Showing papers in "Clinical Pharmacology & Therapeutics in 1993"

Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation

Abstract: To assess the importance of cyclosporine pharmacokinetics on graft outcome and acute rejection episodes, pretransplant and a total of 1868 posttransplant whole-blood cyclosporine pharmacokinetic profiles were performed in 160 consecutive kidney transplant recipients. The following posttransplant pharmacokinetic risk factors were associated with a poorer graft survival and a higher incidence of acute rejection: F, 325 ml/min; steady-state cyclosporine concentrations, < 350 ng/ml during intravenous infusion; or average cyclosporine concentrations, < 400 ng/ml during the first oral study. Although the discrimination between rejecting and nonrejecting patients was greatest for cyclosporine concentrations obtained at 24 hours after drug administration, measurements at 6 and 14 hours, as well as average concentrations, were all highly predictive. Because of the strong association between the cyclosporine concentrations and outcome, an equation is described to provide initial oral dose prediction. Furthermore, this association suggests that improved cyclosporine pharmacokinetic monitoring may aid in improving outcome after kidney transplantation.

Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers.

Abstract: The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (approximately threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

A potentially hazardous interaction between erythromycin and midazolam

Abstract: Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

Abstract: The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

The use of caffeine for enzyme assays : a critical appraisal

Abstract: Clinical Pharmacology and Therapeutics (1993) 53, 503–514; doi:10.1038/clpt.1993.63

Inhibition by fluoxetine of cytochrome P450 2D6 activity

Abstract: Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 mumol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O-demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O-demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O-demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Grapefruit juice : felodipine interaction : mechanism, predictability, and effect of naringin

Abstract: Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single primary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in water at the same concentration as the juice in a randomized crossover trial of nine healthy men. With grapefruit juice, mean +/- SEM felodipine area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were 206% +/- 23% (range, 123% to 330%, p < 0.01) and 170% +/- 24% (range, 127% to 310%, p < 0.02), respectively, compared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) and felodipine Cmax (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) were reduced, consistent with inhibition of presystemic felodipine metabolism. Intersubject changes in felodipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could not be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other factors were important.

Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers

Abstract: Published research suggests that smokers metabolize nicotine and its major metabolite cotinine more rapidly than nonsmokers. To evaluate this possibility, we studied the disposition pharmacokinetics of intravenous deuterium-labeled nicotine in 11 smokers (administered 2.0 and 0.5 µg/kg/min × 30 minutes) and in 11 nonsmokers (0.5 µg/kg/min). Smokers did not metabolize nicotine more rapidly; the clearance of nicotine normalized for body weight was significantly slower in smokers than in nonsmokers. Cotinine elimination rates were similar in the two groups. The disposition pharmacokinetics of nicotine was similar for the low and high doses in the smokers, indicating that metabolism is dose-independent. Our findings argue against “metabolic tolerance” as a mechanism for the dose escalation observed in smokers after initiation of smoking. Our findings suggest that nicotine and cotinine kinetic parameters for smokers may be extrapolated to nonsmokers for estimating exposures to environmental tobacco smoke in nonsmokers. Clinical Pharmacology and Therapeutics (1993) 53, 316–323; doi:10.1038/clpt.1993.27

Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics

Abstract: The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.

The pharmacokinetics of morphine and morphine glucuronides in kidney failure.

Abstract: The pharmacokinetics of morphine and its glucuronide metabolites were investigated in three groups of patients with kidney failure (nondialyzed, receiving dialysis, and transplantation) and compared with a group of normal healthy volunteers Patients in all three renal groups were undergoing surgical procedures (nondialyzed group undergoing arteriovenous fistula formation, dialysis group undergoing placement of a peritoneal dialysis catheter, and the transplant group undergoing live donor kidney transplant) A sensitive, specific high-performance liquid chromatographic assay was used to quantitate morphine, morphine-3-glucuronide, and morphine-6-glucuronide Patients with kidney failure had a significantly increased morphine area under the curve (AUC) compared with control subjects There was also an increase in the metabolites morphine-3-glucuronide and morphine-6-glucuronide that was severalfold greater than the increase in morphine AUC This metabolite accumulation was reversed by kidney transplantation, providing an elegant confirmation on the role of the kidney in morphine pharmacology Clinical Pharmacology and Therapeutics (1993) 54, 158–167; doi:101038/clpt1993127

Smoking cessation, clonidine, and vulnerability to nicotine among dependent smokers

Abstract: Objective This study examines the efficacy of clonidine in smoking cessation and the influence of gender, history of major depression, and measures of nicotine dependence. Methods The study was designed as a 10-week double-blind randomized comparison stratified for gender and major depression. Three hundred subjects who smoked cigarettes heavily were enrolled in the study. Abstinence from smoking was evaluated by self-report and verified by serum cotinine levels. Results Gender, major depression recurrent type, and measures of nicotine addiction were risk factors for treatment failure. There was no clonidine effect in men, but there was a modest effect in women (odds ratio, 2.01; 95% confidence interval, 1.00 to 4.10) that was most pronounced (odds ratio, 8.5; 95% confidence interval, 1.67 to 43.62) among women with the highest risks. Conclusion Measures of addiction and major depression predict treatment failure. Together they are stronger predictors of outcome than drug. Clonidine is a limited aid in cessation, and drug effects come primarily from women at high risk for treatment failure. An increased risk for psychiatric complications after smoking cessation was apparent among smokers with histories of major depression, particularly bipolar disease. Clinical Pharmacology and Therapeutics (1993) 54, 670–679; doi:10.1038/clpt.1993.205

CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone

Abstract: The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6-B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O-demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O-demethylation in the three groups were 28.1 +/- 10.3, 3.4 +/- 2.4, and 5.0 +/- 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more "good opiate effects" and fewer "bad opiate effects" than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.

Gender‐based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Abstract: The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response.

Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6.

Abstract: Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use of Xba I, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 of CYP2D6 were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188 and G4268, as is found in most white subjects. Subjects with T188 or C4268 showed a significant higher log(MR) than subjects with homozygous C188 and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects. Clinical Pharmacology and Therapeutics (1993) 53, 410–418; doi:10.1038/clpt.1993.44

Inhibition and induction of cytochrome P4502E1‐catalyzed oxidation by isoniazid in humans

Abstract: We studied the effect of isoniazid administration on the cytochrome P4502E1-catalyzed elimination of chlorzoxazone and acetaminophen. Isoniazid, 300 mg daily, was administered for 7 days to a group of 10 volunteer slow acetylators. Acetaminophen, 500 mg, and chlorzoxazone, 750 mg, were administered on separate occasions before isoniazid, during the period of isoniazid administration, and after the discontinuation of isoniazid. Isoniazid inhibited the clearance of chlorzoxazone by 58%, as assessed from plasma data, and inhibited the formation of acetaminophen thioether metabolites (a measure of the formation of the hepatotoxin N-acetyl-p-benzoquinone imine and catechol oxidative metabolites of acetaminophen, as determined from their recovery in urine, by 63% and 49%, respectively. Two days after the discontinuation of isoniazid, the clearance of chlorzoxazone was increased over the value before isoniazid by 56%. Acetaminophen thioether but not catechol metabolites were increased by 56% 1 day after the discontinuation of isoniazid and had returned to the pre-isoniazid value 3 days after the discontinuation of isoniazid. We conclude that the time course of the interaction with regard to chlorzoxazone elimination and formation is compatible with an inhibition-induction effect of isoniazid on cytochrome P4502E1. The mechanism of this biphasic effect is probably induction by protein stabilization, which results in inhibition of catalytic activity while isoniazid is present.

Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome.

Abstract: Caffeine was used to assess acetylation status and indexes of oxidative drug metabolism (demethylation, xanthine oxidation, and 8-hydroxylation) in a control group and in three groups of patients infected with human immunodeficiency virus (HIV): patients with acquired immunodeficiency syndrome (AIDS) who had acute illnesses, stable patients with AIDS, and asymptomatic patients infected with HIV. The prevalence of apparent slow acetylation was greater in AIDS patients with acute illnesses compared with control subjects (27 of 29 [93%] versus 18 of 29 [62%]). Indexes of demethylation were decreased and 8-hydroxylation increased in these patients. Xanthine oxidation was the same as that in the control subjects. In the stable AIDS patients, oxidative pathways were altered in a manner similar to that observed in the AIDS patients with acute illnesses, but acetylation was the same as that in the control subjects. In HIV-infected asymptomatic patients, drug metabolism was the same as that in the control subjects. The increased prevalence of apparent slow acetylation and the altered activity of the oxidative pathways in AIDS patients with acute illnesses may partly explain the increased incidence of adverse drug reactions in these patients.

Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men

Abstract: In vitro studies with human liver microsomes have shown that erythromycin N-demethylation, dapsone N-hydroxylation, and the 6 beta-hydroxylation of cortisol are all primarily mediated by P4503A4. Trait measurements to assess the in vivo level of activity of these separate oxidations have also been developed previously. This study investigated the relationships among the three phenotypic trait measurements in 30 young healthy white men. The frequency distributions of the trait values were all unimodal, with a twofold range for the erythromycin breath test and the urinary dapsone recovery ratio; the urinary 6 beta-hydroxycortisol/cortisol ratio was more variable, with a 17-fold range of values. No statistically significant correlations were observed among any of the trait measurements (dapsone recovery ratio versus erythromycin breath test: r = -0.07, p = 0.7; urinary 6 beta-hydroxycortisol/cortisol ratio versus erythromycin breath test: r = -0.12, p = 0.6; urinary 6 beta-hydroxycortisol/cortisol ratio versus dapsone recovery ratio: r = 0.13, p = 0.5. This lack of any relationship was unexpected and the reason(s) is unknown; however, it is possible that factors such as route of administration and extrahepatic metabolism in the intestinal epithelium and kidney are involved. Further studies are required to identify and validate the use of an appropriate in vivo probe of P4503A4 in humans.

Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer

Abstract: The pharmacokinetics and pharmacodynamics of doxorubicin and its metabolite, doxorubicinol, were studied in 35 adult (mean age, 66 1/2 years) patients with small lung cell cancer after a 1-hour intravenous infusion at a dose ranging from 45 to 72 mg/m2. All patients also received concomitant therapy with cyclophosphamide and vincristine. Serum concentrations were sampled to 48 hours after dosing. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for apparent volume of distribution, clearance, and area under the curve (AUC) of 62%, 65%, and 65%, respectively. Four patients with impaired liver function showed a significant (p < 0.05) decrease in clearance (239 versus 666 ml/min/m2) and increases in AUC (4610 versus 1834 ng.hr/ml) and elimination half-life (49.3 versus 25.6 hours) compared with patients with normal hepatic function. A significant relationship was found between systemic exposure of doxorubicin (defined by AUC) and surviving factor of white blood cells (r = 0.57, p = 0.0025). No relationships were noted between doxorubicinol exposure and surviving factor of white blood cells or platelets. These findings show the important relationship between systemic exposure of doxorubicin and the degree of myelosuppression in patients with small cell lung cancer.

Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1

Abstract: Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the elimination half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/- 9.9 versus 38.7 +/- 10.3 micrograms/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazone, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1-activated toxins.

Adverse effects of low-dose aspirin in a healthy elderly population.

Abstract: The adverse effects of low-dose aspirin (100 mg daily) in the elderly were studied over a 12-month period in a double-blind, randomized, placebo-controlled trial of 400 subjects who were 70 years of age or older and had no preexisting major vascular diseases at the time of entry. Subjects were randomized so that 200 subjects received low-dose enteric-coated aspirin (100 mg daily) and 200 subjects received placebo. Compliance with medication, assessed by pill count, was 86%. Gastrointestinal symptoms were reported by 18% (n = 36) of participants receiving aspirin and 13% (n = 26) of those receiving placebo. Clinically evident gastrointestinal bleeding occurred in 3% (n = 6) of subjects receiving aspirin and none receiving placebo. Aspirin-treated subjects had a significant decrease in mean hemoglobin levels of 0.33 gm/dl during the 12-month study period, which was significantly greater than the decrease in the placebo-treated group (0.11 gm/dl; p < 0.05). These rates of unwanted symptoms are comparable with previous studies that used higher doses of aspirin. Until the risk-benefit trade-off from the use of low-dose aspirin in the elderly is established with an appropriate clinical trial, caution should be exercised when this compound is used for primary prevention of cardiovascular disease in this age group.

The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies

Abstract: In contrast to the plethora of publications on placebo effects in patients, very little is known about placebo effects in healthy volunteers during clinical pharmacology studies. We therefore reviewed the adverse events spontaneously reported during placebo administration in 109 double-blind, placebo-controlled studies involving 1228 volunteers. The overall incidence of adverse events in the healthy volunteers during placebo administration was 19%. As expected, complaints were more frequent after repeated dosing (28%) and in elderly subjects (26%). Overall, the most frequent adverse events were headache (7%), drowsiness (5%), and asthenia (4%), with some variation depending on study design and population. In conclusion, these data shed new light on the impact of experimental conditions on the results of safety evaluations in healthy volunteers participating in clinical pharmacology studies.

Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding.

Abstract: In a study in the United States, Sweden, and Hungary, 335 cases of gastric bleeding without predisposing factors were compared with 670 control subjects, and 239 cases of duodenal bleeding were compared with 489 control subjects. For aspirin taken at least every other day during the week before the onset of bleeding (regular use), the relative risk of gastric bleeding was 4.4 (95% confidence interval [CI], 2.9 to 6.7); for occasional use, it was 3.3 (95% CI, 2.1 to 5.0). For ibuprofen, the corresponding estimates were 1.0 (95% CI, 0.4 to 2.6) and 1.1 (95% CI, 0.5 to 2.4). For naproxen, the estimate for regular use was 4.0 (95% CI, 1.5 to 11). The estimates for any use of piroxicam (crude estimate), indomethacin, and diclofenac during the week before onset were 18 (95% CI, 4.1 to 83), 1.6 (95% CI, 0.4 to 5.9), and 0.9 (95% CI, 0.2 to 4.2), respectively. The corresponding relative risks of duodenal bleeding were 7.1 (95% CI, 4.2 to 12) and 2.2 (95% CI, 1.3 to 3.7) for the regular and occasional use of aspirin, 2.4 (95% CI, 0.5 to 11) and 0.8 (95% CI, 0.3 to 2.0) for ibuprofen, 12 (95% CI, 2.8 to 54) and 9.9 (95% CI, 2.3 to 44) for naproxen, 17 (95% CI, 3.6 to 79) for any use of piroxicam (crude estimate), and 1.7 (95% CI, 0.2 to 14) for any use of indomethacin. There was a significant trend in the risk of gastric bleeding with increasing dose of regular aspirin use (p = 0.002). The relative risk estimates for the regular use of 325 mg or less were significantly elevated for both gastric and duodenal bleeding at 3.1 and 6.4, respectively.

Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life

Abstract: Objective To find a dose of fluconazole for very low birth weight infants during an outbreak of Candida parapsilosis. Methods Twelve premature infants (mean gestational age, 27.4 weeks; mean birth weight, 912 gm) receiving fluconazole prophylactically from the first day of life were enrolled in an open phase I-II pharmacokinetics, safety, and tolerance trial. Up to 5 doses of 6 mg/kg were administered intravenously every 72 hours during the first 2 weeks of life. Pharmacokinetic characteristics of fluconazole were determined after the first, third, and fifth doses. Results The mean peak and trough concentrations after the 3 doses were 5.5 and 2.6 μg/ml, 12.8 and 4.3 μg/ml, and 10.0 and 2.9 μg/ml (p= 0.0002 and p = 0.07), respectively. The mean fluconazole half-lives were 88.6 hours (n = 7), 67.5 hours (n = 9), and 55.2 hours (n = 4; p= 0.3). The mean total clearance corrected for weight (CL/kg) was 0.18 ml/min/kg (n = 7), 0.33 ml/min/kg (n = 7), and 0.52 ml/min/kg (n = 4; p= 0.02), and the mean volume of distribution 1.18 L/kg (n = 7), 1.84 L/kg (n = 7), and 2.25 L/kg (n = 4; p = 0.05). Weight-corrected clearance increased with postnatal age (r= 0.61; p= 0.007). Conclusions With the used fluconazole dose (6 mg/kg every 3 days), the mean serum peak and trough concentrations increased during the first week but decreased during the second week. After the first week we suggest a dose of 6 mg/kg every 2 days, or even daily. Clinical Pharmacology and Therapeutics (1993) 54, 269–277; doi:10.1038/clpt.1993.147

The transfer of cocaine and its metabolites across the term human placenta.

Abstract: This study defines human placental transport of cocaine and its two minor, but pharmacologically active, metabolites--norcocaine and cocaethylene. The experimental system was the single, isolated perfused cotyledon of a normal term human placenta, and antipyrine served as a freely diffusible marker. Cocaine was transferred rapidly by the placenta at a rate about 80% that of antipyrine. The transfer had characteristics of passive transport consistent with the high lipid solubility of the drug. We found no evidence of significant placental metabolism of cocaine during its rapid placental transfer. Ethanol did not alter the cocaine transfer rate. Norcocaine and cocaethylene were equally as rapidly transferred. Thus the placenta is no barrier to the transfer of cocaine and its derivatives to the fetus.

Subjective and physiologie effects of intravenous buprenorphine in humans

Abstract: The pharmacologic profile of sublingual and subcutaneous buprenorphine, a partial opioid agonist, indicates it may be useful as a maintenance drug in the treatment of opioid dependence. However, illicit intravenous self-administration suggests that it may have a greater abuse potential by this route of administration. Physiologic and subjective effects of intravenous buprenorphine (0.0, 0.3, 0.6, and 1.2 mg) were determined in a dose-escalation study in six nondependent volunteers with histories of opioid use. Buprenorphine caused miosis and decreased respiratory rate, increased diastolic blood pressure, and transiently increased heart rate. Buprenorphine increased positive responses on a "feel drug" question and scores on scales of "liking," "good effects," euphoria, and apathetic sedation. Physiologic and subjective responses were not consistently dose related, a finding compatible with the pharmacologic profile of a partial agonist. The findings indicate that buprenorphine has substantial potential for abuse when administered intravenously.

Cardiovascular effects, pharmacokinetics, and converting enzyme inhibition of enalapril after morning versus evening administration

Abstract: The cardiovascular effects and pharmacokinetics of once-daily enalapril were studied after single-dose and subchronic treatment in eight patients with hypertension by use of ambulatory blood pressure monitoring. Enalapril, 10 mg, was given at either 7 AM or 7 PM in a randomized crossover design. In addition, inhibition of serum converting enzyme was studied. Subchronic treatment at 7 am significantly reduced blood pressure during the day but was less effective at night. Subchronic dosing at 7 pm significantly further decreased nighttime blood pressure followed by a slow increase during the day, with no effect on elevated afternoon values. Peak concentrations of enalaprilat were found 3.5 hours (morning) and 5.6 hours (evening) after drug intake (p < 0.05), whereas peak effects occurred 7.4 hours (morning) and 12 hours (evening) after drug administration. In conclusion, 24-hour blood pressure profiles in patients with hypertension were significantly influenced by the time of enalapril dosing. Differences in effect profiles could not be attributed to similar changes in pharmacokinetics or to different time courses of angiotensin converting enzyme inhibition. Clinical Pharmacology and Therapeutics (1993) 54, 177–186; doi:10.1038/clpt.1993.129

Ethnic differences in response to morphine

Abstract: Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy mean after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end-tidal PCO2. The slope of the ventilation/PCO2 response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a PCO2 of 55 mm Hg. The morphine-induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.

Pharmacokinetic‐pharmacodynamic modeling of caffeine: Tolerance to pressor effects

Abstract: We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90% reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine.

Pharmacokinetics of prednisolone transfer to breast milk

Abstract: Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Intravenous ciprofloxacin disposition in obesity

Abstract: The pharmacokinetics of ciprofloxacin and its metabolite 1 (desethyleneciprofloxacin) were studied in 17 obese men (mean age, 29.2 +/- 7.5 years; mean weight, 110.7 +/- 20.2 kg; mean body mass index, 36.4 +/- 3.9 kg/m2) and 11 control subjects (men of normal weight; mean age, 25.0 +/- 5.1 years; mean weight, 71.8 +/- 9.9 kg; mean body mass index, 23.3 +/- 2.4 kg/m2). Each subject received a single 400 mg intravenous dose of ciprofloxacin infused over 1 hour. Ciprofloxacin total clearance was significantly increased in obese subjects compared with control subjects (897.44 +/- 159.57 versus 744.44 +/- 120.51 ml/min, respectively; p < 0.05). Ciprofloxacin renal clearance in obese subjects (637.58 +/- 128.89 ml/min) was 29% higher than in control subjects (495.47 +/- 137.85 ml/min; p < 0.05). The elimination half-life values of ciprofloxacin and desethyleneciprofloxacin were not statistically different between groups. Ciprofloxacin steady-state volume of distribution (Vss) was significantly larger in obese group (269.17 +/- 51.64 versus 219.03 +/- 35.80 L; p < 0.01) compared with the control group, and when it was normalized by total body weight, obese subjects exhibited lower Vss/kg than control subjects (2.46 +/- 0.42 versus 3.06 +/- 0.31 L/kg; p < 0.001). These findings indicate that ciprofloxacin is distributed less to adipose tissue than to other tissues, but partial distribution to adipose tissue does occur. To normalize the volume of distribution of obese subjects to that of normal weight subjects, 45% of excess weight (total body weight minus ideal body weight) must be added to the ideal body weights of obese subjects.