methylprednisolone-suleptanate and Asthma

Methylprednisolone suleptanate (Promedrol) is a prodrug of methylprednisolone being developed by Pharmacia Corp (formerly Pharmacia & Upjohn) for the treatment of asthma. It has been approved for this indication in Switzerland and is awaiting registration in several other countries [211246]. Preliminary preclinical data indicated the potential use of methylprednisolone suleptanate for the i.v. treatment of immunological disease. Its anti-inflammatory/bronchodilatory effect was demonstrated in mice and rats and in a guinea pig model [271975]. Animal models have also demonstrated the use of methylprednisolone suleptanate for the treatment of nephritis and hypotension. Efficacy and safety of pulse therapy Promedrol was demonstrated in a phase II trial using lupus nephritis patients. The recommended dose for pulse therapy is 400 mg equivalent/day i.v. [271975]. Other studies in lupus patients have shown that doses of up to 1000 mg/day are well tolerated [307789] and pulse therapy with either 400 or 800 mg/day are efficacious in delaying the onset of CNS symptoms in SLE patients with organic brain disease [307512]. Preclinical studies are also taking place for the potential treatment of spinal cord injury [344254]. In April 2000, Morgan Stanley Dean Witter estimated sales would be US $281 million in 2003, rising to $277 million in 2004 [375906].

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Clinical Trials as Topic; Drugs, Investigational; Humans; Methylprednisolone; Prodrugs; Spinal Cord Injuries; Structure-Activity Relationship

To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma.. Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40 mg (MP equivalents) i.v. 6 hourly for 48 h. The bio-conversion and disposition of a 40 mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase.. Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0 h-1 vs 5.5 h-1 respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7 h vs 3.0 h), steady-state AUC (2007.0 ng ml-1 h vs 2321.0 ng ml-1 h) and steady-state Cmax (698.4 ng ml-1 vs 647.8 ng ml-1) for MP suleptanate and MP succinate respectively.. It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.

Topics: Area Under Curve; Asthma; Bayes Theorem; Body Weight; Chromatography, High Pressure Liquid; Double-Blind Method; Female; Glucocorticoids; Half-Life; Humans; Injections, Intravenous; Male; Methylprednisolone; Methylprednisolone Hemisuccinate; Prodrugs; Sex Factors; Smoking

The efficacy and safety of the methylprednisolone prodrugs methylprednisolone suleptanate and methylprednisolone sodium succinate were evaluated in a multicentre, randomised, double-blind, double-dummy parallel study of 88 patients hospitalised with acute asthma. Each study drug was administered as a bolus intravenous injection of 40mg methylprednisolone equivalents every 6 hours for 48 hours. Methylprednisolone 32mg was administered orally 6 hours after the last dose. Pulmonary function, medical events, and clinical laboratory values were assessed at predefined intervals before and during the 72-hour study. The primary response measure of pulmonary function was per cent predicted forced expiratory volume in one second (FEV1) at 48 hours. Secondary response measures were peak expiratory flow rate (PEFR) and FEV1/forced vital capacity (FVC) ratio. Although both drugs demonstrated within-group mean changes from baseline (starting at 6 hours) that were statistically significant for each response, there were no statistically significant differences between the two groups. The mean percent predicted FEV1 at 48 hours and mean per cent change from baseline were 64% and 13% (p < 0.0001) for the methylprednisolone suleptanate group and 67% and 17% (p < 0.0001) for the methylprednisolone sodium succinate group, respectively. The mean PEFR and FEV1/FVC ratio at 48 hours were 5.77 l/s and 73% for the methylprednisolone suleptanate group and 5.78 l/s and 76% for the methylprednisolone sodium succinate group, respectively. There were no clinically or statistically significant between-group differences in any of the safety parameters. In this study, methylprednisolone suleptanate and methylprednisolone sodium succinate have been shown to be therapeutically equivalent in the treatment of patients hospitalized with acute asthma.

Topics: Acute Disease; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Double-Blind Method; Female; Humans; Male; Methylprednisolone; Methylprednisolone Hemisuccinate; Middle Aged; Prodrugs; Respiratory Function Tests

Effects of U-67590A, an analogue of methylprednisolone, on antigen-induced bronchoconstriction expressed as ventilation overflow were examined in ovalbumin-sensitized guinea pigs. When administered intravenously 17-18 hr before the challenge with antigen, U-67590A at doses of 10 and 30 mg/kg caused dose-dependent inhibition of increased ventilation overflow immediately after challenge. Death due to anaphylactic shock was markedly reduced by U-67590A. At 10 mg/kg (i.v.), U-67590A given 10 min before the challenge significantly inhibited the antigen-induced increase in ventilation overflow; the greatest inhibition seen 5-6 hr prior to the challenge. Pretreatment with 10 mg/kg FPL-55712 attenuated the increase in ventilation overflow during anaphylaxic shock. It is conceivable that inhibition of the leukotriene-mediated response is involved in the glucocorticoid-induced suppression of airway obstruction in anaphylaxis, and that inhibitory action of the glucocorticoid directly acting on the airway may account for the very fast onset of action.

Topics: Anaphylaxis; Animals; Antigens; Asthma; Bronchial Diseases; Chromones; Constriction, Pathologic; Dose-Response Relationship, Drug; Guinea Pigs; Male; Methylprednisolone; Ovalbumin; SRS-A; Time Factors