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At least 19 recordsLinked to original sources
PubMed2000

Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol: protection by triacetyloleandomycin.

Ethanol and isopentanol are the predominant alcohols in alcoholic beverages. We have reported previously that pretreatment of rats with a liquid diet containing 6.3% ethanol plus 0.5% isopentanol for 7 days results in a synergistic increase in acetaminophen hepatotoxicity, compared with rats treated with either alcohol alone. Here, we investigated the role of CYP3A in acetaminophen hepatotoxicity associated with the combined alcohol treatment. Triacetyloleandomycin, a specific inhibitor of CYP3A, protected rats pretreated with ethanol along with isopentanol from acetaminophen hepatotoxicity. At both 0.25 and 0.5 g acetaminophen/kg, triacetyloleandomycin partially prevented elevations in serum levels of alanine aminotransferase. At 0.25 g acetaminophen/kg, triacetyloleandomycin completely protected 6 of 8 rats from histologically observed liver damage, and partially protected the remaining 2 rats. At 0.5 g acetaminophen/kg, triacetyloleandomycin decreased histologically observed liver damage in 7 of 15 rats. In rats pretreated with ethanol plus isopentanol, CYP3A, measured immunohistochemically, was decreased by acetaminophen treatment. This effect was prevented by triacetyloleandomycin. These results suggest that CYP3A has a major role in acetaminophen hepatotoxicity in animals administered the combined alcohol treatment. We also found that exposure to ethanol along with 0.1% isopentanol for only 3 days resulted in maximal increases in acetaminophen hepatotoxicity by the combined alcohol treatment, suggesting that short-term consumption of alcoholic beverages rich in isopentanol may be a risk for developing liver damage from acetaminophen.

Acetaminophen↗
PubMed1969

Therapy of staphylococcal infections in monkeys. IV. Further comparison of triacetyloleandomycin and erythromycins.

Intravenous inoculation of a penicillin-resistant, phage type 80/81 staphylococcus caused lethal infection in 8 of 15 untreated monkeys. Daily intragastric administration of 50 mg/kg of triacetyloleandomycin, erythromycin estolate, and erythromycin ethylsuccinate was followed by mortalities of 0 of 16, 3 of 16, and 3 of 10, respectively. At dose levels of 25 and 12.5 mg/kg, none of 7 and 4 of 7 receiving triacetyloleandomycin and erythromycin estolate, respectively, died, as compared to 3 of 4 deaths in controls. In vitro sensitivity data and serum antibacterial levels would suggest that triacetyloleandomycin would be the least effective therapeutically. However, this prediction was not fulfilled in these studies of experimental infections in monkeys wherein triacetyloleandomycin was a very effective antimicrobial agent.

Animals↗
PubMed1983

[Antibiotic penetration into the otorhinolaryngologic system in children. I. Comparative intratonsillar penetration of ampicillin and triacetyloleandomycin. Apropos of 61 cases].

Tonsillar diffusion of two antibiotics was compared in 61 children, 26 receiving 100 mg/kg/d of ampicillin, and the other 35 being treated with 50 mg/kg/d of triacetyloleandomycin during the 24 hours preceding tonsillectomy. Drug levels were measured by a microbiological method. The mean ampicillin level in the tonsil was 0,84 mcg/ml for a serum level of 4,1 mcg/ml 90 minutes before sampling, concentrations being absent in the tonsil in 12 cases (45 p. cent). Mean triacetyloleandomycin levels in the tonsil were 12,16 mcg/ml for a serum level of 2,27 mcg/ml 90 minutes before sampling, concentrations being absent in the tonsil in only 4 cases (11 p. cent). Very high concentrations of triacetyloleandomycin as against low or no levels of ampicillin were therefore detected in the tonsil. This suggest that macrolides should be employed in preference to ampicillin for the treatment of recurrent sore throats, and tonsillixis, and for preventive treatment of acute rheumatic fever.

Adolescent↗
PubMedDate not supplied

Protection of ethanol-mediated acetaminophen hepatotoxicity by triacetyloleandomycin, a specific inhibitor of CYP3A.

Cytochrome P450 2E (CYP2E) is considered responsible for ethanol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, it has been shown in cultured human and rat hepatocytes and intact rats that ethanol induces CYP3A in addition to CYP2E. Therefore, an investigation was made in rats to see whether or not an inhibitor of CYP3A, triacetyloleandomycin (TAO), would protect against ethanol-mediated increases in APAP hepatotoxicity. Rats, treated with 6.3 percent ethanol in the Lieber-DeCarli diet for 7 days, were administered APAP (lg/kg, i.g.) 11 hrs after removal of the diet. Triacetyloleandomycin (500 mg/kg, saline solution) was injected i.p. 2 hrs before the administration of APAP. In rats pretreated with ethanol, treatment with APAP for 7 hrs resulted in focal centrilobular congestion and steatosis. Triacetyloleandomycin completely prevented the histological liver damage in all 8 animals. These results suggest that, in ethanol-treated rats, CYP3A plays a major role in increasing APAP hepatotoxicity.

Acetaminophen↗
PubMed1970

Serum antibacterial activity after oral suspensions and capsules of triacetyloleandomycin and erythromycin estolate.

Comparison of serum antibacterial activity against a beta-hemolytic streptococcus and a penicillin-resistant staphylococcus was made in a cross-over study in volunteers after ingestion of oral suspensions and capsules of triacetyloleandomycin and erythromycin estolate. Oral suspensions yielded earlier peak titers, but ultimate peak titers and duration of activity were similar to those observed after ingestion of capsules. Antibacterial activity of serum against both organisms was consistently greater with both erythromycin estolate preparations than with the triacetyloleandomycin preparations. These in vitro data were comparable to observations made previously in monkeys infected with the same organisms, although comparative clinical efficacy in monkeys did not reflect these implied therapeutic differences.

Dosage Forms↗
PubMed1977

The use of triacetyloleandomycin in skin and soft tissue infections: results of a New Zealand general-practitioner multi-centre trial.

Fifty-one New Zealand general practitioners observed the treatment of 137 cases of skin and soft tissue infections with triacetyloleandomycin (TAO, Pfizer) over a five-month period. Nearly a third of these lesions occurred in children aged 10 years or less. "Excellent" or "good" results in 129 cases (94.2 percent) confirmed triacetyloleandomycin to be generally effective in these conditions. Twice-daily (12-hourly) oral administration proved as effective as more frequent dosage regimens and no major side-effects were encountered. Twenty cases with associated minor surgery are discussed separately.

Adolescent↗
PubMed1994

Evaluation of triacetyloleandomycin, alpha-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450.

A variety of chemicals, including triacetyloleandomycin (TAO), alpha-naphthoflavone (ANF), and diethyldithiocarbamate (DDC), are widely used as inhibitory probes for select individual human cytochrome P450 (CYP) enzymes, despite the fact that the selectivity of these inhibitors has not been rigorously evaluated. In the present study we take advantage of recent advances in cDNA-directed human P450 expression to evaluate directly the P450 form selectivity of TAO, ANF, and DDC, using a panel of 10 individual cDNA-expressed human P450s. Under experimental conditions known to yield maximal TAO complexation with P450 hemoproteins, TAO (20 microM) inhibited the catalytic activity of expressed CYPs 3A3, 3A4, and 3A5, whereas it did not affect CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, or 2E1 activity. ANF inhibited not only CYPs 1A1 and 1A2 (IC50 = 0.4-0.5 microM), but it was also similarly effective against CYPs 2C8 and 2C9. Increasing the concentration of ANF to 10 microM led to inhibition of CYP2A6 and CYP2B6. Although a previous study suggested that DDC is a selective inhibitor of CYP2E1, the present investigation shows that at concentrations required to inhibit CYP2E1 (IC50 approximately 125 microM when preincubated with NADPH), DDC also inhibited CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 3A3, and 3A4. Decreasing the concentration of DDC to 10 microM, however, led to inhibition of CYP2A6 (65% inhibition) and CYP2B6 (50% inhibition), but none of the other P450s examined, including CYP2E1. Overall, these results establish that (a) TAO is a selective inhibitor of the human CYP3A subfamily; (b) ANF potently inhibits CYP2C8 and CYP2C9, in addition to CYPs 1A1 and 1A2; and (c) DDC cannot be employed as a diagnostic inhibitory probe for CYP2E1.

Benzoflavones↗
PubMed1985

The effects of triacetyloleandomycin and oleandomycin phosphate on the glucocorticoid receptor in cultured skin fibroblasts.

Triacetyloleandomycin (TAO) has been described as a "steroid-sparing" drug in that poorly controlled asthmatic patients can be stabilized or improved with the addition of TAO despite decreasing dosages of steroids, specifically methylprednisolone (MP). It is not clear whether the beneficial effects of TAO are due to decreased MP clearance or are due to enhanced glucocorticoid effect peripherally. We tested the latter possibility by studying the interaction of TAO and oleandomycin phosphate (OLEO), the active metabolite of TAO in vivo, with glucocorticoid receptors in dispersed, intact cultured human skin fibroblasts. With the use of cells incubated with [3H]dexamethasone at 22 degrees C, we examined the competitive binding properties of TAO and OLEO (at varying concentrations) with and without MP as compared with several other steroids and MP alone. We also studied the effects on cellular glucocorticoid receptor number and affinity when TAO at a concentration of 4 X 10(-5) alone, at 10(-5) M in combination with a receptor saturating concentration of MP (5 X 10(-8) M), with MP alone, or with OLEO (10(-5) M) combined with MP was added to fibroblasts in the growth phase 1 wk before assay. TAO and OLEO did not compete for the binding of [3H]dexamethasone to the fibroblast glucocorticoid receptor, nor did they alter the binding properties of MP. With prolonged cellular exposure, TAO alone did not alter the number of glucocorticoid receptors (per cell) or their affinity for [3H]dexamethasone. Interestingly, prolonged exposure to saturating concentrations of MP alone decreased glucocorticoid receptor density; this effect was not altered by the presence of TAO or OLEO.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Count↗
PubMed1980

Carbamazepine intoxication due to triacetyloleandomycin administration in epileptic patients.

In 17 epileptics receiving carbamazepine (CBZ) alone or in combination with other anticonvulsant drugs, administration of triacetyloleandomycin (Tri A) led to an acute and unexpected intoxication (drowsiness, nausea, vomiting, and dizziness). Similar symptoms occurred again in 3 patients after Tri A was administered a second time. The same toxic manifestations were observed in two patients receiving CBZ and erythromycin. A rapid increase in plasma levels of CBZ occurred after institution of Tri A therapy in 6 patients, the CBZ levels quickly returning to normal after withdrawal of Tri A. Thus, it is suggested that the observed intoxication is due to the simultaneous administration of CBZ and Tri A (or erythromycin). The possible role of hepatic dysfunction in this syndrome of intoxication is discussed. Furthermore, the intoxication may be at least partially related to serum electrolyte disturbances, as suggested by one case in which obvious signs of water intoxication were detected. The severity and frequency of intoxication should lead to proscribing Tri A or other macrolide antibiotics in patients receiving CBZ.

Adolescent↗
PubMed1977

Morphometric studies in triacetyloleandomycin-induced ultrastructural modifications of rat hepatocyte mitochondria.

Morphometric parameters of mitochondria such as volumetric density, surface density of envelopes and cristae and numerical density were calculated for control untreated and triacetyloleandomycin (TAO)-treated rat hepatocytes using a point-counting technique. Moreover, morphometric parameters calculated experimentally and those computed on the basis of the least square interpolation and the agreement with the chi2 test, were compared. The equations modelling each main morphometric parameter of experimental motochondria were also computed. Morphometric study revealed that TAO produces a highly reproducible pattern of morphological alterations in the mitochondrial population of rat hepatocytes, and a good agreement between experimental and theoretical data was found. The response of hepatocyte mitochondria to TAO may be modelled by parabolic functions described by equations of the second degree. During the whole experimental period, the number of mitochondria decreases, but the specific volume of mitochondria increases. The area of the cristae surface per mitochondrion does not change substantially during the whole experimental period but since the quantity of internal mitochondrial membranes per hepatocyte is less in the later experimental period than in control material, it can be assumed that the oxidizing capacity per hepatocyte has diminished. The morphometric model based on TAO-treated hepatocyte mitochondria is different from those so far described in the literature for rat liver.

Animals↗
PubMed1983

Cytochrome P-450 isozyme LM3b from rabbit liver microsomes. Induction by triacetyloleandomycin purification and characterization.

Oral administration of triacetyloleandomycin (TAO), 1 mmol/kg/day for 7 days to mature male New Zealand White rabbit results in a significant increase in the content of liver microsomal cytochrome P-450. This increase is accompanied by the occurrence on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the microsomes of a strong band in the zone of electrophoretic mobility associated with the LM3 isozymes and the stimulation of a number of monooxygenase activities of these microsomes including aminopyrine, chlorcyclizine, TAO, and erythromycin demethylation as well as 2-OH-estradiol and 6 beta OH-testosterone hydroxylation. Cytochrome P-450 LM3 (TAO) from these liver microsomes, purified to electrophoretic homogeneity, had Mr = 52,000 as determined by calibrated sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Comparison with isozymes LM3a, LM3b, and LM3c isolated from control animals, by a number of criteria including spectral data, amino acid content, NH2-terminal sequence analysis, peptide mapping, immunological properties, and monooxygenase activities of reconstituted system, indicated that isozymes LM3 (TAO) and LM3b are very similar, if not identical, proteins. We conclude that TAO must be considered as a new type of inducer of microsomal cytochrome P-450 from rabbit liver.

Amino Acid Sequence↗