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PubMed1986

Pharmacokinetics of methylprednisolone, methylprednisolone sodium succinate, and methylprednisolone acetate in dogs.

The absolute bioavailability and pharmacokinetic parameters of two methylprednisolone formulations (methylprednisolone sodium succinate and methylprednisolone acetate) were determined in five dogs. Plasma concentrations of methylprednisolone, methylprednisolone sodium succinate, and methylprednisolone acetate were measured by sensitive and specific high-performance liquid chromatographic methods. After intravenous methylprednisolone sodium succinate administration, methylprednisolone was released rapidly but the extent of availability was rather low (43.6%). This has been tentatively explained in terms of its subsequent single-pass metabolism in the liver, i.e., hepatic hydrolysis of methylprednisolone sodium succinate followed by immediate hepatic elimination of the released methylprednisolone. After intramuscular administration of methylprednisolone acetate, its absorption was slow (half-time of absorption, 69.04 h) and the availability of the released methylprednisolone was low (42.7%). Therapeutic implications of these results are discussed, especially those which are relevant to shock therapy.

Animals↗
PubMed1994

Pilot study of the pharmacokinetics of methylprednisolone after single and multiple intravenous doses of methylprednisolone sodium succinate and methylprednisolone suleptanate to healthy volunteers.

The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first-dose administration, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5- to 1.8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.

Adult↗
PubMed1999

Simultaneous analysis of dextran-methylprednisolone succinate, methylprednisolone succinate, and methylprednisolone by size-exclusion chromatography.

An analytical HPLC method is reported for simultaneous measurement of low (1.0-100 microg ml(-1)) concentrations of dextran-methylprednisolone succinate (DEX-MPS) and its degradation products methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP). The analytes were detected at 250 nm after resolution using a size exclusion column with a mobile phase of KH2PO4 (10 mM): acetonitrile (3:1) and a flow rate of 1 ml min(-1). The resolution of MP and MPS peaks was substantially affected by the pH of the mobile phase; while MP and MPS co-eluted at pH 3.4, they were baseline-resolved at pH > or = 5. Linear relationships (r > or = 0.997) were found between the detector response and the concentrations of the analytes (1.0-100 microg ml(-1) for MP and MPS and 2.5-100 microg ml(-1) for DEX-MPS). Intra- and inter-run error (< 13%) and precision (CV of < or = 6%) data indicated that the assay could accurately and precisely quantitate all three components in the examined concentration range. The application of the assay to determination of degree of substitution, purity, and stability of DEX-MPS was also demonstrated.

Anti-Inflammatory Agents↗
PubMed1986

Synovial fluid and plasma kinetics of methylprednisolone and methylprednisolone acetate in horses following intra-articular administration of methylprednisolone acetate.

Synovial fluid and plasma kinetics of methylprednisolone acetate (MPA) and methylprednisolone (MP) after a single intra-articular administration of MPA at a therapeutic dose (111 mg in toto) was measured in five horses. MPA was detected in synovial fluid for two to six days post injection and MP, which results from synovial MPA hydrolysis, was present in pharmacologically significant concentrations for 4.8 to 39 days, depending on the horse. MPA synovial concentration was maximal (289 +/- 284 micrograms/ml) at the first sampling time (2 h after administration) and MP synovial concentration was maximal (from 58.9 to 379.5 micrograms/ml) at the first or second sampling time (2 to 10 h after administration). Thereafter, both MP and MPA declined rapidly. From time of administration to about five days later, MP synovial fluid concentration fell progressively with a half-time of 9.95 h. Subsequently, the MP synovial fluid concentration decreased more slowly with an apparent half-time of 115 h. During the first 24 h following MPA administration, trace amounts of MP (less than 5 ng/ml) were detected in plasma. Plasma hydrocortisone levels were depressed for three to four days after administration but adrenal responsiveness to adrenocorticotrophic hormone tests remained unaffected.

Adrenal Glands↗
PubMed1986

Bovine plasma and synovial fluid kinetics of methylprednisolone and methylprednisolone acetate after intra-articular administration of methylprednisolone acetate.

After an intra-articular administration of methylprednisolone acetate (MPA) in the cow, methylprednisolone (MP) was detected in the synovial fluid, at pharmacologically significant concentrations, during more than 3 months. From in vitro assay, it was shown that hydrolysis of MPA to MP was rapid both in blood (half-times from 11.8 to 21.7 min) and in synovial fluid (half-times from 45.6 to 130.3 min). After intra-articular administration of MPA as a suspension (200 mg in toto), both MP and MPA decline very rapidly and, 24 hr after injection, less than 1% of the dose was present in the synovial fluid, but systemic availability of MP during the first 24 hr was only 30% of the dose. Twenty-four hours postadministration, post-mortem examinations showed a significant quantity of MPA precipitated at the bottom of the synovial cavity. It was assumed that the relatively slow decline of MP synovial fluid concentration from 24 hr to 5 days postadministration was due mainly to a process of MP absorption. After this delay, the synovial fluid concentration decreased very slowly with an apparent half-time of 18 days. This has been tentatively explained in terms of a slow release of MP from MPA embedded in a fibrin-like deposit. Despite the fact that the quantity of MP absorbed each day was small, long-term systemic effects were observed. During 6 weeks, plasma hydrocortisone levels remained low or undetectable and the return to normal adrenal responsiveness to an adrenocorticotropic hormone test took 12 weeks.

Adrenal Glands↗
PubMed1987

Pharmacokinetics of methylprednisolone succinate, methylprednisolone, and lidocaine in the normal dog and during hemorrhagic shock.

Pharmacokinetics of methylprednisolone succinate and methylprednisolone following methylprednisolone sodium succinate administration were studied in five dogs under normal conditions and then during a severe hemorrhagic shock. In order to evaluate hepatic blood flow, lidocaine clearance was simultaneously measured. In the normal state, the clearance of methylprednisolone succinate was 1.64 +/- 0.499 L/h/kg and its half-life was 15.33 +/- 3.84 min. The systemic availability of methylprednisolone from methylprednisolone succinate was 59.9 +/- 8.3%, and the maximal methylprednisolone concentration was observed after a delay of 7.68 +/- 6.31 min. Using a reservoir technique in anesthetized dogs, severe hemorrhagic shock was obtained. Changes in lidocaine clearance indicated a subsequent reduction of hepatic blood flow. The clearance of methylprednisolone succinate decreased to 0.488 +/- 0.240 L/kg/h, and the half-life increased to 40.66 +/- 23.48 min. The exact availability of methylprednisolone from methylprednisolone succinate during shock was not calculable because methylprednisolone kinetics were time dependent. The plasma methylprednisolone concentration was relatively high and persistent during the shock. It was concluded that methylprednisolone sodium succinate is a prodrug which can be released in sufficient quantities as its active moiety (i.e., methylprednisolone) during severe hemorrhagic shock in the dog. In addition, after a single intravenous administration, the slow process of methylprednisolone elimination may give sustained methylprednisolone concentrations for several hours.

Animals↗
PubMed1995

Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by cisplatin-based chemotherapy. A prospective randomized trial.

BACKGROUND: A single-institution, randomized open trial was prospectively performed to compare orally administered granisetron with or without intramuscularly administered methylprednisolone to metoclopramide plus methylprednisolone in the prevention of delayed nausea and vomiting induced by cisplatin-based chemotherapy. The effects of antiemetic treatments were evaluated from days 2 to 5 of the first cycle after cisplatin administration among patients who had never before received chemotherapy. METHODS: All patients were treated with chemotherapeutic regimens containing cisplatin greater than or equal to 80 mg/m2 and received antiemetic therapy with granisetron 3 mg intravenously for the control of acute emesis. Patients who responded to treatment during the first 24 hours were randomized to receive (1) metoclopramide (0.5 mg/kg) intramuscularly three times daily plus methylprednisolone (125 mg) intramuscularly once a day or (2) granisetron (1 mg) orally twice daily or (3) oral granisetron (1 mg) orally plus methylprednisolone (125 mg) intramuscularly from days 2 to 5. RESULTS: Of the patients treated with metoclopramide plus methylprednisolone (n = 92), 53% had complete protection from delayed emesis, 16% a major response, 15% a minor response, and 15% no response. Of the patients treated with granisetron alone (n = 84), 33% had a complete response, 21% a major response, 23% a minor response, and 21% no response. In the patients treated with orally administered granisetron plus intramuscularly administered methylprednisolone (n = 86), 47% had a complete response, 17% a major response, 23% a minor response, and 13% no response. These differences reached statistical significance only when the complete response rate achieved in the metoclopramide plus methylprednisolone group was compared with that recorded in the oral granisetron group (P = 0.012). Moreover, the metoclopramide plus methylprednisolone and the orally administered granisetron plus corticosteroid arms were superior to the orally administered granisetron alone arm in preventing nausea (P < 0.038 and P < 0.002, respectively). No extrapyramidal side effects were noted for the granisetron alone and the granisetron plus methylprednisolone arms, whereas 6% of patients treated with metoclopramide had extrapyramidal adverse effects. Headache was recorded in 8% of patients treated with granisetron alone, in 9% treated with granisetron plus methylprednisolone, and in 3% treated with metoclopramide plus methylprednisolone. CONCLUSIONS: These data suggest that orally administered granisetron with or without methylprednisolone may be given safely to patients with cancer as prophylactic therapy against delayed emesis after high dose cisplatin therapy. Orally administered granisetron alone was less active than a standard combination of metoclopramide plus methylprednisolone. However, the addition of corticosteroid to orally administered granisetron improved the control of delayed emesis. The efficacy of the combination of metoclopramide plus methylprednisolone and oral granisetron with or without methylprednisolone against delayed emesis still is not entirely satisfactory.

Administration, Oral↗
PubMed1996

Seventy-two hour comparison of methylprednisolone suleptanate and methylprednisolone sodium succinate in patients with acute asthma.

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.

Acute Disease↗
PubMed1993

Detrimental effects of high-dose methylprednisolone sodium succinate on serum concentrations of hepatic and renal function indicators in severe sepsis and septic shock. The Methylprednisolone Severe Sepsis Study Group.

OBJECTIVE: To evaluate the effects of high-dose methylprednisolone sodium succinate on biochemical markers of hepatic and renal function in patients with severe sepsis and septic shock. DESIGN: Retrospective analysis of serial serum chemistries in 382 patients who were entered prospectively into a randomized, placebo-controlled, double-blind clinical trial of high-dose methylprednisolone or placebo in the sepsis syndrome. SETTING: The original study was conducted at 19 academic centers. PATIENTS: Adult patients in severe sepsis or septic shock who met the study entry criteria, which included a clinically defined source of infection and signs of systemic sepsis, were enrolled into the study. Three hundred eighty-two patients were evaluated. INTERVENTIONS: Patients received either methylprednisolone (30 mg/kg) or placebo by iv infusion every 6 hrs for four doses. Hemodynamic variables and serum concentrations of creatinine, urea nitrogen, bilirubin, and aspartate aminotransferase (AST) were recorded on entering the study, at 12 and 24 hrs, and at 3, 7, and 14 days after the first infusion of methylprednisolone or placebo. These data were analyzed retrospectively. MAIN OUTCOME MEASUREMENTS: Hemodynamic and biochemical data were analyzed to determine whether or not hepatic and renal function in the sepsis syndrome had been influenced by methylprednisolone treatment. RESULTS: Differences between methylprednisolone and placebo in hemodynamic variables, the occurrence rate of shock and recovery from shock, mortality rates and serum concentrations of creatinine and AST were not statistically significant. At 12 and 24 hrs, and at 3 and 7 days after the first drug infusion (of methylprednisolone or placebo), blood urea nitrogen was increased from baseline values in a significantly (p < .01) greater proportion of the methylprednisolone-treated patients compared with placebo-treated patients. The frequency of increased serum bilirubin concentrations was significantly (p < .01) greater among methylprednisolone patients vs. the placebo group at 12 and 24 hrs. CONCLUSIONS: The frequency of acutely increased blood urea nitrogen and bilirubin concentrations in severe sepsis was increased significantly with high-dose methylprednisolone therapy. Similar frequencies of circulatory shock in the study groups excluded differences in global perfusion as a cause of this phenomenon. Possible adverse effects of pharmacologic concentrations of methylprednisolone in critically ill patients should be considered in planning treatment.

Aspartate Aminotransferases↗
PubMed1992

Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group.

BACKGROUND AND METHODS: Treatment with methylprednisolone and chlorambucil may protect renal function and increase the chance of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. To determine whether similar results might be obtained with methylprednisolone alone, we compared the effects of methylprednisolone and chlorambucil with those of methylprednisolone alone in 92 patients with the nephrotic syndrome caused by idiopathic membranous nephropathy. The patients were randomly assigned to receive either alternating one-month courses of methylprednisolone and then chlorambucil for a total of six months (group 1) or methylprednisolone alone for six months at the same cumulative dosage (group 2). RESULTS: Four of the 45 patients in group 1 (9 percent) and 1 of the 47 in group 2 (2 percent) stopped treatment because of side effects. At one, two, and three years, the percentage of patients who did not have the nephrotic syndrome was significantly higher in group 1 than in group 2. It was 58, 54, and 66 percent, respectively, in group 1, as compared with 26, 32, and 40 percent in group 2 (P = 0.002, 0.029, and 0.011). By year 4, the difference was no longer statistically significant: 62 percent of the patients in group 1 and 42 percent of those in group 2 did not have the nephrotic syndrome (P = 0.102). The patients in group 1 were in remission longer than those in group 2 (P = 0.008). CONCLUSIONS: In patients with the nephrotic syndrome caused by idiopathic membranous nephropathy, treatment with methylprednisolone and chlorambucil for six months induces an earlier remission of the nephrotic syndrome than methylprednisolone alone, but the difference may diminish with time.

Adolescent↗
PubMed2006

Methylprednisolone reduces pain, emesis, and fatigue after breast augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 mg, parecoxib 40 mg, and placebo.

We compared methylprednisolone 125 mg IV (n = 68) and parecoxib 40 mg IV (n = 68) with placebo (n = 68) given before breast augmentation surgery in a randomized, double-blind parallel group study. Surgery was performed under local anesthesia combined with propofol/fentanyl sedation. Methylprednisolone and parecoxib decreased pain at rest and dynamic pain intensity from 1 to 6 h after surgery compared with placebo (mean summed pain intensity(1-6 h): methylprednisolone [17.25; 95% confidence interval [CI], 14.85-19.65] versus placebo [21.7; 95% CI, 19.3-24.1]; P < 0.03; parecoxib [15.25; 95% CI, 13.25-17.25] versus placebo; P < 0.001; mean summed dynamic pain intensity(1-6 h): methylprednisolone [22.7; 95% CI, 20.1-23.3] versus placebo [28.4; 95% CI, 26.0-30.8]; P < 0.01; parecoxib [20.9; 95% CI, 18.6-23.2] versus placebo; P < 0.001). Both rescue drug consumption and actual pain (all observations before and after rescue) during the first 6 h were similar in the two active drug groups and significantly reduced compared with placebo. Using a composite score of actual pain intensity and rescue analgesic use, the active drugs were significantly superior to placebo (P < 0.001 for both active drugs). Postoperative nausea and vomiting was reduced after methylprednisolone administration (incidence, 30%), but not after parecoxib (incidence, 37%), during the first 24 h compared with placebo (incidence, 60%; P < 0.001). Fatigue was reduced by methylprednisolone (incidence, 44%), but not by parecoxib (incidence, 59%), compared with placebo (incidence, 66%; P < 0.05). In conclusion, methylprednisolone 125 mg IV given before breast augmentation surgery had analgesic and rescue analgesic-sparing effects comparable with those of parecoxib 40 mg IV. Methylprednisolone, but not parecoxib, reduced nausea, vomiting, and fatigue.

Adult↗
PubMed1984

Analysis of cortisol, methylprednisolone, and methylprednisolone hemisuccinate. Absence of effects of troleandomycin on ester hydrolysis.

A sensitive, selective, and reproducible high-performance liquid chromatographic assay for the simultaneous measurement of cortisol and methylprednisolone using dexamethasone as the internal standard is presented. Samples are extracted with methylene chloride, washed with sodium hydroxide and then water, and chromatographed on a microparticle silica gel column with ultraviolet detection at 254 nm. Sensitivity is greater than 10 ng/ml and the intra-day coefficient of variation is less than 5% for both steroids. The use of porcine liver esterase allows the quantitation of the hemisuccinate ester of methylprednisolone. This assay has been applied in pharmacokinetic studies including investigations of troleandomycin--methylprednisolone interactions. A typical plasma concentration--time profile for methylprednisolone and its ester prodrug is presented for one subject before and after receiving troleandomycin therapy. Although methylprednisolone elimination is reduced in the presence of troleandomycin therapy, there is no effect on the pharmacokinetics of methylprednisolone sodium succinate.

Adult↗
PubMed1988

Analysis of methylprednisolone, methylprednisone and corticosterone for assessment of methylprednisolone disposition in the rat.

A sensitive, specific and precise high-performance liquid chromatographic assay for the simultaneous determination of methylprednisolone, methylprednisone and corticosterone using betamethasone as the internal standard is reported. Rat serum (0.5 ml) is extracted with methylene chloride, washed with sodium hydroxide, then water and the extract is injected onto a microparticulate silica gel column with ultraviolet detection at 254 nm. Calculated limits of quantitation are less than 10 ng/ml and the intra-day coefficient of variation is less than 5% for each steroid. This assay has been applied to preliminary studies of methylprednisolone disposition in the rat. The plasma concentration-time profile for each steroid was determined following intravenous administration of methylprednisolone (10 mg/kg). Peak serum methylprednisone concentrations of ca. 250 ng/ml occurred within 5 min of methylprednisolone administration and the average area under the curve ratio (methylprednisolone/methylprednisone) was 9.3. These findings demonstrate that methylprednisone is a metabolite of methylprednisolone in the rat and suggest that the metabolic back-conversion of methylprednisone to methylprednisolone may be less than in other species.

Animals↗
PubMed1998

A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.

To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr.

Adolescent↗
PubMed1988

Failure of methylprednisolone acetate to prolong the antinauseant effect of intravenous methylprednisolone sodium succinate in patients receiving chemotherapy.

The efficacy of intramuscular methylprednisolone acetate in maintaining the antinauseant effect of intravenous methylprednisolone sodium succinate was assessed in a prospectively-randomized, double-blind, crossover-design trial. Of 150 patients entered, 127 were evaluable. There was no statistically significant difference between methylprednisolone acetate and saline placebo, although patient preferences slightly favoured the methylprednisolone acetate for nausea, vomiting, and overall effectiveness.

Adult↗
PubMed1981

Serum methylprednisolone levels following intra-articular injection of methylprednisolone acetate.

Twenty-one patients with rheumatoid arthritis received injections of either 40 mg or 80 mg of methylprednisolone acetate into one or both knee joints. Serum methylprednisolone and cortisol levels were measured at intervals up to 1 week following injection. Peak serum levels of methylprednisolone were reached at between 2 and 12 hours following injection, and increasing the injected dose resulted in correspondingly higher serum levels. Injection of 80 mg of methylprednisolone as 40 mg into each knee produced consistently higher peak serum levels than when given as a single intra-articular injection. Serum cortisol levels were substantially suppressed for up to 1 week, and this effect was seen at all dose levels.

Arthritis, Rheumatoid↗
PubMed2000

Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: immunosuppressive effects after in vivo administration to rats.

PURPOSE: To study the immunosuppressive activities of a macromolecular prodrug of methylprednisolone (MP), dextran-methylprednisolone succinate (DEX-MPS), in rats. METHODS: Single 5 mg/kg (MP equivalent) doses of MP or DEX-MPS were administered intravenously to rats, and blood and spleen samples were collected over 96 h. The immunosuppressive activity was determined by the effects of the free or dextran-conjugated drug on the mitogen-stimulated spleen lymphocyte proliferation. Additionally, the number of lymphocytes in the spleen cell suspensions was estimated. Further, the plasma and spleen concentrations of the conjugated and free MP were determined using size-exclusion and reversed-phase chromatographic methods, respectively. RESULTS: Both MP and DEX-MPS injections resulted in the inhibition of the spleen lymphocyte proliferation. However, the maximal effect of DEX-MPS was significantly (P < 0.003) more intense (approximately 100% inhibition) and delayed (24 h) relative to that of MP (approximately 50% inhibition at 2 h). The DEX-MPS injection also resulted in a significantly (P < 0.0001) higher decline in the estimated number of spleen lymphocytes (approximately 80% at 24 h), compared with the MP injection (approximately 30% at 2 hr). Whereas the plasma and spleen concentrations of MP could not be measured at > or = 2 h after the drug injection, relatively high concentrations of DEX-MPS persisted in plasma and spleen for 24 h and 96 h, respectively. CONCLUSION: Dextran-methylprednisolone conjugate can effectively deliver the corticosteroid to its site of action for immunosuppression, resulting in more intense and sustained effects when compared with the free drug administration.

Animals↗
PubMed1999

[Efficacy of combination with granisetron and methylprednisolone for nausea, vomiting and appetite loss in remission induction chemotherapy of acute myeloid leukemia--a randomized comparative trial between granisetron alone and granisetron plus methylprednisolone].

The prevention of nausea, vomiting and appetite loss induced by remission induction chemotherapy for acute myeloid leukemia was compared by randomization between granisetron alone and combination with granisetron plus methylprednisolone. Granisetron was administered at 40 micrograms/kg during chemotherapy, and methylprednisolone was administered concomitantly at 125 mg/body for 3 days or more in the combination group. The single and combination groups comprised 14 and 13 patients, respectively, and there was no significant difference between the background of both groups. To evaluate the effect they were scored according to 4 grades, and evaluated every 24 hours from the start of chemotherapy to 5 days after its completion. The complete inhibition rate of vomiting was as high as 71.4% and 92.3% in the single and combination groups, respectively, showing no significant difference. The grade of vomiting was mild in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the inhibitory effect tended to be higher in the combination group. Appetite loss developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly higher in the combination group. The prevention effects on nausea 7, 8 and 10 days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2-5 days after its completion, were higher in the combination group. Granisetron revealed an excellent inhibitory effect on vomiting induced by remission induction chemotherapy for acute myeloid leukemia, but combination with granisetron and methylprednisolone was considered useful for nausea in the latter half of the treatment period and for appetite loss during the whole period.

Acute Disease↗