Orlistat maintains biliary lipid composition and hepatobiliary function in obese subjects undergoing moderate weight loss.

OBJECTIVES: Orlistat, an intestinal lipase inhibitor, has recently been approved by the US Food and Drug Administration for treatment of obesity. The effects of orlistat on hepatobiliary function have not been previously defined. A 4 wk study was performed involving modest weight loss in obese subjects to observe any short-term hepatobiliary responses that occur after initiating treatment with orlistat and a hypocaloric diet. METHODS: A total of 23 obese (BMI 30-41 kg/m2) subjects were randomized to a double blind t.i.d. treatment with 120 mg of orlistat or a placebo in conjunction with a hypocaloric diet (1200-1500 kcal/day). The study was designed to achieve similar modest weight loss in both groups in order to be able to directly assess the effects of orlistat. Cholesterol saturation, bile composition, and gallbladder motility were measured. RESULTS: At the end of the treatment period, mean weight loss of 3.8 kg was achieved in the orlistat group (vs 2.3 kg with placebo, p = NS). Total bile acid concentration decreased significantly with placebo (-18.57 +/- 6.99 mmol/L; 95% CI = -32.26 to -4.87), but not with orlistat. Biliary phospholipid concentration decreased significantly with placebo (-4.38 +/- 1.91 mmol/L; 95% CI = -8.13 to -0.64) but not with orlistat. Mean changes from the baseline in cholesterol saturation index and gallbladder motility were similar in both groups. Microscopy of bile failed to reveal cholesterol microcrystals before or after treatment in either group. CONCLUSIONS: Our findings indicate a primary initial effect of weight loss is a reduction in biliary bile acids and phospholipids. Orlistat blocks these adverse changes in biliary lipid composition and maintains hepatobiliary function. We speculate that the risk of formation of gallstones during weight loss may actually be lowered with orlistat.

Short-term orlistat treatment does not affect mineral balance and bone turnover in obese men.

Orlistat is a gastrointestinal lipase inhibitor that is used to reduce dietary fat absorption and to enhance weight loss in subjects consuming a hypocaloric diet. To assess whether orlistat has an effect on the metabolism of six minerals, a 21-d, double-blind, randomized, parallel-group, placebo-controlled mineral balance study was conducted in obese (body mass index > 30 kg/m(2)) men. Subjects consumed a hypocaloric diet with a constant daily mineral content and received daily oral treatment with orlistat (120 mg three times daily) (n = 14) or placebo (three times daily) (n = 14) for 21 d. After a 14-d equilibration period, calcium, phosphorus, magnesium, iron, copper and zinc balances were assessed for d 15-21. In addition, the effect of diet and orlistat treatment on bone metabolism was estimated from measurement of biomarkers of bone formation and bone resorption. Serum and urine electrolytes were also measured at baseline and at the end of treatment. Orlistat inhibited fat absorption by approximately 33% (P < 0.05). There were no significant differences in mineral apparent absorption, urinary mineral loss or mineral balance between the orlistat and placebo groups. Markers of bone turnover and serum and urine electrolytes did not differ between the orlistat and placebo groups. Orlistat was well tolerated; adverse events were of mild or moderate intensity, and the majority of these events were unrelated or remotely related to study treatment. In obese men consuming a hypocaloric diet, the administration of orlistat had no significant effect on the balance of six selected minerals. In addition, biomarkers of bone turnover, as well as serum and urine electrolytes, were not affected by orlistat treatment.

Comparative evaluation of fecal fat excretion induced by orlistat and chitosan.

OBJECTIVE: To compare the effects of chitosan and orlistat on fecal fat excretion. RESEARCH METHODS AND PROCEDURE: A randomized, open-label, two-period sequential design study was used. A total of 12 healthy adult volunteers within 20% of their ideal body weight entered a 7-day run-in diet period before being randomized to orlistat (120 mg) or chitosan (890 mg) three times daily for 7 days. Subjects then crossed over treatment regimens for an additional 7-day period. Subjects followed a standardized diet (2500 kcal/d, 30% as fat) for the entire 21-day study. Feces were collected on days 4 to 7 of the run-in period (baseline) and during the two treatment periods. Mean daily fecal fat excretion was measured at baseline and during each treatment regimen. RESULTS: Mean baseline fecal fat excretion for all subjects was 1.36 +/- 0.45 g/d. During orlistat treatment, mean fecal fat excretion significantly increased from baseline (+16.13 +/- 7.27 g/d; p < 0.001). No significant effect was observed with chitosan (+0.27 +/- 1.02 g/d; p = 0.379). Fecal fat excretion was significantly greater with orlistat than with chitosan (p < 0.001; 95% confidence intervals: 11.73; 20.00 g/d). DISCUSSION: This study provides additional evidence of the inhibitory effect of orlistat on dietary fat absorption. Chitosan, however, has no effect on fecal fat excretion.

Orlistat fails to alter postprandial plasma lipid excursions or plasma lipases in normal-weight male volunteers.

OBJECTIVES: After 10 d of orlistat administration (120 mg three times/day), the primary objective was to determine the drug's effect on postprandial plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities on day 10 after an oral fat-load. The secondary objectives were to determine the effects of orlistat on 12 h postprandial measures of: (1) preheparin HTGL and LPL; and (2) serum triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and free fatty acids. METHODS: Twenty-four normal-weight, healthy male volunteers were randomized to either 120 mg orlistat (n=12) or placebo (n=12) three times a day with meals for 10 d. Preheparin LPL and HTGL activities and LPL specific activity were measured in the fasted state on days 1, 5, and 10. On days 5 and 10 the study medication (orlistat or placebo) was taken at the beginning of a fat-rich breakfast and serum lipid and lipoprotein levels monitored for 12 h postprandially. On day 10, 15 min postheparin HTGL activity was measured 8 h after the fat-rich breakfast. RESULTS: No differences were found between groups in fasting levels of preheparin LPL or HTGL activity or in LPL-specific activity on days 1, 5 and 10. No difference was found between the two treatment groups in postheparin HTGL activity 8 h after the fat-rich breakfast. Also, no differences were found between the two groups in plasma triglycerides or lipoproteins. CONCLUSION: The results indicate that the oral administration of orlistat (120 mg t. i.d.) does not significantly alter plasma triglycerides or lipoproteins, and that the inhibitory effect of orlistat on lipases is limited to the gastrointestinal tract and is not manifested systemically.

The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers.

OBJECTIVES: The primary objective was to investigate the possible interference of ethanol on the orlistat effect on inhibition of dietary fat absorption and the possible interference of orlistat on the pharmacokinetics of ethanol. Secondary objectives were to assess the tolerability during concomitant dosing of orlistat and ethanol and to determine the ethanol effect on plasma levels of orlistat. METHODS: This was a double-blind, placebo-controlled, parallel, randomized study performed in 30 (three parallel groups of ten subjects each) healthy normal weight male subjects between the ages of 20 and 30 years. A 5-day run-in period to accustom subjects to a standardized diet of 2500 kcal/day (30% fat) and to establish baseline fecal fat excretion was followed by a 6-day treatment period. Subjects were randomly assigned to one of three treatment groups (A = orlistat 120 mg t.i.d. and ethanol placebo, B = orlistat 120 mg t.i.d. and 40 g ethanol qd on days -1 and 6, and 40 g bid on days 1-5, and C = orlistat placebo tid and 40 g ethanol qd on days -1 and 6, and 40 g b.i.d. on days 1 5). Serial blood samples were collected for determination of ethanol serum concentrations at specified times over 5 h after each dose of ethanol on days -1 and 6, and for determination of orlistat plasma concentrations on days 1, 3, 5, and 6. Feces were collected quantitatively on days -5 through 8 for analysis of fecal fat. RESULTS: The means of baseline-corrected fecal fat excretion values were comparable: 23.7 g for group A (orlistat) and 22.7 g for group B (orlistat and ethanol). No significant difference was found regarding ethanol pharmacokinetic parameters between treatments with orlistat and placebo. No apparent differences existed between the number of plasma samples with measurable orlistat concentrations in groups A and B. CONCLUSION: Concomitant ingestion of social amounts of ethanol did not alter the inhibitory effect of orlistat on dietary fat absorption during short-term treatment (6 days) with orlistat. Short-term treatment with orlistat had no significant influence on ethanol pharmacokinetics.

Mode of action of orlistat.

Gastric and pancreatic lipases are enzymes that play a pivotal role in the digestion of dietary fat. Orlistat, a semisynthetic derivative of lipstatin, is a potent and selective inhibitor of these enzymes, with little or no activity against amylase, trypsin, chymotrypsin and phospholipases. It exerts its effect within the gastrointestinal (GI) tract. Orlistat acts by binding covalently to the serine residue of the active site of gastric and pancreatic lipases. When administered with fat-containing foods, orlistat partially inhibits hydrolysis of triglycerides, thus reducing the subsequent absorption of monoaclglycerides and free fatty acids. This effect can be measured using 24h faecal fat excretion as a representative pharmacodynamic parameter. Orlistat's pharmacological activity is dose-dependent and can be described by a simple Emax model which exhibits an initial steep portion of the dose-response curve with a subsequent plateau (approximately 35% inhibition of dietary fat absorption) for doses above 400 mg/d. At therapeutic doses (120 mg tid with main meals) administered in conjunction with a well balanced, mildly hypocaloric diet, the inhibition of fat absorption (approximately 30% of ingested fat) contributes to an additional caloric deficit of approximately 200 calories. Orlistat does not produce significant disturbances to GI physiological processes (gastric emptying and acidity, gallbladder motility, bile composition and lithogenicity) or to the systemic balance of minerals and electrolytes. Similarly, orlistat does not affect the absorption and pharmacokinetics of drugs with a narrow therapeutic index (phenytoin, warfarin, digoxin) or compounds frequently used by obese patients (oral contraceptives, glyburide, pravastatin, slow-release nifedipine).

The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

To assess the effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin, a third-party blind, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers. Each participant received single 30-mg oral doses of racemic warfarin sodium (Coumadin; DuPont Pharma, Wilmington, DE) administered on the eleventh day of treatment with 120 mg orlistat (treatment A) and placebo (treatment B) three times a day for 16 days; the two treatments were separated by a 3-week washout period. Serial blood samples were collected before and at appropriate intervals after each dose of warfarin to determine plasma concentrations of R-warfarin and S-warfarin and blood prothrombin time (PT) and plasma Factor VII concentration. In addition, serum concentrations of vitamin K1 and its epoxide and of osteocalcin and its undercarboxylated form were measured before breakfast on days -7, 1, 4, 6, and 10. Equivalent results between treatments with orlistat and placebo were found with regard to all pharmacokinetic parameters of R- and S-warfarin (except for time to maximum concentration of R-warfarin). Pharmacodynamic parameters of warfarin (PT and Factor VII) and vitamin K nutritional status parameters (ratios of vitamin K1 to vitamin K1 epoxide and undercarboxylated osteocalcin to osteocalcin) also were unaltered by orlistat. Orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics and pharmacodynamics of a single 30-mg oral dose of warfarin in healthy volunteers.

Oral and intravenous zidovudine pharmacokinetics: the effect of granulocyte-macrophage colony stimulating factor.

Combination therapy with zidovudine and recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) may be warranted, owing to the bone marrow suppressive effects of zidovudine. A study of 16 patients, 8 of whom had acquired immune deficiency syndrome (AIDS) and 8 of whom were infected with human immunodeficiency virus (HIV) but were asymptomatic, was conducted. The effect of 4 days of rHU GM-CSF versus placebo on intermittent zidovudine therapy (200 mg every 8 hours) was evaluated using a randomized, cross-over study design. Pharmacokinetics of oral and intravenous zidovudine were determined on days 1 (oral), 3 (oral), and 4 (intravenous) of rHu-GM-CSF (placebo) administration. After intravenous dosing, zidovudine plasma clearance for placebo and rHu GM-CSF averaged 1.4 +/- 0.2 and 1.3 +/- 0.2 L/hr/kg, respectively (P = 0.017), mean residence time averaged 1.5 +/- 0.5 and 1.9 +/- 0.6 hours, respectively (P = 0.012), and the steady-state volume of distribution was 2.0 +/- 0.7 and 2.3 +/- 0.7 L/kg, respectively (P = 0.027) for the two treatment arms. Stratified data for patients with AIDS and those with asymptomatic HIV infection revealed no significant difference in plasma clearance or mean residence time between the two patient groups. These pharmacokinetic results indicate that dosage adjustments for zidovudine are not warranted when administered with rHu GM-CSF owing to the small changes observed. However, the statistically significant increase in Vss suggests the possibility of enhanced zidovudine cellular uptake in the presence of rHu GM-CSF.

Pharmacokinetics of isepamicin in paediatric patients.

The pharmacokinetics of isepamicin were evaluated in 50 paediatric patients ranging from newborn to 13 years old. Children with subdivided according to age: Group I (6-13 years); Group II (4 months to 6 years); Group III (16 days to 4 months); and Group IV (newborn to 16 days). All patients received isepamicin 7.5 mg/kg every 12 hours except those in Group IV who received 7.5 mg/kg once daily. Isepamicin was administered initially as an intravenous 30-minute infusion and then either intravenously or intramuscularly for between 4 and 12 days. Plasma samples were obtained after the first or second dose on day 1 at 0, 0.5, 1, 4, 6, 8 and 12 hours after the initiation of dosing and at 0.5 and 12 hours on other dosing days. Additional samples were collected in the Group IV patients at 18, 20 and 24 hours. Isepamicin showed a similar plasma concentration-time profile in Groups I, II and III (children from 16 days to 13 years), and in these groups the profile was generally similar to that observed in adults. Neonates up to the age of 16 days (Group IV) showed a distinctly different pharmacokinetic profile: a significantly larger AUC, longer half-life, lower Cmax and lower total body clearance. Isepamicin 7.5 mg/kg administered once daily to children less than 16 days old and twice daily to children aged 16 days to 13 years appears to be pharmacokinetically appropriate. The drug was very well tolerated by children of all age groups.

The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers.

To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose-lowering effect) of glyburide, an open-label, placebo-controlled, randomized, two-way crossover study was done in 12 healthy male volunteers. Each subject received single 5-mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80-mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five-day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80-mg three times daily does not significantly alter the pharmacokinetics and blood glucose-lowering effect of a single 5-mg oral dose of glyburide in healthy volunteers.

Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers.

Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.

Human liver xanthine oxidase: nature and extent of individual variation.

Xanthine oxidase catalyzes the biotransformation of many drugs, including the thiopurines and methyl-xanthines. We used a sensitive radiochemical assay to determine optimal conditions for the assay of human liver xanthine oxidase activity. We then used those assay conditions to study the nature and extent of individual variation of xanthine oxidase activity in 189 samples of hepatic tissue from patients undergoing clinically indicated partial hepatectomy or open liver biopsy. The average hepatic xanthine oxidase activity was 21% higher in samples from male patients than in those from female patients (1.27 +/- 0.43 [mean +/- SD, n = 92] versus 1.05 +/- 0.38 U/gm tissue [n = 97, p less than 0.0001], respectively). Seventy-nine of these tissue samples had been obtained from patients with normal liver function studies and normal serum creatinine values. Average xanthine oxidase activity in these 79 samples remained approximately 20% higher for men than for women (1.35 +/- 0.38 versus 1.12 +/- 0.33 U/gm tissue, respectively). Probit analysis of the data for samples from patients with normal liver function studies and normal creatinine values suggested the presence of a subgroup of samples with relatively low xanthine oxidase activity in 21% (9 of 42) of male patients and 27% (10 of 37) of female patients. These observations may have implications with regard to individual variation in the biotransformation of drugs metabolized by xanthine oxidase.

Thiopurine methyltransferase regulation in rat kidney: immunoprecipitation studies.

1. Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. TPMT activity in the kidneys of male Sprague-Dawley (S-D) rats is approximately twice that present in the kidneys of female S-D rats, and this difference is testosterone-dependent. Renal TPMT activities in these animals also increase dramatically during growth and development. 2. Our studies were conducted to determine whether variations in TMPT activity in the S-D rat kidney were due to differences in the quantity of TPMT protein. Rabbit polyclonal antibodies to partially purified rat kidney TPMT were used to develop an immunoprecipitation assay for immunoreactive TPMT protein. 3. Gender-related differences in renal TPMT activities in S-D rats were due to a lower content of immunoreactive TPMT protein in kidneys of female animals. TPMT enzyme activities and immunoreactive protein levels were also directly correlated in renal preparations from castrated and sham-operated male rats, from testosterone-treated castrated and sham-operated male rats, and from testosterone-treated and control female rats. 4. There was also a significant positive correlation between TPMT enzymic activities and immunoreactive TPMT protein levels in renal tissue from different aged male S-D rats (rs = 0.955, n = 15, P less than 0.001.) 5. These results demonstrate that changes in S-D kidney TPMT activity during growth and development, in the two sexes and in response to testosterone, were due to variations in the quantity of immunoreactive TPMT protein.

Mouse kidney histamine N-methyltransferase: assay conditions, biochemical properties and strain variation.

Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine and structurally-related compounds. Levels of HNMT activity in the human red blood cell are regulated by inheritance. The inbred mouse is an ideal laboratory animal in which to study the genetics of inherited traits. Therefore, HNMT activity was measured in renal homogenates of A/J mice to establish optimal assay conditions and to determine the properties of mouse kidney HNMT as a first step toward testing the hypothesis that large strain-related variations in HNMT activity might exist among inbred strains of mice. Apparent Km values for histamine and S-adenosyl-L-methionine, the two cosubstrates for the reaction, were 26 and 1.7 microM, respectively. IC50 values for the inhibition of mouse kidney HNMT by amodiaquine and S-adenosyl-L-homocysteine were 1.67 and 11.8 microM, respectively. HNMT activity levels were then measured under optimal assay conditions in renal preparations from male animals of eleven inbred mouse strains chosen because of the availability of recombinant inbred (RI) animals derived from the parental strains. Average values for renal HNMT activity varied among strains by less than two-fold and ranged only from 26.2 +/- 0.51 (mean +/- SEM) units/mg protein in AKR/J mice to 39.1 +/- 2.58 units/mg protein in C57BL/6J animals. Renal HNMT activities in females of the three strains in which both sexes were studied were 11-13% higher than were those in renal tissue from males of the same strain. In summary, the properties of HNMT in the mouse kidney are similar to those of HNMT in other species, but strain variation in levels of enzyme activity among the 11 inbred mouse strains studied was insufficient for these animals to be used in biochemical genetic experiments.

Human liver nicotinamide N-methyltransferase: ion-pairing radiochemical assay, biochemical properties and individual variation.

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide, pyridine, and structurally related compounds. The products of this reaction are positively charged pyridinium ions that cannot be removed from aqueous solution by simple organic solvent extraction. We developed an assay for human liver NNMT based on the extraction of the positively charged reaction product into 60% isoamyl alcohol in toluene in the presence of the ion-pairing reagent 1-heptanesulfonic acid. Nicotinamide was the methyl acceptor for the reaction, and [14C-methyl]-S-adenosyl-L-methionine (Ado-Met) served as the methyl donor. Apparent Km values of human liver NNMT for nicotinamide and Ado-Met were 347 and 1.76 mumol/l, respectively. The product of the reaction was identified as N1-methylnicotinamide (NMN) by high performance liquid chromatography. NNMT activity was inhibited by the reaction products, NMN and S-adenosyl-L-homocysteine. NNMT activity was not affected by inhibitors of other methyltransferases including Ca2+, SKF 525A and 3,4-dimethoxy-5-hydroxybenzoic acid. Individual variation in NNMT activity was studied by measuring hepatic enzyme activities in 163 human liver biopsy samples obtained during clinically-indicated surgery. The average NNMT activity in these samples was 51.5 +/- 32.5 U per mg protein (mean +/- SD), and there was not a significant correlation of enzyme activity with patient age or with the time of storage of the biopsy samples at -80 degrees C. The distribution of activities was bimodal, and approximately 26% of the samples were included in a subgroup with high NNMT activity. It will now be possible to test the hypothesis that individual differences in hepatic NNMT activity might be related to variation in the N-methylation of pyridine compounds and to individual differences in either toxicity or the therapeutic efficacy of such compounds.

Pharmacokinetics of vincristine in cancer patients treated with nifedipine.

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium-entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least-square regression program (SAS-NLIN). A tri-exponential model fitted the raw data better than a bi-exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2 alpha was shorter in NIF-treated patients, whereas the T1/2 gamma was longer in the NIF-treated group. The NIF-treated group showed an increase in the AUC O-infinity and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7-day urinary excretion of VCR was reduced in the NIF-treated patients. These data suggest that, when VCR is administered to NIF-treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.

Effects of cefamandole on hemostasis in patients undergoing hip replacement with heparin prophylaxis.

The aim of this study was to compare the effects of the prophylactic use of cefamandole versus oxacillin plus gentamicin on hemostasis in patients undergoing hip replacement with heparin prophylaxis. Twenty-four patients with a normal hemostatic profile were randomly allocated to receive either cefamandole or oxacillin plus gentamicin. All the patients received calcium heparin. Platelet count, bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TCT), fibrinogen and serum FDP were assessed before treatment and every day of antibiotic administration. Surgical bleeding was assessed using a four-grade score system. Platelet count, bleeding time, fibrinogen and serum FDP did not show any change with both treatments. PT, aPTT and TCT showed a similar and mild prolongation in the two groups of patients. No difference in the surgical bleeding was observed between the two groups. We conclude that a short-term prophylaxis with cefamandole is a safe regimen in patients undergoing hip replacement with heparin prophylaxis.

Effects of the new glycopeptide antibiotic teicoplanin on platelet function and blood coagulation.

Teicoplanin, a new glycopeptide antibiotic, is structurally related to ristocetin, an antibiotic known to induce human platelet agglutination and, thus, thrombocytopenia and thromboembolic side effects. The aim of this study was to evaluate the effects of teicoplanin on platelet function in vitro and ex vivo and on blood coagulation ex vivo. In the in vitro studies, spontaneous platelet aggregation; platelet aggregation induced by ADP, collagen, and ristocetin; and the release of beta-thromboglobulin from platelets were assessed. Platelets from healthy subjects were incubated with teicoplanin at final concentrations of 100, 1,500, 5,000, and 10,000 micrograms/ml. The maximal achievable concentration with therapeutic doses is 100 micrograms/ml. When compared with saline, teicoplanin at concentrations of 100 and 1,500 micrograms/ml had no effect on platelet function, but at concentrations of 5,000 and 10,000 micrograms/ml, it induced greater spontaneous platelet aggregation (P less than 0.01) and inhibited platelet aggregation induced by ADP, collagen, and ristocetin (P less than 0.01). Teicoplanin at concentrations of 100, 1,500, and 5,000 micrograms/ml did not induce the release of beta-thromboglobulin, in contrast to teicoplanin at a concentration of 10,000 micrograms/ml and ristocetin at a concentration of 1.5 mg/ml (P less than 0.01). In the ex vivo studies, platelet count, bleeding time, plasma beta-thromboglobulin, platelet aggregation induced by ADP, ristocetin, and epinephrine, activated partial thromboplastin time, prothrombin time, thrombin clotting time, and serum fibrinogen degradation products were evaluated at days 0, 3, and 6 and at 72 h after the end of therapy. All subjects completed the study without evidence of side effects. When compared with the pretreatment values, none of the values from these assays showed a significant change at any time during and after treatment. We concluded that platelet function and blood coagulation are not affected by therapeutic concentrations of teicoplanin and that in vitro platelet function is affected only by concentrations of teicoplanin far in excess of those that are clinically achievable.

Viridans streptococci septicemia in cancer patients: a clinical study.

Viridans streptococci septicemia was documented in ten cancer patients, 7 of whom were neutropenic (less than 1000/mmc). Pneumonia was presumed to be the source of bacteremia in six patients. Viridans streptococci isolated from sputum culture in an immunocompromised host must be regarded as the potential etiological agent, then further characterized and checked for antibiotic sensitivity.