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Biomedical subjects

S C Laizure

Publications and source records attributed to S C Laizure.

At least 19 recordsLinked to original sources
PubMed2005

Studies on itraconazole delivery and pharmacokinetics in mallard ducks (Anas platyrhynchos).

Avian aspergillosis is commonly treated with itraconazole (ITZ). This paper describes two studies using mallard ducks (Anas platyrhynchos). The first study evaluated in vivo release of ITZ from subcutaneously injected controlled-release gel formulations and the second study compared pharmacokinetic parameters for two ITZ oral suspensions. ITZ-A suspension was prepared by mixing contents of commercially available capsules with hydrochloric acid and orange juice. ITZ-B suspension was prepared by dispersing the complex of the drug with hydroxypropyl-beta-cyclodextrin in water. Concentrations of ITZ and its active metabolite, hydroxyitraconazole (OH-ITZ), in plasma and tissue samples were measured using high-performance liquid chromatography. In the second study, drug concentrations in plasma samples were also analyzed using a bioassay. After administration of two ITZ controlled-release formulations, plasma and tissue concentrations of ITZ and OH-ITZ were either very low (< or = 52 ng/mL) or undetectable. Exceptions included skin, subcutaneous fat, and muscle adjacent to the injection site. The drug from ITZ-A and ITZ-B suspensions was absorbed after oral administration. ITZ pharmacokinetic parameters for both suspensions in mallard ducks were similar and the bioassay successfully measured ITZ equivalents in plasma samples from ducks.

Administration, Oral↗
PubMed1999

Cocaethylene formation in rat, dog, and human hepatic microsomes.

The dog and rat are important animal models for studying the role of cocaethylene in the pharmacodynamic interaction between cocaine and ethanol. In a previous study in our laboratory it was found that a cocaine dose of 3 mg/kg IV and ethanol 1 g/kg IV failed to produce detectable concentrations of cocaethylene in the plasma of dogs. In follow up to this result, the pharmacokinetic disposition of cocaine and cocaethylene in the dog were determined to be similar. These results suggested significant differences between animal and human cocaethylene formation may occur. To test this possibility the in vitro formation of cocaethylene was determined in rat, dog and human hepatic microsomal preparations containing cocaine (0-7 mM) and ethanol (50 mM). Nonlinear least-squares regression was used to estimate Km and Vmax and the results were compared statistically. The mean +/- standard deviation for Km and Vmax in the rat, dog and human were 0.53 +/- 0.04, 0.97 +/- 0.07, and 0.56 +/- 0.08 mM, and 390 +/- 9, 233 +/- 6, and 60 +/- 3 pmol/minute/mg protein, respectively. The Km in the dog was significantly greater (p<0.05) than the Km in the rat and human. The Vmax was statistically different among all three species (rat>dog>human; p<0.05). These results demonstrate that cocaethylene formation is greater in dog than human hepatic microsomes, which is in contrast to in vivo studies that appear to show that humans produce more cocaethylene than dogs. It is suggested by the authors that route of cocaine administration may be an important factor in the formation of cocaethylene when cocaine and ethanol are co-administered.

Animals↗
PubMed1999

Selective serotonin reuptake inhibitors for migraine prophylaxis.

The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis. Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis, but this is the first report with sertraline. Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period. Subjects were then randomized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period. Subjects completed a daily diary reporting the occurrence, severity, and degree of impairment associated with migraine. The headache index, a composite measure of migraine frequency and severity, scores did not significantly improve between assessments at baseline (20.8 +/- 14.88), 8 weeks (17.6 +/- 12.27), and 12 weeks (16.7 +/- 6.38) in the treatment group (n=6) (P=0.956). This finding is compared to other studies with the serotonin selective reuptake inhibitors, fluoxetine, fluvoxamine, and paroxetine. The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers, tricyclic antidepressants, or divalproex sodium, but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective.

Adult↗
PubMed1999

Disposition of morphine in tissues of the pregnant rat and foetus following single and continuous intraperitoneal administration to the mother.

Foetal exposure to maternally administered opiates such as morphine represent a serious human health problem but disposition studies in man are difficult to perform. Morphine disposition was therefore investigated in pregnant rats and their foetuses near term as a model. Disposition was examined either following intraperitoneal dosing as a single dose or continuous infusion. A high-pressure liquid chromatography assay for morphine in plasma and tissue was developed and validated. Following the single morphine dose, foetal distribution was rapid and concentrations in foetal and placental tissue were from 2.6 (whole foetus) to 27.6 (placenta) times higher compared with maternal plasma. The rank order of the area under the concentration vs time curve (AUC) of morphine in tissues was: placenta > or = foetal liver > foetal brain > whole foetus > maternal brain. The foetal brain to maternal brain AUC ratio for morphine was 9.5, suggesting large differences in their blood-brain barrier permeability. Following continuous administration of morphine there were significant linear relationships between maternal plasma and tissue concentrations with the same rank order as the single dose study. However, following continuous administration the relative amount of morphine in placenta and foetal liver was reduced by half and one-third, respectively, compared with the single dose study. These results document why the rat foetus is particularly susceptible to the pharmacodynamic effects of morphine following maternal administration.

Analgesics, Opioid↗
PubMed1998

Evaluation of dose-dependent pharmacokinetics of cocaethylene and cocaine in conscious dogs.

Cocaine use continues to be widespread in the United States. Most cocaine users co-ingest ethanol resulting in decreased elimination of cocaine and formation of the active cocaine metabolite, cocaethylene, by hepatic carboxylesterases. In a recent study from our laboratory in dogs to evaluate the cocaine-ethanol interaction, we demonstrated a similar ethanol-induced reduction in cocaine metabolism, although we were unable to detect cocaethylene when the two drugs were given together. This unexpected finding could be explained by ethanol-induced inhibition of cocaine metabolism via a pathway that does not involve hepatic carboxylesterases or formation of cocaethylene that inhibits cocaine metabolism and is then rapidly cleared. The purpose of the present study is to determine which of these mechanisms best explain our data by characterizing the pharmacokinetics of cocaine and cocaethylene over a range of doses in conscious dogs. Seven adult mongrel dogs received 1, 3, and 5 mg/kg cocaine and cocaethylene HCl base with each drug dose administered i.v. on a separate study day. Arterial blood samples were collected at various times after each dose and analyzed for cocaine and cocaethylene by HPLC. Cocaine clearance was dose-dependent with clearance decreasing from 1.53 +/- 0.31 to 1.09 +/- 0.11 l/min as the dose was increased from 1 to 5 mg/kg (p<0.05). Vmax x Vss and Km for cocaine were 0.95 +/- 0.40 l/min/kg and 11.2 +/- 6.2 mg/kg, respectively. Cocaethylene pharmacokinetics were similar to those of cocaine, but were not dose-dependent over the dose range of 1-5 mg/kg. These results suggest that cocaethylene is not formed and rapidly cleared after co-administration of cocaine and ethanol to the dog, but rather suggests that cocaethylene is not formed in appreciable quantities in the dog. Therefore, we conclude that the decrease in cocaine elimination in the dog associated with ethanol administration is due to ethanol-mediated inhibition cocaine metabolism, rather than inhibition by cocaethylene.

Animals↗
PubMed1997

Decreased hypoprothrombinemic effect of warfarin associated with furosemide.

The authors describe a case of furosemide possibly inhibiting the hypoprothrombinemic effect of warfarin. The initiation of furosemide dosing in a patient receiving a stable dose of warfarin was associated with an 28% decrease in the international normalized ration (INR). Using normal volunteers, two previous controlled studies of an interaction between warfarin and chlorthalidone, and between warfarin and spironolactone, assert that volume depletion produced by forced diuresis results in the inhibition of warfarin's hypoprothrombinemia. Consistent with this hypothesis, the authors found that their patient's hematocrit (believed to reflect hydration status) correlated with the INR: r2 = 0.78, p < 0.05. This case provides further evidence suggesting that acute diuresis can decrease the hypoprothrombinemic effect of warfarin.

Anticoagulants↗
PubMed1996

Quantitation of cocaine and cocaethylene in canine serum by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic procedure for the determination of cocaine and cocaethylene in canine serum has been developed. The compounds were extracted from 1 ml of alkalinized canine serum with hexane. Chromatographic separation was achieved with a cyanopropyl column (250 x 4.6 mm I.D., 5 microns) using a mobile phase of acetonitrile and phosphate buffer, pH 7.40 (38:62, v/v) flowing at 1 ml/min. Eluate was monitored by a variable-wavelength UV detector set to 230 nm. The extraction procedure yields an average recovery of 99 and 96% for cocaine and cocaethylene, respectively. The between-day coefficients of variation, at 2400 ng/ml, for cocaine and cocaethylene were both 8.6% and the within-day coefficients of variation, at 400 ng/ml, for cocaine and cocaethylene were 7.3 and 8.0%, respectively. A concentration-time profile resulting from administration of 3 mg/kg cocaine and cocaethylene to the dog revealed a similar disposition between cocaine and cocaethylene, with a clearance and volume of distribution at steady-state values of 72.8 and 61.0 ml/min/kg and 2.6 and 2.7 1/kg, respectively.

Acetonitriles↗
PubMed1996

Effects of ethanol and cocaethylene on cocaine pharmacokinetics in conscious dogs.

Coingestion of cocaine and ethanol is common among cocaine users, and this combination is reported to enhance the euphoric effects of cocaine. The cardiovascular effects of cocaine are increased in the presence of ethanol, although the mechanism(s) involved in this interaction are poorly understood. Recent studies suggest the enhanced cardiac effects may be caused by ethanol-mediated inhibition of cocaine metabolism leading to higher cocaine plasma concentrations. However, these studies were all performed in animals or humans that form cocaethylene when ethanol and cocaine are coadministered. Thus, it is also possible that cocaethylene could inhibit cocaine's metabolism. Preliminary studies in our laboratory indicate the dog does not form detectable quantities of cocaethylene after coadministration of cocaine and intravenous ethanol. Thus, the dog may be a useful model for isolating the individual contributions of ethanol and cocaethylene to this interaction. The purpose of the present study was to confirm this observation, and to determine the effects of ethanol and cocaethylene on cocaine pharmacokinetics in the conscious dog. Six dogs received cocaine (3 mg/kg i.v.) alone, ethanol (1 g/kg i.v.) followed by cocaine (3 mg/kg i.v.), and cocaine (3 mg/kg i.v.) + cocaethylene (3 mg/kg i.v.). Cocaethylene was not detected in any of the plasma samples from the six dogs after administration of cocaine and ethanol. Ethanol and cocaethylene reduced mean cocaine clearance by 47% and 26%, respectively. Inhibition of cocaine's metabolism by both ethanol and cocaethylene may play an important role in mediating the enhanced effects of cocaine in the presence of ethanol.

Animals↗
PubMed1995

Factors affecting serum protein binding of cocaine in humans.

The free (unbound) drug in serum is an important determinant of pharmacologic response. The present study was performed to more completely identify and evaluate factors affecting cocaine binding to human serum proteins. Protein binding was determined by ultrafiltration with [3H] cocaine. Cocaine binding parameters in serum from eight healthy volunteers were determined over a concentration range of 0.003 to 300 microM (0.001-100 micrograms/ml) and indicated cocaine binds to two classes of independent binding sites; one with high affinity [association constant (Ka) = 0.42 +/- 0.09 microM-1] and low capacity (N1 = 12.3 +/- 2.9 microM) and one with low affinity and high capacity (gamma = 0.41 +/- 0.05). Binding was concentration dependent with free fraction increasing from 0.16 +/- 0.05 to 0.68 +/- 0.02 over this concentration range. The binding capacity was significantly correlated with alpha-1-acid glycoprotein (AAG) concentration (r2 = 0.71, P = .0009). Binding studies were performed using AAG and human serum albumin (HSA) alone and together in phosphate buffer to determine the specific proteins responsible for cocaine binding. These studies revealed the binding of cocaine to AAG is potentiated by the presence of HSA as Ka for the first binding site increased from 0.08 microM-1 with AAG alone to 0.46 microM-1 with AAG combined with HSA 4 g/dl. Binding parameter estimates and cocaine free fraction in human serum and AAG 75 mg/dl plus HSA 4 g/dl in phosphate buffer were similar indicating that AAG and HSA are the principal binding proteins in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗
PubMed1993

Multiple-dose pharmacokinetics of 12 milligrams of trimethoprim and 60 milligrams of sulfamethoxazole per kilogram of body weight per day in healthy volunteers.

The disposition of 12 mg of trimethoprim and 60 mg of sulfamethoxazole per kg of body weight in six healthy male volunteers is described. The daily dose was evenly divided and administered orally every 6 h for 13 consecutive doses. Individual drug components were assayed by high-performance liquid chromatography. Steady-state concentrations in serum for trimethoprim and sulfamethoxazole were within the purported therapeutic ranges for treating Pneumocystis carinii pneumonia. Co-trimoxazole was well tolerated, and no subject withdrew from the study because of toxicity. Comparison of the pharmacokinetic parameters in this study with those of our previous findings indicates that the elimination of trimethoprim-sulfamethoxazole follows a first-order process within the dose ranges assessed. Administration of 15- to 20-mg/kg trimethoprim and 75- to 100-mg/kg sulfamethoxazole in four evenly divided doses for the first 24 h followed by 12 and 60 mg/kg/day, respectively, for the remainder of therapy rapidly attains concentrations in serum within the proposed P. carinii pneumonia therapeutic range. Clinical trials are indicated to evaluate this dosing scheme, which may decrease exposure to potentially excessive concentrations of trimethoprim and sulfamethoxazole.

Adult↗
PubMed1991

Use of low-dose trimethoprim-sulfamethoxazole thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients.

We conducted an open prospective clinical trial to evaluate the efficacy and toxicity of trimethoprim-sulfamethoxazole given as one double-strength tablet thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus-infected (HIV+) patients. A total of 104 HIV+ patients were evaluated, with 74 being in the primary prophylaxis group and 30 being in the secondary prophylaxis group. All except six patients received concomitant zidovudine; five patients on primary prophylaxis and one patient on secondary prophylaxis refused zidovudine. There were 70 patients evaluated for the efficacy of primary prophylaxis. The mean CD4 count was 124.4 +/- 110.1 cells per microliter. The mean follow-up time was 11.8 +/- 5.8 months (median, 12 months; range, 1 to 32 months). Two noncompliant patients developed PCP after 1 and 3 months of chemoprophylaxis. The failure rate (under the intention to treat principle) was 2 of 70 patients (2.9%; 95% confidence interval, 0.35 to 10%), or 1 per 413 patient-months of observation. There were 27 patients evaluated for the efficacy of secondary prophylaxis. The mean follow-up time was 12.4 +/- 7.2 months (median, 11 months; range, 1 to 29 months). Two patients, one of whom was noncompliant, were treatment failures, developing PCP after 14 and 15 months of chemoprophylaxis; this gave a failure rate of 2 of 27 patients (7.4%; 95% confidence interval, 0.9 to 24.3%), or 1 per 167 patient-months of observation. Adverse reactions sufficient to permanently terminate therapy occurred in 9 of 104 patients (8.7%; 95% confidence interval, 4 to 15.7%) overall. The serum trimethoprim, sulfamethoxazole, and N4-acetyl-sulfamethoxazole concentrations measured by high-pressure liquid chromatography were uniformly low. One double-strength tablet of trimethoprim-sulfamethoxazole taken weekly on Monday, Wednesday, and Friday appeared to be well tolerated and efficacious for the prophylaxis of PCP in HIV+ patients at high risk and deserves further investigation.

Adult↗
PubMed1991

Pharmacokinetics and adverse effects of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in healthy adult subjects.

The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia (PCP). Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concentrations in serum and urine were measured by high-performance liquid chromatography. Five subjects withdrew from the study because of intolerable gastrointestinal and central nervous system toxicities. In the seven subjects that completed the study, the mean maximum serum drug concentrations after the last dose were 13.6 +/- 2.0, 372 +/- 64, and 50.1 +/- 10.9 micrograms/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 +/- 3.5, 14.0 +/- 2.3, and 18.6 +/- 4.3 h, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concentrations of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concentration-time curve (for all three parameters, r2 = 0.6 and P less than 0.05). Our findings add to the evidence that serum drug concentrations in adults following the conventional dose of trimethoprim-sulfamethoxazole for PCP are excessive and contribute to certain adverse reactions. Further studies are indicated in patients to optimize the dosing regimen of trimethoprim-sulfamethoxazole in the treatment of PCP.

Administration, Oral↗
PubMed1990

Disposition of bupropion in healthy volunteers and subjects with alcoholic liver disease.

Bupropion hydrochloride is a new monocyclic antidepressant. In humans, its disposition results in the formation of three major metabolites: the morpholinol metabolite, the erythroamino alcohol, and the threoamino alcohol metabolite. Bupropion's disposition was monitored following a single oral 200 mg dose in eight healthy volunteers and eight age- (44.5 +/- 8.4 years) and weight- (77.4 +/- 6.7 kg) matched volunteers with alcoholic liver disease. This latter group is of interest because the incidence of depression is more frequent in alcoholics than in the general population, and the liver is the major route of elimination for cyclic antidepressants. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32.2 +/- 13.5 vs. 21.1 +/- 4.9 hours (p less than 0.05), while the differences in bupropion (17.3 +/- 8.6 hours vs. 16.5 +/- 10.4 hours for healthy subjects and subjects with alcoholic liver disease, respectively), erythroamino alcohol (26.1 +/- 13.3 hours vs. 29.8 +/- 6.9 hours for healthy subjects and subjects with alcoholic liver disease, respectively), and threoamino alcohol (25.5 +/- 8.6 hours vs. 23.4 +/- 10.7 hours for healthy subjects and subjects with alcoholic liver disease, respectively) were minimal. Mean area under the plasma concentration time curves for bupropion and metabolites were increased in subjects with alcoholic liver disease; however, clear differences between means of these small groups did not emerge, probably due to the increased variability of bupropion pharmacokinetics in these subjects. As a therapeutic agent for the treatment of depression in chronic alcoholics who may consume alcohol in combination with their antidepressant therapy, the lack of sedation with bupropion could be advantageous.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Bupropion in depression. II. The role of metabolites in clinical outcome.

We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.

Adult↗