Effect of increasing intraperitoneal infusion rates on bupropion hydrochloride-induced seizures in mice.

BACKGROUND: It is not known if there is a relationship between input rate and incidence of bupropion-induced seizures. This is important, since different controlled release formulations of bupropion release the active drug at different rates. METHODS: We investigated the effect of varying the intraperitoneal infusion rates of bupropion HCl 120 mg/kg, a known convulsive dose 50 (CD50), on the incidence and severity of bupropion-induced convulsions in the Swiss albino mice. A total of 69 mice, approximately 7 weeks of age, and weighing 21.0 to 29.1 g were randomly assigned to bupropion HCl 120 mg/kg treatment by intraperitoneal (IP) administration in 7 groups (9 to 10 animals per group). Bupropion HCl was infused through a surgically implanted IP dosing catheter with infusions in each group of 0 min, 15 min, 30 min, 60 min, 90 min, 120 min, and 240 min. The number, time of onset, duration and the intensity of the convulsions or absence of convulsions were recorded. RESULTS: The results showed that IP administration of bupropion HCl 120 mg/kg by bolus injection induced convulsions in 6 out of 10 mice (60% of convulsing mice) in group 1. Logistic regression analysis revealed that infusion time was significant (p = 0.0004; odds ratio = 0.974) and increasing the IP infusion time of bupropion HCl 120 mg/kg was associated with a 91% reduced odds of convulsions at infusion times of 15 to 90 min compared to bolus injection. Further increase in infusion time resulted in further reduction in the odds of convulsions to 99.8% reduction at 240 min. CONCLUSION: In conclusion, the demonstration of an inverse relationship between infusion time of a fixed and convulsive dose of bupropion and the risk of convulsions in a prospective study is novel.

Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice.

BACKGROUND: It is known that following chronic dosing with bupropion HCl active metabolites are present in plasma at levels that are several times higher than that of the parent drug, but the possible convulsive effects of the major metabolites are not known. METHODS: We investigated the convulsive liability and dose-response of the three major bupropion metabolites following intraperitoneal administration of single doses in female Swiss albino mice, namely erythrohydrobupropion HCl, threohydrobupropion HCl, and hydroxybupropion HCl. We compared these to bupropion HCl. The actual doses of the metabolites administered to mice (n = 120; 10 per dose group) were equimolar equivalents of bupropion HCl 25, 50 and 75 mg/kg. Post treatment, all animals were observed continuously for 2 h during which the number, time of onset, duration and intensity of convulsions were recorded. The primary outcome variable was the percentage of mice in each group who had a convulsion at each dose. Other outcome measures were the time to onset of convulsions, mean convulsions per mouse, and the duration and intensity of convulsions. RESULTS: All metabolites were associated with a greater percentage of seizures compared to bupropion, but the percentage of convulsions differed between metabolites. Hydroxybupropion HCl treatment induced the largest percentage of convulsing mice (100% at both 50 and 75 mg/kg) followed by threohydrobupropion HCl (50% and 100%), and then erythrohydrobupropion HCl (10% and 90%), compared to bupropion HCl (0% and 10%). Probit analysis also revealed the dose-response curves were significantly different (p < 0.0001) with CD50 values of 35, 50, 61 and 82 mg/kg, respectively for the four different treatments. Cox proportional hazards model results showed that bupropion HCl, erythrohydrobupropion HCl, and threohydrobupropion HCl were significantly less likely to induce convulsions within the 2-h post treatment observation period compared to hydroxybupropion HCl. The mean convulsions per mouse also showed the same dose-dependent and metabolite-dependent trends. CONCLUSION: The demonstration of the dose-dependent and metabolite-dependent convulsive effects of bupropion metabolites is a novelty.

Alcohol significantly lowers the seizure threshold in mice when co-administered with bupropion hydrochloride.

BACKGROUND: Bupropion HCl is a widely used antidepressant that is known to cause seizures in a dose-dependent manner. Many patients taking antidepressants will consume alcohol, even when advised not to. Previous studies have not shown any interactions between bupropion HCl and alcohol. However, there have been no previous studies examining possible changes in seizure threshold induced by a combination of alcohol and bupropion HCl. METHODS: Experimentally naïve female Swiss albino mice (10 per group) received either single doses of bupropion HCl (ranging from 100 mg/kg to 120 mg/kg) or vehicle (0.9% NaCl) by intraperitoneal (IP) injection in a dose volume of 10 ml/kg, and single-dose ethanol alone (2.5 g/kg), or vehicle, 5 min prior to bupropion dosing. The presence or absence of seizures, the number of seizures, the onset, duration and the intensity of seizures were all recorded for 5 h following the administration of ethanol. RESULTS: The results show that administration of IP bupropion HCl alone induced seizures in mice in a dose-dependent manner, with the 120 mg/kg dose having the largest effect. The percentage of convulsing mice were 0%, 20%, 30% and 60% in the 0 (vehicle), 100, 110, and 120 mg/kg dose groups, respectively. Pretreatment with ethanol produced a larger bupropion HCl-induced convulsive effect at all the doses (70% each at 100, 110 and 120 mg/kg) and a 10% effect in the ethanol + vehicle only group. The convulsive dose of bupropion HCl required to induce seizures in 50% of mice (CD50), was 116.72 mg/kg for bupropion HCl alone (CI: 107.95, 126.20) and 89.40 mg/kg for ethanol/bupropion HCl (CI: 64.92, 123.10). CONCLUSION: These results show that in mice alcohol lowers the seizure threshold for bupropion-induced seizures. Clinical implications are firstly that there may be an increased risk of seizures in patients consuming alcohol, and secondly that formulations that can release bupropion more readily in alcohol may present additional risks to patients.

mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.

Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.

Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 +/- 2.4 and 7.2 +/- 4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 +/- 32 and 136 +/- 57 ng.h.mL-1 at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66 years), or weight (42-132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.

Clinical development of an everolimus pediatric formulation: relative bioavailability, food effect, and steady-state pharmacokinetics.

The immunosuppressant everolimus used in organ transplantation is formulated as a conventional tablet for adults and a dispersible tablet that can be administered in water for pediatric use. As part of the pediatric clinical development program, the relative bioavailability and food effect for the dispersible tablet were evaluated in healthy adult subjects as a prelude to characterizing the steady-state pharmacokinetics in pediatric kidney allograft recipients. In a randomized, open-label, three-way crossover study, 24 healthy adults received single 1.5-mg oral doses of everolimus as (1) six 0.25-mg dispersible tablets in water, (2) two 0.75-mg conventional tablets, and (3) six 0.25-mg dispersible tablets in water after a high-fat breakfast. Cmax and AUC were evaluated by standard bioequivalence testing to determine relative bioavailability and to quantify the effect of food. In a multicenter open-label efficacy/safety trial, pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as dispersible tablets in water. Serial trough concentrations over the first week and a steady-state pharmacokinetic profile on day 7 posttransplant were collected in 19 patients ranging from ages 2 to 16 years old. The bioavailability of everolimus from the dispersible tablet was 10% lower relative to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76-1.07). After a high-fat meal, tmax was delayed by a median 2.5 hours, and Cmax was reduced by 50%. Overall absorption, however, was not affected by food inasmuch as the fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric patients, steady state was reached between days 3 and 5. The corresponding steady-state parameters were as follows: Cmin, 4.4 +/- 1.7 ng/ml; Cmax, 13.6 +/- 4.2 ng/ml; and AUC, 87 +/- 27 ng.h/ml. Steady-state concentration-time profiles in pediatric transplant patients receiving the dispersible tablet were comparable to those of adult patients receiving the conventional tablet when both were dosed to yield similar trough concentrations. If a pediatric patient is converted from the everolimus dispersible tablet to the conventional tablet, this should be based on a 1:1 milligram switch with subsequent therapeutic drug monitoring to further individualize the dose as needed. The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time.

Administration diluents differentiate Neoral from a generic cyclosporine oral solution.

A non-microemulsion cyclosporine oral solution was recently recalled from the market because of the lack of bioequivalence when administered with apple juice compared with water as the diluent. This open-label, randomized, two-period, crossover study assessed the effect of apple juice on Neoral, a microemulsion cyclosporine oral solution. The study enrolled 34 subjects who received 180 mg Neoral oral solution diluted in 200 mL tap water or apple juice. Cyclosporine was measured in whole blood by a liquid chromatography method. Pharmacokinetic parameters were compared by standard bioequivalence tests. With water vs. apple juice, cyclosporine Cmax was 1263 +/- 203 vs. 1191 +/- 225 ng/mL and AUC was 4714 +/- 1117 vs. 4788 +/- 1320 ng h/mL, respectively. Bioequivalence was demonstrated for both parameters. These data were comparable with those from a previous study in which subjects received 180 mg Neoral oral solution with orange juice. Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label.