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PubMed1981

Effects of troleandomycin administration on cholesterol 7 alpha-hydroxylase activity and bile secretion in rats.

Repeated administration of troleandomycin increased bile flow but decreased the biliary secretion of bile acids in rats. The increased bile flow was associated with a parallel increase in the biliary clearance of [14C]erythritol. Analysis of the relationship between bile flow and bile acid secretion indicated that, for any given rate of bile acid secretin, bile flow was higher in troleandomycin-treated rats than in control rats. The increased bile flow was associated with an increased activity of Na+,K+-adenosine triphosphatase in liver plasma membranes. The decreased bile acid secretion into bile was associated with a similar decrease in the bile acid pool size, a decreased bile acid synthesis rate and a decreased activity of microsomal cholesterol 7 alpha-hydroxylase. The concentration of bile acids in serum, the hepatic extraction ratio of [3H]taurocholate and its biliary transport maximum were not modified. It is concluded that repeated administration of troleandomycin increases the canalicular bile acid-independent flow but decreases the activity of cholesterol 7 alpha-hydroxylase, the synthesis, the pool size and the biliary secretion rate of bile acid in rats.

Animals↗
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↗
PubMed1991

Effects of troleandomycin and josamycin on thyroid hormone and steroid serum levels, liver function tests and microsomal monooxygenases in healthy volunteers: a double blind placebo-controlled study.

Serum TSH levels are moderately but significantly (P ANOVA: 0.05) decreased by troleandomycin (T; 1 g bid over a 10-day period) compared with josamycin (J) (same doses) and placebo (P) in healthy volunteers. T also significantly increases serum estradiol concentration (P ANOVA: 0.03). This effect may be related to a T-induced inhibition of some P450 monooxygenase isoenzymes and more specifically P 450 NF, determined in our study by a decrease in urinary excretion of 6-beta-hydroxy-cortisol. Troleandomycin and josamycin both show poor upper GI tolerance. Liver enzymes (SGOT, SGPT, alkaline phosphatase and gGT) are significantly altered by T compared with J and P (P ANOVA: 0.007, 0.001, 0.09 and 0.04 respectively). After J, liver function tests are very close to control values (placebo). Liver enzymes are significantly more altered by T than by J (P 0.004, 0.001 and 0.06 for SGOT, SGPT and gGT respectively). Using 6 volunteers in a latin-square designed study, some established effects of oral macrolides were confirmed (poor upper GI tolerance; liver toxicity of T). Some other effects of T were also elicited, which were either unknown (decrease in serum TSH) or expected but which had not previously been assessed in man (increase in serum estradiol; decreased urinary excretion of 6-beta-hydroxy-cortisol).

Adult↗
PubMed1985

Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children.

Oral methylprednisolone combined with troleandomycin has been reported to be successful in treating poorly controlled, severe asthma in adults. We found this drug combination to be effective in treating 11 steroid-dependent children with poorly controlled asthma who were aged 7 to 13 years, for 12 to 28 months. Improvement of clinical and pulmonary functions was achieved within seven days, with the forced expiratory volume in 1 s increasing by 38% and the maximal midexpiratory flow rate increasing by 55% over the baseline value. By one year, the former improved to 98% of predicted value and the latter, to 79% of predicted value. Compared with the prior 12 months, patients at this time required fewer emergency visits, missed fewer days of school, and had fewer hospitalizations. Side effects included transient-increased cushingoid features, abdominal pain, and liver enzyme level elevation. Patients showed less evidence of adrenal suppression.

Administration, Oral↗
PubMed1991

Effect of glutathione depletion on the in vivo inhibition of drug metabolism by agents forming an inactive cytochrome P-450 Fe(II):metabolite complex. Studies with amiodarone and troleandomycin.

The relative contribution of competitive inhibition versus formation of a P-450:metabolite complex to the in vivo inhibition of drug metabolism for several agents is unclear. The present investigation examined the contribution of these two mechanisms to the in vivo inhibition of drug metabolism by amiodarone through manipulation of glutathione turnover. In vivo P-450-dependent metabolism in rats was assessed by determining antipyrine clearance. Pretreatment with amiodarone (50 mg/kg, iv) decreased antipyrine clearance with or without prior glutathione depletion. Depletion of glutathione by buthionine sulfoximine (1.6 g/kg, ip) did not enhance the magnitude of inhibition of antipyrine clearance by amiodarone. Moreover, administration of a normally subinhibitory dose of amiodarone after buthionine sulfoximine pretreatment did not influence antipyrine clearance. Similarly, depletion of glutathione via buthionine sulfoximine or diethylmaleate (1 mL/kg, po) did not influence the magnitude of inhibition caused by a single po dose of troleandomycin (500 or 350 mg/kg, respectively). These data indicate that glutathione content may not be a critical determinant for the in vivo inhibition of drug metabolism by agents which form a P-450:metabolite complex.

Amiodarone↗
PubMed1991

Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma.

In nine children with steroid-dependent asthma, ranging in age from 2 and 11/12 to 14 and 4/12 years, troleandomycin (TAO) was administered at a dose of 250 mg po QD or BID, along with oral methylprednisolone. Both medications were then rapidly changed to a QOD schedule. Baseline daily steroid dosage requirements decreased from 15.3 +/- 9.1 mg methylprednisolone to 1.4 +/- 0.7 mg (P less than 0.01, paired t-test), and the number of steroid bursts (1-2 mg/kg/day) per year decreased from 12.2 +/- 4.8 to 4.1 +/- 2.0 (P less than 0.01, paired t-test). There was also a significant decrease in the number of hospitalizations per year from 3.4 +/- 4.6 to 0.6 +/- 0.7 (P less than 0.05, paired t-test). The incidence of steroid side effects increased, despite the decrease in the amount of steroid required. Specifically, the prevalence of cataracts increased from 11% to 33% (chi 2 = 4.5, P = 0.15) and the prevalence of hypercholesterolemia increased from 22% to 78% (chi 2 = 16.67, P less than 0.001). There was no elevation of serum transaminases in any of our patients on TAO. Although TAO appears to be efficacious, caution is warranted when TAO is considered for use in younger children with steroid-dependent asthma.

Adolescent↗
PubMedDate not supplied

Troleandomycin effects on methylprednisolone and methylprednisone interconversion and disposition in the rabbit.

A study of the effects of troleandomycin (TAO) on the disposition of intravenous methylprednisolone in rabbits was performed in order to develop an animal model to further evaluate the mechanism of TAO/steroid beneficial effects in severe asthma. The plasma concentration-time profiles of methylprednisolone and methylprednisone were determined in the presence and absence of single and multiple dose TAO regimens. Pharmacokinetic analysis revealed a significant decrease in total plasma clearance of methylprednisolone in the presence of multiple dose TAO. Alterations in the disposition of the reversible metabolite, methylprednisone, were also observed. The TAO-methylprednisolone interaction may involve decreasing the degree of interconversion between the steroid and its reversible metabolite. TAO also decreases metabolite turnover more than three-fold. The antibiotic does not cause marked deviation from linear biexponential elimination of methylprednisolone as observed in man. The rabbit may serve as a useful animal model for further studies of the TAO/methylprednisolone interaction.

Animals↗
PubMed1988

In vivo and in vitro effects of a new macrolide antibiotic roxithromycin on rat liver cytochrome P-450: comparison with troleandomycin and erythromycin.

The effects of a new macrolide antibiotic (Roxithromycin) and one of its major metabolite (RU 39001) on rat hepatic drug metabolizing enzymes were compared to those of erythromycin, erythralosamine and troleandomycin (TAO) both in vitro and in vivo. In contrast to erythromycin, erythralosamine and TAO, roxithromycin and its metabolite RU 39001 exhibit: (i) a very poor affinity for rat liver cytochrome P-450, (ii) an unability to be metabolized into a stable inhibitory metabolite-cytochrome P-450 complex and (iii) a decreased ability to induce liver cytochrome P-450 PCNE, an isozyme implicated in drug associations involving some macrolide antibiotics.

Animals↗
PubMed1989

Rat liver microsomal progesterone metabolism: evidence for differential troleandomycin and pregnenolone 16 alpha-carbonitrile inductive effects in the cytochrome P-450 III family.

The effect of Troleandomycin (TAO) and pregnenolone 16 alpha-carbonitrile (PCN) on the hepatic microsomal progesterone metabolism in the rat is evaluated. Over thirteen hydroxylated progesterone derivatives are detected, including the novel 6 beta, 21-, 6 beta, 16 alpha-, 6 beta, 16 beta- and 2,21-dihydroxy derivatives, suggesting the induction of several cytochrome P-450 isozymes. PCN treatment results overall in an augmented production of progesterone metabolites whereas TAO treatment both induces and represses specific hydroxylase activities. Progesterone metabolism with purified isozymes isolated from liver microsomes from TAO and PCN treated rats differs significantly from that observed with intact microsomes, reflecting the complexity of the induction pattern of the cytochrome P-450 III family.

Animals↗
PubMed1980

Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma.

Sixteen severe, corticosteroid-dependent yet resistant outpatient asthmatics were treated with troleandomycin (TAO), a macrolide antibiotic, in an attempt to both induce a clinical remission and reduce methylprednisolone requirements. Within the first 2 wk of initiating TAO therapy, 50% of the patients experienced a greater than 20% increase in forced expiratory volume in 1 sec (FEV1) and 80% noted a greater than 20% increase in forced vital capacity between 25% and 75% (FVC 25%-75%). Maximal increases in FEV1 and FVC 25%-75% were noted in all patients within the first 6 wk on TAO and methylprednisolone. There was a concomitant clinical improvement in all patients. Corticosteroid-induced side effects, gastrointestinal tract discomfort, and elevated serum glutamic pyruvic transaminase (SGPT) were common yet generally transient during TAO and methylprednisolone therapy. After a 4- to 18-mo follow-up 15/16 patients were well-controlled on TAO and methylprednisolone. Methylprednisolone requirements were reduced at least four- to fivefold in most patients during TAO therapy. Normal morning serum cortisol levels were documented after varying intervals in most patients when both TAO (250 mg) and methylprednisolone (4 to 16 mg) could be reduced to alternate-day administration. Only one patient was forced to discontinue therapy due to side effects. The present study extends the effectiveness of TAO therapy to ambulatory asthmatics, establishes a clinical strategy that maximizes benefit/risk factors, and provides practical guidelines for the long-term use of TAO and methylprednisolone.

Adolescent↗
PubMed1980

The effect of troleandomycin on methylprednisolone elimination.

Troleandomoycin (TAO), a macrolide antibiotic, has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthma. This study was designed to investigate the effect of TAO on methylprednisolone elimination. Pharmacokinetic studies were performed before and 1 wk after starting TAO in 10 severe steroid-dependent asthmatics. Baseline total body clearance of methylprednisolone was 406 +/- 139 (mean +/- SD) ml/min/1.73 m2 and decreased significantly (p < 0.001) to 146 +/- 57 ml/min/1.73 m2 1 wk after TAO therapy was initiated. Methylprednisolone half-life was 2.46 +/- 0.75 hr before TAO and increased significantly (p < 0.01) to 4.63 +/- 1.35 hr after 1 wk on TAO therapy. A follow-up evaluation of methylprednisolone pharmacokinetics in three patients after at least 1 mo on TAO therapy demonstrated continuation of the reduced methylprednisolone elimination. TAO inhibition of methylprednisolone clearance may contribute to the beneficial effects observed initially with combined methylprednisolone-troleandomycin therapy in severe steroid-dependent asthma.

Adolescent↗
PubMed1982

Steroid-specific and anticonvulsant interaction aspects of troleandomycin-steroid therapy.

Troleandomycin (TAO) is a macrolide antibiotic that has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthmatic patients. Recent observations demonstrated the effect of TAO on inhibiting methylprednisolone elimination, possibly contributing to its beneficial effects. Prednisolone and methylprednisolone disposition were studied before and 1 wk after initiation of TAO therapy in three patients. Methylprednisolone elimination was characteristically impaired in the presence of TAO therapy; however, there was no apparent effect on prednisolone elimination. Methylprednisolone elimination was also evaluated before and after initiation of TAO therapy in three patients receiving concomitant anticonvulsant therapy with phenobarbital-1, phenytoin-2. Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication. Methylprednisolone clearance was subsequently reduced by approximately 70% in the presence of TAO therapy. The effect of TAO on corticosteroid disposition is steroid-specific and TAO can diminish the effect of certain drugs on the induction of corticosteroid metabolism.

Asthma↗
PubMed1986

An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma.

An improved protocol was developed for the use of troleandomycin (TAO) in severe, steroid-requiring subjects with asthma. Compared to previous reports, this protocol uses a lower starting dose of TAO and a rapid steroid taper. Fifteen patients were treated with TAO following the new guidelines. Steroid requirements in the 15 patients dropped by 68% within 2 weeks, and 13 of the 15 patients were able to be maintained on alternate day steroids. In spite of rapid steroid taper, both FEV1 and mean FVC increased significantly (p less than 0.001). There was a low incidence of side effects and, in contrast to previous reports on TAO, no patient had even a transient increase in cushingoid appearance. Glucose intolerance was observed initially in three patients but resolved with continued steroid taper. Transient liver-enzyme elevation was noted in four patients and in each case reversed with a reduction in TAO dosage. The revised protocol is associated with an improved risk-benefit ratio. New guidelines are presented for the use of TAO in severe steroid-requiring subjects with asthma.

Adult↗
PubMed1993

Troleandomycin in the treatment of difficult asthma.

BACKGROUND: For difficult asthma, treatment is aimed at improving airway obstruction and minimizing adverse effects of systemic corticosteroids. The combination of troleandomycin (TAO) with methylprednisolone (MP) reportedly has a beneficial steroid-sparing effect on difficult asthma. METHODS: To test the steroid-sparing effect of TAO, 14 subjects with severe corticosteroid-dependent asthma were studied before and during treatment with MP and TAO. RESULTS: Treatment with MP and TAO resulted in a clear reduction in respiratory symptoms, asthmatic attacks, corticosteroid and hospitalization requirements, improvement in pulmonary function tests, and a remarkable decrease in peak expiratory flow rate circadian variability when compared with the period before TAO treatment (with corticosteroids). Treatment with MP and TAO was fairly well tolerated. Only a reduction (-5.2%, p < 0.01) in bone mineral content and an increase in plasma glucose levels (from 81.7 to 94.3 mg/dl, p < 0.05) were found, in comparison with pre-TAO values. One subject discontinued MP-TAO treatment because of a mild but persistent increase in serum alanine aminotransferase. In an evaluation of the clinical and pulmonary function test results, eight of the 14 subjects were responders and six were nonresponders. During follow-up three subjects discontinued TAO and consequently had an asthmatic attack after 4, 7, or 15 days, respectively. CONCLUSIONS: This study confirms that treatment with MP and TAO has a beneficial effect in a subgroup of severely steroid-dependent asthma patients.

Asthma↗
PubMed1993

Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma.

BACKGROUND: Troleandomycin (TAO), a macrolide antibiotic, was studied as an alternative treatment in 18 children with severe, steroid-requiring asthma. METHODS: In this investigation three treatment arms were used in randomized, double-blind, parallel fashion: combination TAO and methylprednisolone (MPn), combination TAO and prednisone, and MPn alone. RESULTS: All groups tolerated a considerable reduction in glucocorticoid dose over the 12 weeks of the study: 80% +/- 6% for TAO-MPn, 55% +/- 8% for TAO-prednisone, and 44% +/- 14% for MPn alone. These reductions are all statistically significant (p < 0.05) within groups, and the differences between groups were statistically significant between the TAO-MPn and MPn alone groups. The concentration of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second and pulmonary function were not significantly improved in any treatment group. Safety parameters including blood chemistry and hematology, adrenal function assessment; bone densitometry, and muscle strength testing, were not altered significantly. Two patients who received TAO had elevated liver enzyme levels; one required discontinuation of TAO and one experienced spontaneous resolution without intervention. Lack of statistically significant changes in the efficacy parameters were likely a result of small sample size and effects of the glucocorticoid dose taper. CONCLUSIONS: TAO is safe and may be a reasonable treatment alternative in a limited trial for patients who are unable to tolerate tapering of their glucocorticoid dosage. Therapy should be guided by the goal of treatment, that is, glucocorticoid dose reduction or improvement of pulmonary function with appropriate monitoring of pulmonary function and adverse effects.

Adolescent↗
PubMed1982

Dose- and time-related effect of troleandomycin on methylprednisolone elimination.

Effects of varying doses of troleandomycin (TAO) on methylprednisolone disposition were examined in five steroid-dependent asthmatic patients. The characteristic reduction in methylprednisolone elimination in the presence of TAO after a 40 mg IV methylprednisolone was also present after methylprednisolone doses as low as 4 mg. In patients receiving continuous TAO on an every-other-day basis, inhibition of methylprednisolone elimination was impaired to a greater extent on the "day on" TAO than on the "day off" TAO Methylprednisolone elimination on the day off TAO was still slower than that before TAO, however, TAO on a multiple-dose schedule resulted in greater reduction of methylprednisolone elimination than after a single TAO dose. These results suggest that TAO induces immediate and continued inhibition of methylprednisolone disposition.

Asthma↗
PubMed1997

Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A.

AIMS: In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N-demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N-demethylation of IMI. METHODS: Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250 mg daily for 2 days before a single oral dose of 100 mg IMI was administered. RESULTS: Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971 +/- 938 vs 3134 +/- 2000 microg l(-1) h, 95% confidence interval for difference between means: 218 to 2108 microg l(-1) h, P < 0.05) and decreased its oral clearance by 30% (60.9 +/- 27.4 vs 42.5 +/- 22.7 l h(-1), 95% confidence internal for difference between means: 7.2 to 31.7 l h(-1), P < 0.05). CONCLUSIONS: We conclude that CYP3A may play an important role in the in vivo N-demethylation of IMI.

Adult↗
PubMed2003

Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent.

1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily for 2 days before the dose of OP was administered. Blood samples were obtained and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by reversed-phase HPLC. 2. The mean C(max), AUC and CL for OP in poor metabolizers (PMs) were greater with TAO than without TAO. The C(max) and AUC of 5-OH-OP in PMs were significantly (p < 0.05) less with TAO than without TAO. The differences in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus without TAO were similar to those observed in PMs, except for the AUC. However, in homozygous EMs, there were no statistical differences for the effect of TAO. 3. The effect of TAO on the metabolism of OP and its two principal metabolites differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant role in the formation of OP sulfone, but also it contributes to the 5-hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination of 5-OH-OP and OP sulfone.

Adult↗