced glutathione content. It can be conclude that marjoram oil could play an important role in treatment of depression and alter behavior

Effect of malt extract on the neuron-behavioral changes in clonidine-induced depressed rats

Depression is a serious disorder that represents a major public disease often associated with symptoms at the psychological and physiological levels. Herbs and herbs-derived products have attracted much attention in relation to prevention of many diseases including psychiatric illnesses. Their therapeutic potential has been assessed in a variety of animal models, and the mechanisms of action have been investigated through neurochemical approaches. The aim of the present study is to investigate the possible antidepressant effects of malt extract using the open field and forced swimming tests and evaluation of brain neurotransmitters and oxidative stress biomarkers in the clonidine-induced depressed rats. Clonidine hydrochloride [0.8mg/kg] was injected intraperitoneally into rats daily for seven days in order to induce depression. Brain contents of serotonin, norepinephrine and dopamine as well as malondialdehyde and reduced glutathione were estimated. Effect of the antidepressant drug fluoxetine was also studied. Malt extract normalized the clonidine-induced altered behavior in the open field and forced swimming tests. Malt extract as well as fluoxetine normalized the reduced brain serotonin and dopamine contents winle fluoxetine increased the brain content of norepinephrine in the clonidine-induced depressed rats. In addition, both malt extract and fluoxetine normalized the altered oxidative biomarkers. The behavioral and biochemical results revealed that malt extract may have antidepressant activity which may he mediated through changes in the brain neurotransmitters and oxidative stress biomarkers

Influence of malt extract and marjoram oil on the neurobehavioral changes of scopolamine -induced demented rats

Dementia can result from Neurodegenerative diseases: Alzheimer's disease, multiple sclerosis, toxic insults and sleep disorder. Alzheimer's disease [AD] is a progresstve degenerative condition that represents the most common cause of dementia. Scopolamine is a reference substance for inducing Alzheimer-like cognitive deficits in both man and animals Donepezil hydrochloride is highly selective for the CNS and is used for the symptomatic treatment of mild to moderately severe dementia in Alzheimer's disease. Malt extract and marjoram oil are natural products used in folk medicine for the treatment of some psychiatric disorders. The present work aims to study the influence of malt extract and marjoram oil on the behavioral responses, cholinesterase activity, brain monoamines, malondialdehyde and reduced glutathione of scopolamine induced demented rats. The results show that scopolamine decreased the ambulation and rearing frequencies in the open field test. Norepinephrine, dopamine and reduced glutathione contents were also decreased. However, cholinesterase activity and malondialdehyde content were increased significantly. Treatment of demented rats with donepezil, malt extract or marjoram oil individually could normalize the effect of scopolamine on these measured parameters. Data revealed that malt extract and marjoram oil could play an important role in treatment of demented rats by improving the changed behavioral parameters, altered brain neurotransmitters, cholinesterase activity and oxidative biomarkers

Influence of exposure to vapour of certain pyrethroids household mosquito repellant preparations on the neurobehavioral action of fluoxetin in rats

The environment includes increasing number of synthetic chemical compounds that cause environmental contamination . One of the most popular contaminating compounds are pyrethroids insecticides .Therefore, their wide spread use in agriculture and puplic health stimulated our attention for studying their possible toxic effect[s] on drug action .Fluoxetine is a selective inhibitor of serotonin reuptake which is widely used as an antidepressant . The aim of this work was to study the effect of inhalational exposure to vapour of two commonly used mosquito repellant preparations containing pyrethroids on the neurobehavioural action of fluoxetine . Sprague Dawley adult male rats were allocated into 3 main groups namely, control, and Ezalo and Ragon exposed groups .Exposure was performed 20 mm/day for 7 days in a static chamber . Twenty four hours later, i.p injection of fluoxetine [10 mg/kg] was performed . Contents of serotonin, norepinephrine and dopamine were determined in differtent brain regions one hour after fluoxetine injection . Behavioural parameters were also determined using open field and swimming test techniques.The obtained results showed that pre-exposure to Ezalo vapour induced significant increase in ambulation and rearing frequencies, while pre-exposure to Ragon vapour induced significant increase in ambulation, grooming and rearing frequencies as compared to fluoxetine-treated animals . Contents of serotonin and dopamine were also significantly altered in most brain regions .The obtained changes in the neurobehavioural parameters may be due to the effect[s] of pyrethroids and or the accompanying substances present in the mosquito repellant preparations on the biotransformation of fluoxetine

Influence of physical exercise on the anti- inflammatory. action of diclophenac sodium in female rats

Inflammation is the complex biological response of vascular tissues to the harmful stimuli, such as pathogens, damaged cells, or irritants. Regular exercise offers protection against all causes of mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. This work aimed for studying the effect of short term daily exercise [15 min free swimming/day for seven days] on experimentally induced models of inflammation [rat paw edema and carrageenan soaked sponge models]. 80 adult female Sprague-Dawley rats were divided into two equal main groups, untrained sedentary rats and trained rats [where animals were subjected to physical exercise as free swimming]. 24 hours after the last training, animals of each main group were subdivided into two subgroups, where each subgroup was subjected to one of the models mentioned before and the pharmacological action of diclophenac sodium under these conditions was estimated. Results showed that exercise significantly increased rat paw edema weight and that diclophenac sodium significantly decreased the inflammation induced both in normal and trained animals. To the contrary, exercise significantly decreased exudates volumes and number of leucocytes infiltrate in the carrageenan soaked sponge model. Administration of diclophenac sodium significantly reduced the exudates volumes and number of leucocytes in normal untrained rats only. The results will be discussed in view of the roles of pro-inflammatory and anti-inflammatory cytokines as well as the difference in the two models used

Influence of imiprothrin and diflubenzuron on an atopic disease model induced by bordetella pertussis and hiberix vaccines in mice

Atopic diseases seemed to merge as a dramatic clinical problem especially in developing and poor countries. This work aimed to study the possible influence of the insecticides imiprotherin and difubenzuron on the atopic phenomenon induced by Bordetella pertusis [B-p] and Hiberix vaccines. Swiss albino mice were fed on insecticide free diet, imiprothrin or difubenzuron containing diet. The insecticide concentrations were ten times the acceptable daily intake given for four weeks. Animals were vaccinated either with B-p. or Hiberix vaccines in single or repeated doses and blood eosinophil counts were then determined. The results revealed that: - Severe eosinopenia appeared in animals fed by diet containing imiprotherin or diflubenzuron compared with animals fed by insecticide free diet [before vaccination]. - Single or repeated vaccination with either B-p or Hiberix induced a phase of eosinopenia followed by an eosinophilic phase in animals fed insecticides free diet. - Single or repeated vaccination with either B-p or Hiberix induced continuous phase of eosinophilia in animals fed imiprothrin or diflubenzuron containing diet, which was more potentiated compared with control group. - The onset of eosinophilia starts first day after vaccination

possible protective effect[s] of linseed oil against nephrotoxicity of some drugs

Linseed oil is a popular dietary element in Egypt It was found to decrease hepatic toxicity and acute lethality of acetaminophen and to decrease renal toxicity induced by gentamycin or acetaminophen [Metwally et al, 2001]. The present work aims for studying the possible protective effect[s] of linseed oil against nephrotoxicity induced by cisplatin [anticancer], cyclosporine [immunosuppressant], as well as streptomycin [amino glycoside antibiotic]. Adult male Sprague Dawely rats were fed daily by either control diet [control rats], or diet containing 5% linseed oil for 15 days. Twenty four hours later, animals of each group were subdivided into 4 subgroups and treated as follows: control [drug free], cisplatin [4mg/kg i.p. X 1 day], cyclosporine [50mg/kg orally X 6 days] or streptomycin [800mg/kg i.p. X 6 days]. Seven days after administering the first dose of the nephrotoxic agents the following parameters were assessed: serum creatinine and urea, glomerular filtration rate, urea clearance, serum and urine sodium and potassium as well as specific gravity and urine volume. Kidney histopathology and relative weights were evaluated. The results showed that linseed oil causes pronounced protective effect against streptomycin nephrotoxicity, slight protection against cyclosporine and very slight protective effect against cisplatin treated animals. The obtained results will be discussed in view of the possible impacts on eicosanoids and throinboxane synthesis

Influence of the state of dehydration and rehydration on the in-situ intestinal absorption of carotene in rats

This work aimed to evaluate the influence of an experimental model of diarrhea as well as the rehydration process on the in situ intestinal absorption of carotene in rats. Reproducible models of mild and severe infectious diarrhea were produced by peroral challenges with Salmonella typhimurium in adult male rats. The in situ intestinal absorption of carotene was evaluated along 90 minutes in cases of diarrhea in the presence and absence of oral rehydration solution as well as after rehydration. The utilized concentration of carotene was 0.83 mg%. Absorption was evaluated by determining the circulating fractions of carotene as well as the rate constants of absorption from the lumen to the intestinal membrane [K1] and from the intestinal membrane to the central compartment [K2]

Influence of the states of dehydration and rehydration on the in-situ intestinal absorption of calacctose and clucose in rats

This work aimed to evaluate the influence of an experimental model of diarrhea as well as the dehydration and rehydration rats. Reproducible model of mild and severe infectious diarrhea was produced by peroral challenges with Salmonella typhimurium in adult male rats. The in situ intestinal absorption of galactose and glucose was evaluated along 90 minutes in case of diarrhea in the presence and absence of oral rehydration solution as well as after rehydration. The utilized concentration of galactose was 325 mg%. Absorption was evaluated by determining the circulating fractions of galactose and glucose as well as the rate constants of absorption [K1 and K2]. A statistically significant reduction in the circulating amounts of sugar was occurred in the infected animals

Influence of the states of dehydration and rehydration on the in-situ intestinal absorption of histidine

In this study, experimental models for mild and severe infectious diarrhea were produced by peroral challenge with Salmonella typhimurium. The in situ intestinal absorption of histidine was evaluated along 90 minutes in the cases of diarrhea in presence of saline or oral rehydration solution [ORS] as the perfusion fluid and rehydration solution ORS following exposure to diarrhea. The concentration of histidine was 18.1 mg%. Significant differences in absorption and exsorption of histidine have been obtained according to the animal condition and the perfusion fluid. Diarrhea disturbed the amino acid pool. The presence of ORS augmented the transport of histidine in the diseased animals

Effect of protein malnutrition on the immune system of normal rats treated with some immuno depressant drugs

The aim of the present work is to investigate the influence of protein malnutrition on the immuno-toxicological effect of cyclophosphamide [15mg/kg body weight /day for 5 days] and azathioprine [5mg/kg per day for 6 days] treatment on male rats. Two diet groups were used, each of 40 rats, a protein standard diet and a protein malnourished one. Protein malnutrition was induced by restricting the amount of casein in diet to 5% instead of 20% which is the approximate ideal concentration. Histopathology of spleen and thymus, body weight, organ weight and circulating immunoglobulin were chosen as parameters for this study. Histologically, the splenic haemopoeisis was reduced and was a loss in the follicular cells after cyclophosphamide and azathioprine treatment in the normal protein group. The tyniphoid follicles became more structurally disorganized and contained fewer cells in protein malnourished treated group. Thymuses from all treated groups revealed severe loss of lymphocyts but more depletion was obtained in malnourished rats after cyclophosphamide and azathioprine treatments. Significant decrease in circulating immunoglobulin, body weight and organ weight in treated groups was also noticed

Preliminary toxicological evaluation of salicyl hydroxamic acid in rats and dogs

Salicyl hydroxamic acid [SHAM] has been found to prevent and treat urinary stones caused by urea splitting hacteria. The present work aims at delineation of its acute toxicity in rats and dogs and its organotropic toxic potential in rats. The obtained results showed that in rats, the oral LD50 of SHAM was 5.0 [3.74 - 7.20] g/kg, while the i.p. LD50 was 0.60 [0.44 - 0.82] g/kg. Administration of 1800 mg.i.p. in dogs resulted in reversible allergic-like skin reactions. The 90 days oral toxicity study of 200 and 500 mg/kg in rats resulted in increased body weight and fluctuations in blood glucose, in addition to hepatic, renal, splenic, and cardiac toxicological and biochemical reactions. Subacute exposure to SHAM in rats has resulted in significant changes in brain amino acid neurotransmitters and an immunosuppressant effect on serum IgG. The obtained results rate are to be utilized for planning of the full preclinical toxicological evaluations

Influence of age on pharmacokinetcs of orally administered nitrofurantoin and furazolidone in buffalo

The present work aims at studying the disposition kinetics of single doses of nitrofurantoin [NFT] and furazolidone [FZ] in buffalos of different ages. The experiments were conducted on animals of 6-8 years, 2-12 months and less than 2 months old. The pharmacokinetic analysis of the determined levels of the two tested drugs during 24 hours following their administration has showed age-dependent variations. The rate constant of elimination [Kel] was decreasing with the increase of age with a consequent prolongation of the elimination half life [tB 1/2]. As a net result of the different induced changes in pharmacokinetics, the area under the plasma level curve has been markedly decreased in the young age animals. As a conclusion, dosage regimens of NFT and FZ in buffalo calves should be adjusted according to the age of the animals

Keten-s,s-gem, dithiols Interaction with heterogeneous radicals and study the effect of products as antimicrobial agents

3, 3-dimercapto-1-[p-tolyl] 2-propen-1-one [ketene-S, S-gem, dithiol] was prepared and its chemical reactions were studied. This includes acylation, alkylation, reaction with quinones, amines, alpha-amino acids and carbonyl compounds

Interaction of capsaicin with mixed function oxidases: exvivo and in-vivo studies

Capsaicin was recently found to alter the in-vitro biphenyl hydroxylation by the 9000 xg supernatent of the liver homogenate of rats. The present work aims at evaluating the effect of subcutaneously administered capsaicin on the ex-vivo metabolism of biphenyl in rats. The produced changes were compared with that of enzyme induction by phenobarbital. In addition, the in-vivo effect of capsaicin on drug metabolism was evaluated by use of the model of hexobarbital sleeping time. It is concluded that subcutaneous administration of capsaicin produces marked activation of drug metabolising enzymes

Influence of capsaicin on enzyme induction by phenobarbital in rats

The present work aims at studying the possible influence of capsaicin on enzyme induction by phenobarbital. A pharmacodynamic model [pentobarbital hypnosis] was utilized for testing the change in enzyme induction. Experiments were performed on adult male Wistar rats. Animals were treated daily for 9 days with phenobarbital alone or together with 1 or 8 mg/kg of capsaicin [p.o.]. All animals received pentobarbital [50 mg per kg, i.p.] one day after the last dosage. The duration of sleep by pentobarbital was reduced by 87.52% under influence of pretreatment with phentobarbital. This percentage was significantly [P < 0.01] reduced as a result of the concomitant administration of capsaicin with phenobarbital. Possible mechanism [s] for this effect are discussed

Influence of capsaicin on drug absorption and transport across biological membranes I Effect on buccal absorption of sulfathiazole

The present work aims at studying the effect of capsaicin on the buccal absorption of sulfathiazole sodium. The study was conducted on 22 volunteers by use of the Beckett-Triggs model of buccal absorption. The absorbed amount of sulfathiazole was significantly higher in eaters of capsicum in comparison with those who do not eat it. The degree of enhancement was much higher in non eaters of hot peppers

Effect of capsaicin on drug absorption and transport across biological membranes III Effect on buccal absorption of glucose

In the persent work, a study was made on the effect of capsaicin on the buccal absorption of glucose by human being. Different incubation periods in the buccal cavity, as well as different concentrations of capsaicin and glucose were utilized. The obtained results indicate an enhancement in the buccal absorption of glucose under influence of capsaicin