Potentiating effect of rifampicin on methimazole induced hepatotoxicity in mice

Methimazole [MMI] is a widely used drug for hyperthyroidism. However, its clinical use is associated with hepatotoxicity. Though the precise mechanism of hepatic damage is still far from clear, role of metabolic activation and reactive metabolites have been implicated. The present study was designed to investigate the role of enzyme induction in bio activation based hepatotoxicity of methimazole in mice. Thirty male mice were randomly divided into five groups. Hepatotoxicity was induced by single intraperitoneal injection of methimazole [1000mg/kg]. Pretreatment with rifampicin which is a potent enzyme inducer was carried out for 6 days prior to administration of methimazole. The extent of hepatic damage was determined by measuring serum alanine aminotransferase [ALT] and alkaline phosphatase [ALP] along with histopathological grading of liver samples. The elevated levels of biochemical markers by methimazole were potentiated by pretreatment with rifampicin. This potentiation of hepatic injury was also observed in liver histopathological examination. These findings suggest induction of microsomal enzymes as a potentiating factor of methimazole induced hepatotoxicity

Alpha-tocopherol ameliorates nephrotoxicity associated with the use of colistin in rabbits

The alarming rise in the rate of multi drug resistant, life threatening gram negative infections has brought renaissance in the use of Colistin for last two decades. The major constraint in its utilization is its nephrotoxicity. Therefore it is being underused which is favoring the development of resistance. This study assesses the prevention of nephrotoxicity associated with high and low toxic doses of Colistin by alpha-tocopherol. Thirty rabbits were randomly divided into five groups. Baseline serum urea, creatinine and electrolytes were estimated. A loading dose of colistin was given in the form of infusion followed by I.M injections for six days. In the preventive groups alpha-tocopherol was additionally given orally for two weeks. Rabbits were sacrificed 24 hours after the last dose. The kidney slides graded and statistically analyzed using [chi square]. The results of serum analysis were compared using one way analysis of variance followed by post hoc tukey test. There was marked nephrotoxicity in high toxic group where as in low toxic group mild nephrotoxicity was evident. Alpha-tocopherol attenuated the renal insult in both the toxic groups. As damage induced by colistin is oxidative in nature, thus it was concluded that the protection offered by alpha- tocopherol is due to its antioxidant activity

Aliskerin: a direct renin inhibitor improves pancreatic functional b cell mass in type 2 diabetic mice

Objective: To evaluate the effects of Aliskerin on functional pancreatic beta cell mass in type 2 diabetic mice. Study Design: Analytical experimental study. Place and Duration of Study: The study was conducted at the animal house of National Institute of Health, Islamabad. Duration of the study was of twelve weeks after initial acclimatization of one week

Material and Methods: Twenty four BALB/c mice, both male and female, of 35 to 40 grams were used for this study. Animals were randomly divided into four groups. Two served as control, one was normal and the other was diabetic control. The remaining two were used as interventional groups and received either pioglitazone or aliskerin for four weeks after induction of diabetes. Fasting blood glucose levels with fasting insulin levels were estimated. Insulin resistance was determined by calculating homa IR and pancreatic morphology was assessed by evaluating pancreatic beta cell mass

Results: After treatment, pioglitazone reduced all the biochemical parameters significantly when compared with diabetic control and negative correlation between glucose and insulin was changed into positive correlation [r value, 0.92] with significant p-value [0.015], while aliskerin caused a significant rise [p-value 0.009] in functional pancreatic beta cell mass

Conclusion: Aliskerin has a significant anti-diabetic role as far as pancreatic morphology is concerned

Study of protective effects of melatonin on cisplatin-induced nephrotoxicity in rabbits

Objective: To evaluate the protective effects of melatonin on cisplatin-induced nephrotoxicity in rabbits. Study Design: Laboratory based randomized control trial. Place and Duration of Study: Department of Pharmacology and Therapeutics in collaboration with Clinico Pathologic Laboratory, Army Medical College, Rawalpindi, from Apr to Jun 2015

Material and Methods: Eighteen rabbits were divided into three groups, each consisting of six rabbits. Baseline serum urea, creatinine, sodium and potassium were measured. Rabbits were weighed for dose calculation. A single dose of cisplatin 10mg/kg was given as I/P injection to the toxic group. The protective group received 5 mg/kg I/P melatonin for three days. Rabbits were sacrificed 72 hours after the cisplatin dose and both kidneys were sent for histopathology. Statistical analysis was carried out by using Microsoft Office Excel 2010 and SPSS version 21. Student's t-test and one way ANOVA, followed by 'Post Hoc Tukey' test was used for biochemical parameters, while Chi Square' test was used for histopathological comparison

Results: Moderate nephrotoxicity [grade-II] was seen in the toxic group, with substantial elevations of serum urea and creatinine [p<0.001], and serum sodium and potassium [p<0.01]. Melatonin ameliorated the renal injury

Conclusion: The protective effects of melatonin on cisplatin-induced nephrotoxicity were due to its antioxidant properties

Ondansetron: a newer aspect of dose response relationship on ileal smooth muscles of rabbit

There are several life threatening deadly diseases in our world but 'Cancer' out powers them all in recent years. Chemotherapy may be used on its own or an adjunct to other forms of therapy. Despite the advancement in cytotoxic drug therapy and supportive treatment almost 70% of patient suffer from chemotherapy induced nausea and vomiting [CINV]. Ondansetron, a 5-HT[3] receptor antagonist has now become a gold standard in the treatment of chemotherapy induced nausea and vomiting. The central actions of ondansetron are well established but its peripheral actions are not well recognized. The aim of our study was to explore the peripheral actions of ondansetron. Experiments were performed in five groups [n=6] and ileal smooth muscles activity was recorded on power lab [USA]. The effects of increasing concentrations of acetylcholine, serotonin and ondansetron alone was observed in first three groups. In the next two groups effects of acetylcholine and serotonin pretreated with fixed concentration [1ml] of ondansetron [10 Omega M] were studied. The maximum response obtained by acetylcholine served as a control for our study. Maximum response with acetylcholine was taken as 100% and with serotonin was 177 percent of control. Cumulative dose response curve with ondansetron was triphasic. At 10 PSI M it was 28.8%, whereas with 10XI M the amplitude decreased to 16.87%, it reached to plateau at 10 Omega M. Response of acetylcholine and serotonin was decreased to 57% and 78% respectively in the presence of fixed concentration of ondansetron [10 Omega M]. Ondansetron reduces the acetylcholine and serotonin induced gastrointestinal motility. Our study has indicated that ondansetron apart from having central action also has marked peripheral actions that play an important role in CINV and may act as a partial agonist

Protective effect of pioglitazone on gentamicin induced nephrotoxicity in rabbits

Objective: To evaluate potential role of pioglitazone in protecting kidneys from nephrotoxic insult produced by Gentamicin

Study design: Comparative study on animal model

Place and Duration of Study: Department of Pharmacology Army Medical College, duration of study was six months

Material and Methods: Twenty four rabbits were randomly divided into four groups [n=6]. Group [Gp]-1 received 1 milliliter [ml] isotonic saline intraperitoneally [IP] daily for 13 days. Gp-2 received gentamicin 40 miligram/kilogram/day [mg/kg/day] IP daily for 13 days. Gp-3 received pioglitazone salt 10 mg/kg/day dissolved in drinking water via feeding tube for 13 days. Gp-4 received pioglitazone salt 10 mg/kg/day via feeding tube plus gentamicin 40 mg/kg/day IP for 13 days. Blood was collected on days 0 and 14 for estimation of serum urea and creatinine. All animals were sacrificed and kidneys were removed for renal histological examination

Results: Pioglitazone did not show any nephroprotective effect against gentamicin induced nephrotoxicity

Conclusion: Pioglitazone fails to exhibit nephroprotective potential when administered along with nephrotoxic dose of gentamicin

IS CO Q10 really valuable in shielding statin induced myopathy-an exploration

Objective: This study was designed to scrutinize the shielding effects of Co enzyme Q10 [Co Q10] supplementation in statin associated muscular adverse effects in rabbits

Study Design: Randomized controlled trial

Place and Duration of Study: Pharmacology dept Army Medical College Rawalpindi from Jan 2012 to Jun 2012

Material and Methods: Twenty two healthy rabbits were taken and divided into four equal groups randomly with six in each batch. The two groups [Gl and G2] were given toxic doses of simvastatin [60mg/kg/day] with and without Co Q10 [5mg/kg/day] orally for 14 days and rest of two groups [G3 and G4] were kept on therapeutic doses [Img/kg/day] of simvastatin with and without Co Q10 [5mg/kg/day] orally for 90 days. Blood samples were drawn and serum creatinine kinase [CK] and lactate dehydrogenase [LDH] were assessed before and after the drug therapy. Histopathological examination was done to observe the inflammatory changes under light microscope. The results were analyzed by applying paired [t] test, independent [t] test and ANOVA test for biochemical markers and 'Chi-Square test' for histopathologcal findings. The p-value < 0.05 was considered significant

Results: The biochemical markers went up sharply [Gl. CK=28899.5 +/- 874.09 IU/L and LDH = 4694.33 +/- 352 IU/L] and [G2. CK = 29191.33 +/- 3019.79 IU/L and LDH = 4334.83 +/- 143.44 IU/L] as compared to baseline values

They were given toxic doses of simvastatin with and without Co Q10. Histopathological examination of muscular tissue also revealed gross inflammatory changes in these groups. However histopathological examination of groups who were given therapeutic doses of simvastatin with and without Co Q10 for 90 days showed mild to moderate inflammatory changes but serum CK and LDH remained in the normal ranges in these groups

Conclusion: Our results suggest that Co Q10 supplementation could not produce any beneficial effects on the statin induced muscular adverse effects

Ranitidine potentiates the effect of metoclopramide on gastro-intestinal motility in rabbits

Objective: To explore the synergistic potential of ranitidine on prokinetic activity of metoclopramide on isolated duodenal model of rabbit

Study Design: Laboratory based randomized controlled trial

Place and Duration of Study: Multi-disciplinary Laboratory, Army Medical College, Rawalpindi with study duration of 12 months

Material and Methods: Dose response curve of ranitidine and metoclopramide were constructed by adding cumulatively increasing concentrations of the two drugs on isolated duodenum of rabbits separately. A fixed dose of ranitidine was then selected for studying its potentiating effect on increasing concentrations of metoclopramide on isolated duodenum of rabbits utilizing iWorx Data acquisition unit AHK/214

Results: Ranitidine enhances the prokinetic effect of metoclopramide

Conclusion: Ranitidine enhances the contractile effect of the gut in vitro and potentiates the prokinetic effect of metoclopramide. So we conclude that ranitidine is a better choice for patients suffering from gastroesophageal reflux disease [GERD] along with gastroparesis as it enhances the prokinetic effect of metoclopramide

Comparative study of protective effects of salbutamol and beclomethasone against insulin induced airway hyper-reactivity on isolated tracheal smooth muscle of guinea pig

Inhalational insulin was withdrawn from the market due to its potential to produce airway hyper-reactivity and bronchoconstriction. So the present study was designed to explore the acute effects of insulin on airway reactivity of guinea pigs and protective effects of salbutamol and beclomethasone against insulin induced airway hyper-responsiveness on isolated tracheal smooth muscle of guinea pig. Effects of varying concentrations of insulin [10[-7] to 10[-3] M], insulin pretreated with fixed concentration of salbutamol [10[-7] M] and beclomethasone [10[-6] M] were studied on isolated tracheal tissue of guinea pig by constructing cumulative concentration response curves. Changes in tracheal smooth muscle contractions were recorded on four channel oscillograph. The mean +/- SEM of maximum amplitudes of contraction with increasing concentrations of insulin, insulin pretreated with fixed concentration of salbutamol and beclomethasone were 35 +/- 1.13 mm, 14.55 +/- 0.62 mm and 22 +/- 1.154 mm respectively. Although salbutamol and beclomethasone both had a profound inhibitory effect on insulin induced airway hyper-reactivity, yet salbutamol is more efficacious than beclomethasone. So we suggest that pretreatment of inhaled insulin with salbutamol may be preferred over beclomethasone in amelioration of its potential respiratory adverse effects such as bronchoconstriction

Protective effect of metformin against gentamicin induced nephrotoxicity in rabbits

Gentamicin is used against gram negative infections, but major problem encountered is nephrotoxicity that occurs in 10-20% of therapeutic regimes. Gentamicin induced oxidative stress plays an important role in this nephrotoxicity. Recent data has shown metformin to possess antioxidant activity. Purpose of study was to evaluate potential role of metformin in protecting kidney from nephrotoxicant insult. Thirty-six rabbits were randomly divided into six groups [n=6]. G-1 received 1 ml isotonic saline intraperitoneally [IP] daily for 13 days. G-2 received gentamicin [150 mg/kg/day] IP for last 6 days of 13 days. G-3 received gentamicin [40 mg/kg/day] IP for 13 days. G-4 received metformin salt [100 mg/kg/day] dissolved in drinking water via feeding tube for 13 days. G-5 received metformin salt [100 mg/kg/day] via feeding tube for 13 days plus gentamicin [150 mg/kg/day] IP for last 6 days of 13 days. G-6 received gentamicin [40 mg/kg/day] IP plus metformin salt [100 mg/kg/day] via feeding tube for 13 days. Blood was collected on days 0 and 14 for serum urea and creatinine estimation. All animals were sacrificed and kidneys were removed for renal histological examination. Metformin showed nephroprotective effect. It blunted nephrotoxic insult at 150 mg/kg/day of gentamicin, whereas showed complete nephroprotection at 40 mg/kg/day of gentamicin. Metformin offers complete nephroprotection at low toxic dose ranges of gentamicin. This could offer an efficacious and cheaper treatment alternative in those diabetics who also suffer from gram-negative infections

Comparative study of succinylcholine and precurarization with rocuronium on muscular effects in patients undergoing surgery under general anaesthesia

Succinylcholine remains the drug of choice in conditions where rapid paralysis and airway control are priorities. However it is associated with muscular side effects that have an overall incidence ranging from five to 83 percent. The administration of small doses of nondepolarizing muscle relaxants before the administration of succinylcholine has been shown to decrease the incidence and severity of muscular side effects experienced by the patients. This study was aimed at evaluating the efficacy of technique in reducing the muscular side effects of succinylcholine. Sixty healthy adults were enrolled in the study who were scheduled for minor muscle cutting surgeries under genera lanaesthesia. They were assigned at random to two groups of thirty patients each. They randomly received succinylcholine for intubation and a precurarization dose of rocuronium followed by succinylcholine for intubation. Intraoperative fasciculations and postoperative myalgia were graded and scored. There was a significantly increased incidence of fasciculations and myalgia in the succinlcholine group. In the precurarization group the incidence and severity of fasciculations and myalgia was significantly less as compared to the group which received succinylcholine alone. We found significant correlation between fasciculations and myalgia in the succinylchloine group. Present study concluded that precurarization with rocuronium was effective in reducing the succinylcholine-induced fasciculations and myalgia

Determination of the effects of ciprofloxacin in prevention of aminoglycoside induced nephrotoxicity in rabbits: a comparative study

The effect of ciprofloxacin on gentamicin-induced nephrotoxicity was evaluated in rabbits. Animals were injected for 15 days with saline [NaCI; 0.9%], gentamicin alone at doses of 20 mg/kg of body weight/12 h [intramuscularly] and the combination of gentamicin [20 mg/kg/12 h] with low and high therapeutic doses of ciprofloxacin [20 mg/kg/12 h and 40 mg/kg12h respectively] by intraperitoneal route. Gentamicin induced nephrotoxicity was evaluated by histopathological and serum analysis. The extent of these changes were significantly increased when gentamicin was given in combination with ciprofloxacin both in low and high doses. although the mechanisms by which ciprofloxacin enhances the nephrotoxic potential of gentamicin are unknown, it is proposed that ciprofloxacin induced allergic interstitial nephritis, enhances the nephrotoxicity and it was indicated by increased amount of interstitial inflammatory infiltrate in the renal proximal tubules of the animals treated with ciprofloxacin-gentamicin combination