Clinical Pharmacology & Therapeutics

Published by American Society for Clinical Pharmacology and Therapeutics
Online ISSN: 1532-6535
Print ISSN: 0009-9236
Our knowledge of the toxic effects of drugs on fetal tissues is still incomplete. We are in need particularly of additional comparative information on human and animal fetal tissues. Our future efforts should be directed toward the establishment of significant correlations for drug damage.
The effectiveness of a 0.1 per cent triamcinolone acetonide cream was evaluated by the method of simultaneous and symmetrical paired comparison with 1 per cent hydrocortisone free alcohol in the same base applied topically by a selected group of patients with dermatoses usually benefited by local corticosteroid therapy. With few exceptions the triamcinolone acetonide 0.1 per cent cream proved to be as effective as the 1 per cent hydrocortisone and sometimes more so. In two other smaller but similarly carefully controlled series of patients, a cream and an ointment containing a higher concentration of triamcinolone acetonide, namely, 0.5 per cent, were compared with 0.1 per cent triamcinolone acetonide in the same cream and ointment bases. The preparations containing the higher concentration of triamcinolone acetonide appeared to be superior in many of the patients. The significance of these findings in relation to their use in practice is discussed.
This is the last of a series of therapeutic trials designed to decide the value of equine antitoxin in tetanus. In the first study antitoxin was administered to half the patients and withheld front half. It was concluded that antitoxin (200,000 I.U.) reduced mortality. Sequential analysis was used for ethical reasons. Since antitoxin appeared useful it was obviously desirable to discover the minimum effective dose o f this expensive and sometimes dangerous treatment. Plainly it was impermissible, on ethical grounds, to include a group of untreated patients as controls in subsequent dosage comparisons. It was therefore decided to use the dose of antitoxin found effective in the first study as a reference standard for the subsequent trials. This seemed to be scientifically justifiable as well as ethically permissible. The series comprises doses ranging between 500,000 LU. and 10,000 I.U. It is concluded that antitoxin reduces the mortality in tetanus, and that 10,000 I.U. is an adequate dose.
Origin of HLA-A*31:01 risk variant and proxy SNP rs1061235T carriers. (a) Self-reported origins of HLA-A*31:01-positive patients’ grandparents (n = 12 patients) and of (b) rs1061235T carriers’ grandparents (n = 21 patients) are shown. Aboriginal, Aboriginal Canadian, including First Nations, Inuit, Métis; HLA, human leukocyte antigen; SE/E Asia, southeast or east Asia; S/W Asia, south or western Asia; SNP, single-nucleotide polymorphism.
The occurrence of hypersensitivity reactions including rare but life-threatening Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) limits the use of the anticonvulsant carbamazepine (CBZ). HLA-B*15:02 and HLA-A*31:01 have been identified as predictive genetic markers for CBZ hypersensitivity in Asian and European patients. To replicate these genetic associations in pediatric patients from North America with a diverse ethnic background, we investigated HLA-A*31:01 and HLA-B*15:02 in 42 children with CBZ hypersensitivity, and 91 CBZ-tolerant children from across Canada. HLA-A*31:01 was significantly associated with CBZ-HSS (odds ratio (OR): 26.4, p=0.0025) and maculopapular exanthems (OR: 8.6, p=0.0037), but not with CBZ-SJS. Conversely, HLA-B*15:02 was associated with CBZ-SJS (OR: 38.6, p=0.002), but not HSS and maculopapular exanthems. This study is the first to demonstrate the association of HLA-A*31:01 with CBZ hypersensitivity in children, providing important replication of this association and highlighting the importance of HLA-A*31:01 as a predictive biomarker across various ancestries.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 18 March 2013; doi:10.1038/clpt.2013.55.
It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists.Clinical Pharmacology & Therapeutics (2013); advance online publication 6 March 2013. doi:10.1038/clpt.2013.10.
While the putative pharmacological targets of synthetic cannabinoids (SCBs) abused in "K2" and "Spice" are similar to Δ(9) -tetrahydrocannabinol (Δ(9-) THC), it remains unclear why SCB toxicity is similar yet different from marijuana. There are obvious potency and efficacy differences, but also important metabolic differences that help explain the unique adverse reactions associated with SCBs. This brief review discusses the limited research on the metabolism of the SCB JWH-018 and contrasts that with the metabolism of Δ(9-) THC. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.
5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase. Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed. These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.
The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human tissue-type plasminogen activator and is unglycosylated because of its expression in Escherichia coli cells. Pharmacokinetics for activity and hemostatic effects of BM 06.022 were studied in 18 healthy male volunteers after an intravenous bolus injection over 2 minutes. BM 06.022 was administered successively at doses of 0.1125, 0.55, 2.2, 3.3, 4.4, and 5.5 MU to three volunteers. Plasma fibrinogen was unchanged; effects of BM 06.022 were observed on plasminogen only at higher doses, and dose-dependent effects were seen on alpha 2-antiplasmin and fibrin D-dimers. The concentration of plasminogen and alpha 2-antiplasmin was 87% +/- 3% and 79% +/- 3%, respectively, of baseline 2 hours after injection of 5.5 MU of BM 06.022. Fibrin D-dimers were highest with 1147 +/- 380 ng/ml at 5.5 MU of BM 06.022. The area under the activity concentration-time curve (AUC) increased dose-dependently and linearly. At 5.5 MU of BM 06.022, the AUC was 313 +/- 47, the total plasma clearance was 306 +/- 40 ml/min, and the half-life was 14.4 +/- 1.1 minutes.
To evaluate the relationship between dose of N-0861 ([+/-]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 microg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor.
The hormonal effects after a 10-day administration of a 4-azasteroid inhibitor of 5 alpha-reductase, MK-0963 (previously L-654,066), were evaluated in 35 healthy male volunteers in an increasing-dose, five-panel design. Marked suppression of serum dihydrotestosterone was observed after the once-daily administration at each active dose level (placebo, 0.1, 0.5, 1.0, 10, and 25 mg). Maximum dihydrotestosterone suppression occurred at doses greater than or equal to 10 mg. The mean percentage (+/- SE) decreases in dihydrotestosterone at 24 hours after the last dose in the groups treated with the 10 and 25 mg doses were 78% +/- 4.9% and 80% +/- 2.9%, respectively. The 25 mg dose maintained a dihydrotestosterone suppression of at least 70% for more than 6 days after the last dose. No consistent changes in serum testosterone were noted. This study shows that administration of multiple doses of MK-0963 results in a substantial suppression of serum dihydrotestosterone with no consistent influence on serum testosterone concentrations.
To examine the effect of frequency of oral administration of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) on urinary iron excretion. Sustained serum concentrations of L1 will cause more iron chelation than the same daily dose given in larger but less frequent amounts. Ten patients with thalassemia with a mean age of 20.9 +/- 4.7 years (range, 13 to 27 years), who were receiving regular treatment with 75 to 100 mg/kg/day oral L1, received 75 mg/kg/day L1 orally in equally divided doses: every 6 hours for 3 days and every 12 hours for 3 days. The two study periods occurred 1 month apart immediately after the monthly blood transfusions. Urine was collected for two consecutive 24-hour periods during each of the different schedules. Serial blood samples were collected from six patients over a 6-hour period and analyzed for total L1 and the L1 glucuronide metabolite concentrations. The patient's mean hemoglobin levels (138.8 +/- 12.5 and 139.0 +/- 11.6 gm/L) and ferritin levels (2856.4 +/- 2207.8 and 2890.0 +/- 2264.4 micrograms/L) were similar during the every-6-hour and every-12-hour L1 administrations, respectively. There was significantly more urinary iron excretion when L1 was administered every 6 hours (0.59 +/- 0.29 mg/kg/day) versus every 12 hours (0.40 +/- 0.26 mg/kg/day; p = 0.0129). Calculated 24-hour area under the plasma concentration-time curve of L1 was similar during the every-6-hour (7023.9 +/- 2637.8 mg.min/L) and every-12-hour (7050.1 +/- 1668.8 mg.min/L) experiments. These data suggest that the sustained presence of L1 in the blood results in greater chelation of iron than that observed with larger, less frequent doses.
Pharmacokinetic studies have been carried out with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). HPLC analysis of serum of a normal volunteer and seven transfusional iron loaded patients who ingested a 3 gm dose of L1 revealed that L1 was most probably absorbed from the stomach and was transferred to the blood with a half-life of 0.7 to 32 minutes. L1 reached maximum concentration in the serum 12 to 120 minutes after administration with 85% to 90% elimination within the first 5 to 6 hours, with a half-life of 47 to 134 minutes. L1 and its glucuronide metabolite were identified in serum and urine but not in feces. In most cases hydrolysis of 24-hour urine samples with use of beta-glucuronidase resulted in almost complete recovery of the administered dose. Urinary iron excretion was proportional to the iron load but not to the serum or urine concentration of L1. The therapeutic efficiency of L1 can therefore be improved by repeated administration of 2 to 3 gm doses at least every 6 hours.
The addictiveness of a new synthetic isoquinolinc. analgesic (I-K-1) has been compared with that of morphine, codeine, and D-propoxyphene in former opiate addicts. Single oral doses of 600 and 1,200 mg. of I-K-1 (ten to seventeen times the recommended anolgesic dose) did not induce subjective or objective patterns of morphinelike effects. Intramuscularly and intravenously, I-K-1 was identified as an opiate, but it was not possible to give repeated doses of the drug by these routes because of its water insolubility and tissue irritant properties. When I-K-1 was substituted for morphine in patients addicted to morphine, it partially prevented development of withdrawal symptoms, but it was only one-seventh as potent as codeine in this respect. In a direct addiction test that lasted 60 days, using maximally tolerated doses (750 to 1,500 mg. orally daily), I-K-1 was disliked by former addicts and when it was discontinued abruptly withdrawal signs were insignificant. It is concluded that I-K-1 has substantially less addiction liability than morphine and codeine and even less addictiveness than D-propoxyphene.
A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 microg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration-time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Pre-dose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone-lowering effect of the drug does not vary with dosing time.
Streptozotocin (STZ) was combined with 1,3 bis-(2 chloroethyl)-1-nitrosourea (BCNU) and with BCNU and 5-fluorouracil (FU) in a 2- and 3-drug clinical chemotherapeutic trail. The premise that STZ and BCNU are qualitatively different with regard to marrow suppression was the primary rationale of the study. The 2- and 3-drug regimes were associated with a higher incidence of severe leukopenia and thrombopenia (47% and 100%, respectively) and a lower mean nadir for each (1,700/mm3 and 15,000/mm3) than the reported experience with single drug BCNU therapy. However, this synergism did not apply to therapeutic effects. The reasons for potentiation of marrow toxicity may be related to specific aspects of direct drug interaction as well as alterations in pharmacologic reactions.
The pharmacology of BCNU, an active antitumor agent in. animal and man, was studied with the use of the C14-labeled drug. Radioactivity was excreted slowly in man and monkeys and rapidly in mice. Urinary excretion accounted for the major portion of the isotope although as much as ten per cent was excreted as CO2. The compound is rapidly degraded and promptly after administration no intact drug is demonstrable, although plasma levels of the isotope are prolonged by protein binding of a portion of the drug. Part of the drug may be recirculated in the bile and partially accounts for the prolonged plasma levels. The drug is stable in an acid milieu and well absorbed orally. Its high lipid solubility allows it to readily cross the blood-brain barrier. The active moiety of this agent is still unknown. The contrast of the short biologic half-life of intact BCNU to the delayed clinical toxicity and prolonged plasma levels of carbon-14 is interesting.
Plasma concentrations over time of GHB (⧫) and BD (•) after a single oral dose of 25 mg/kg BD. Data shown as means±SEMs (n=8).
ADH-IB G143A genotype and individual CL/F values for BD (P=0.061 for wild-type (GG) versus variant (GA, AA) genotypes, by Mann-Whitney U-test).
Mean pharmacokinetic parameters of GHB after a single oral dose of 25 mg/kg BD
1,4-Butanediol (BD) is converted to gamma-hydroxybutyrate (GHB) after ingestion, and is associated with cases of dependence, coma, and death. The pharmacology of BD after oral ingestion has not been described in humans. Eight healthy volunteers (five men) were administered 25 mg/kg BD in a single oral dose after an overnight fast in a double-blinded, placebo-controlled, crossover study. Vital signs were monitored, and serial blood samples collected over 24 h for gas chromatography-mass spectrometry analysis of BD and GHB levels. Subjective mood and symptoms responses were assessed by visual analog scale. All subjects completed the study without significant adverse effects. BD was quickly absorbed and cleared, with time to maximal plasma concentration of 24+/-12 min, and elimination half-life (T(1/2)) of 39.3+/-11 min. BD was extensively converted to GHB, with a mean maximum GHB concentration of 45.6+/-19.7 mg/l reached 39.4+/-11.2 min after BD ingestion. GHB T(1/2) averaged 32.3+/-6.6 min. Some subjects exhibited slow oral clearance of BD, which tended to correlate with a variant haplotype of the alcohol dehydrogenase gene ADH-IB G143A. Mean CL/F was 151.5+/-176.5 ml/min kg for four subjects with variant haplotype versus 598.8+/-446.6 ml/min kg for four wild-type subjects (P=0.061). Subjects reported feeling less awake and alert, less able to concentrate, and more lightheaded in the first 90 min after BD ingestion. Pulse oximetry readings were lower 45 min after BD dosing with a mean oxygen saturation of 98.5% with BD versus 99.6% with placebo (P=0.031). Transient increases in mean systolic and diastolic blood pressure were observed, but other vital signs remained unchanged. BD was extensively converted to GHB after oral administration, but significant inter-individual variability in the rate of metabolism, possibly related to variants in ADH-IB, was observed. At the modest dose studied, significant clinical effects were not seen.
Since September 2010, over 10,000 patients have undergone preemptive, panel-based pharmacogenomic testing through the Vanderbilt Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) program. Analysis of the genetic data from the first 9,589 individuals reveals the frequency of genetic variants is concordant with published allele frequencies. Based on five currently implemented drug-genome interactions, the multiplexed test identified one or more actionable variants in 91% of the genotyped patients and in 96% of African-American patients. Using medication exposure data from electronic medical records, we compared a theoretical "reactive," prescription-triggered, serial single-gene testing strategy to our preemptive, multiplexed genotyping approach. Reactive genotyping would have generated 14,656 genetic tests. These data highlight three advantages of preemptive genotyping: 1)the vast majority of patients carry at least one pharmacogene variant; 2)data are available at the point of care; and 3)there is a substantial reduction in testing burden compared to a reactive strategy.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 19 November 2013 doi:10.1038/clpt.2013.229.
Carbamazepine-(CBZ)-10,11-epoxide (CBZ-E) was found to decompose in gastric juice in vitro. An antacid did not affect the bioavailability of single CBZ doses given to three subjects and was therefore used to neutralize gastric juice when administering CBZ-E. CBZ-E was given orally as a suspension in two single doses ranging from 10 to 200 mg to each of four healthy subjects. Plasma concentrations of CBZ and CBZ-E were determined with high-performance liquid chromatography. Plasma concentrations and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-CBZ (trans-CBZ-diol) were measured by mass fragmentography. After dosing with CBZ-E, peak plasma concentrations of the parent compound were reached within 2 hr. Urinary recovery of trans-CBZ-diol was 90 +/- 11% (mean +/- SD) of the dose, indicating almost complete absorption. Plasma kinetics of the epoxide fitted an open one-compartment model with elimination half-lifes (t 1/2s) of 6.1 +/- 0.9 hr. Clearance was 89 +/- 25 ml x kg-1 x hr-1. The urinary excretion t 1/2 of the trans-CBZ-diol was 12.4 +/- 0.9 hr, which is longer (P less than 0.001) than the epoxide plasma t 1/2. There was no indication of dose-dependent kinetics of the epoxide. After 200 mg CBZ to the same subjects, plasma CBZ t 1/2 was 26.0 +/- 4.6 hr and clearance was 23.4 +/- 4.6 ml x kg -1 x hr -1. Of the CBZ dose, 20.5 +/- 2.9% was excreted as the trans-CBZ-diol, which gives an estimate of the percentage of CBZ that is metabolized by the epoxide-diol pathway in healthy subjects. These observations provide a basis for the administration of CBZ-E in patients to assess its clinical effects.
The plasma steady-state concentration of carbamazepine (CBZ) and its metabolite (carbamazepine-10,11-epoxide, CBZ-epoxide) was assessed in 43 children (2-15 yr) on CBZ (Tegretol) treatment. Twenty of the children received combined treatment with other anticonvulsant drugs simultaneously. The plasma concentrations were in the same range as had been found in adult patients on corresponding doses. Only a weak correlation was noted between dose and plasma CBZ concentration in the group of children on single-drug treatment, and there was no correlation in the group of children on combined drug regimen. Plasma levels of CBZ correlated with those of the metabolite. Children on combined treatment had lower CBZ concentration and, expressed as percent of the parent drug, the metabolite concentration was significantly higher than in children treated only with CBZ. In 2 children the plasma half-life of CBZ was estimated and found to be slightly shorter than has previously been reported in adults. In evaluating the plasma level-effect relationship of CBZ, the plasma concentration of the CBZ-epoxide should be measured simultaneously because of its anticonvulsant effect and interindividual variability.
In a double-blind, randomized, single-dose trial the analgesic contribution of acetaminophen, 1000 mg, and codeine, 60 mg, was determined. The study was a 2 X 2 factorial experiment in which 120 patients suffering from pain as a result of oral surgery rated their pain intensity and pain relief for up to 5 hours after a single dose of one of: 1000 mg acetaminophen, 60 mg codeine, 1000 mg acetaminophen plus 60 mg codeine, or placebo. The factorial analysis showed that both 1000 mg acetaminophen and 60 mg codeine made a statistically significant (P less than 0.05) contribution to the analgesic effectiveness of the combination on all measures of efficacy (sum of pain intensity differences, largest pain intensity difference, total pain relief, largest pain relief, and time to remedication). The incidence of adverse effects did not appear to differ among the treatments, including placebo.
A clinical, physiologic, and biochemical study was made of Ro 5-1025, a short-acting MAO inhibitor. Ro 5-1025 did not show antidepressant properties and did not lower blood pressure at 20 to 60 mg. per day. The radioactioe serotonin test for MAO showed that Ro 5-1025 was a weak MAO inhibitor without accumulative effects at the doses indicated.
Structure of aminoglycoside bound to rRNA. Paromomycin (red) binds to helix 44 in 16S rRNA. Adenine in position 1408 is critical for high-affinity interaction with bacterial ribosome, with other residues critical for codon–anticodon cognition also indicated. Atomic coordinates are from 1IBK.
Genetic diseases and aminoglycoside-based pharmocogenetic therapy
A third of inherited diseases result from premature termination codon mutations. Aminoglycosides have emerged as vanguard pharmacogenetic agents in treating human genetic disorders due to their unique ability to suppress gene translation termination induced by nonsense mutations. In preclinical and pilot clinical studies, this therapeutic approach shows promise in phenotype correction by promoting otherwise defective protein synthesis. The challenge ahead is to maximize efficacy while preventing interaction with normal protein production and function.
Between weeks 34 and 104, we explored different schema for administering fenfluramine plus phentermine in open-label fashion. At week 34, the original placebo group participants began taking fenfluramine plus phentermine (placebo-to-active group). Those receiving fenfluramine plus phentermine between weeks 6 and 34 either continued to receive medication or began targeted intermittent therapy. Participants who did not lose 10% of initial weight received an augmented dose (60 mg fenfluramine plus 30 mg phentermine. The placebo-to-active group lost an additional 9.1 +/- 0.8 kg (mean +/- SEM) in the period from week 34 to week 60. At week 60, they were assigned to either continue medication, intermittent therapy, or augmented therapy. More than 68% (83) of the original participants completed up to study week 104. At that point, overall weight loss was 10.8 +/- 0.7 kg (11.6 +/- 0.8% of initial weight); participants who continued to receive fenfluramine plus phentermine lost 11.6 +/- 0.8 kg, participants receiving intermittent therapy lost 11.6 +/- 1.3 kg, and participants receiving augmented therapy lost 6.5 +/- 1.5 kg. Although 41% of the participants complained of dry mouth, neither serious adverse effects nor evidence of medication abuse appeared. There were 29 dropouts in the period from weeks 34 to 104. Sixteen of those were related to medication (adverse effects, lack of efficacy, and fear of medication). Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise continued to be efficacious for up to 2 years.
Between weeks 104 and 156 we attempted to optimize response by adjusting the doses of fenfluramine and phentermine. Dosing changes were based on an algorithm that aimed to achieve 120% of ideal body weight (IBW) while minimizing adverse effects. The dose groups were as follows: stage I, 30 mg fenfluramine plus 15 mg phentermine in the morning; stage II--continuous or targeted intermittent, 60 mg fenfluramine plus 15 mg phentermine in the morning; stage III, 60 mg fenfluramine plus 30 mg phentermine in the morning; stage IV, 60 mg fenfluramine plus 30 mg phentermine in the morning and 30 mg fenfluramine in the evening; and stage V, 60 mg fenfluramine plus 30 mg phentermine in the morning and 60 mg fenfluramine in the evening. Seventy-seven participants began this segment of the study and 59 completed to week 156. Completers of this segment of the study gained an average of 2.7 +/- 0.5 kg between weeks 104 and 156 but remained 9.4 +/- 0.8 kg (10.5%) below baseline. On average, weight loss from baseline by group was as follows: for stage I (n = 2), 14.1 +/- 6.8 kg; for stage II continuous (n = 14), 10.9 +/- 0.7 kg; for stage II targeted intermittent (n = 7), 8.8 +/- 2.4 kg; for stage III (n = 9), 7.7 +/- 2.6 kg; for stage IV (n = 8), 10.5 +/- 2.6 kg; and for stage V (n = 19), 8.4 +/- 2.4 kg. Upward dose adjustment (n = 36) resulted in further weight loss in 11 and no gain in six participants.(ABSTRACT TRUNCATED AT 250 WORDS)
Retardation of meal carbohydrate absorption by inhibition of starch degradation improves glucose tolerance in normal and diabetic humans. To determine the effects of Bay-m-1099, a new alpha-glucosidase inhibitor, on insulin requirements and prandial glucose tolerance in patients with insulin-dependent diabetes mellitus (IDDM), plasma glucose, triglyceride, and free insulin concentrations were measured after ingestion of a standard breakfast, lunch, and dinner in nine patients with IDDM in a single-blind, randomized, crossover design. A 20% reduction in insulin was given 30 minutes before the meals when the subjects received Bay-m-1099 (50 mg). This resulted in the AUC for plasma insulin to be significantly less with Bay-m-1099 (AUC, 8.2 +/- 1.3 vs. 12.8 +/- 1.6 microU/ml/min with placebo; P less than 0.01). Despite this reduction in plasma insulin levels, postprandial plasma glucose concentrations were reduced for the breakfast (73 +/- 15 vs. 112 +/- 14 mg/dl/min with placebo; P less than 0.01) and dinner (23 +/- 8 vs. 4 +/- 1 mg/dl/min with placebo; P less than 0.05) meal with Bay-m-1099. Bay-m-1099 did not affect postprandial plasma triglycerides and was well tolerated, the major side effect being flatulence (4/9) and mild diarrhea (4/9). We conclude that inhibition of intestinal alpha-glucosidases by Bay-m-1099 in IDDM reduces meal insulin requirements by at least 20% and that such an agent could be useful in the management of diabetes mellitus by reducing hyperinsulinemia.
14C-DMHP (200 μg/70 kg man) was administered by the intravenous route to 3 healthy male casual marihuana smokers. Tachycardia occurred within 10 minutes and persisted for from 1 1 2 to 6 hours. Blood pressure fell slightly with time when subjects were supine, while standing for less than I minute resulted in marked hypotension. In these 3 subjects, except for dizziness on standing there were essentially no demonstrable psychologic effects, neither euphoria nor dysphoria. Subjects did, however, report symptoms similar to those after marihuana or Δ9-THC, including dry mouth, decreased salivation, and drowsiness. After intravenous dimethyl heptyl tetrahydrocannabinol (DMHP), plasma levels of total radioactivity and 14-C-DMHP declined in a multiphasic fashion; the half-life of the terminal phase for DMHP was 39 hours. Approximately 69% of the administered radioactive dose was recovered in 7 days. Radioactivity was excreted predominantly in the feces (58%) and to a lesser extent in urine (II %) during the 7 day collection period.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.
An antiadrenal compound, 2-(p-aminophenyl)-2-phenylethylamine, which inhibited adrenocortical 17-alpha and 11-beta hydroxylase activity in animals, was administered for 3 week periods to 10 patients with diabetes of juvenile onset in an attempt to ameliorate the severity of the diabetes and was given for a lesser period to one patient with spontaneous Cushing's syndrome. The drug did not alter the intensity of the diabetes but it produced a partial remission of the Cushing's syndrome. In diabetes, ingestion of the dl form increased urinary 17-ketosteroids, Porter-Silber chromogens, and 11-desoxycortisol metabolites in 3 and possibly 4 o f 5 patients. This was observed only once in 4 trials with the d form. This suggests that the l form is more effective than the d form in inhibiting 11-beta hydroxylase. Inhibition of 17-alpha hydroxylase by the d form was either minimal or absent judging from the urinary levels of Porter-Silber chromogens and 11-desoxycortisol metabolites. In diabetes neither the d nor the dl preparation affected the basal plasma 17-hydroxycorticosteroids nor the rise in this index which followed upon intravenous injection of ACTH. The basal plasma 17-hydroxycorticosteroids were markedly lowered in Cushing's syndrome.
Hematologic toxicity after cancer chemotherapy and other drug effects that occur late compared to the exposure are usually modeled with use of some summary exposure variable such as the area under the concentration-time curve (AUC model) or the time of exposure above a threshold concentration (threshold model). An underlying assumption for both of these models is that the drug exerts a direct effect while present in the body and that it is the time integral of this direct effect that is related to the ultimate observed effect, either linearly (AUC model) or by a step function (threshold model). We propose a more general model that allows this relationship to be characterized by a nonlinear continuous function. Data on survival fraction of neutrophiles and time course of leukopenia from 92 courses of paclitaxel therapy in 21 patients with breast or ovarian cancer was related to paclitaxel concentration-time profiles with the AUC, threshold, and general models. The properties of the general model were also investigated with use of simulations. For both pharmacodynamic end points, the general model described the data significantly better than the AUC or threshold models. The general model is an extension to the present way of relating concentration-time profiles to late-effect measures, and it may provide an improved description of the concentration-response relationship and more accurate predictions of the ultimate effect when doses and schedules are varied. It can explain complex relationships between concentration-time profiles and the observed effect, and predictions from it lack some of the counterintuitive properties that the AUC or threshold model have when extrapolations are made.
After cannabis consumption there is only limited knowledge about the pharmacokinetic (PK) and metabolic properties of 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (CTHC), which is formed by oxidative breakdown from Delta(9)-tetrahydrocannabinol (THC). Despite widely-varying concentrations observed in smoking studies, attempts have been made to interpret consumption behavior with special regard to a cumulated or decreasing concentration of CTHC in serum. Ten healthy nonsmoking white male individuals received 5 mg CTHC intravenously over 10 min. Highest serum concentrations of CTHC were observed at the end of the infusion (336.8+/-61.7 microg/l) followed by a quick decline. CTHC concentration could be quantified up to 96 h after administration, with a terminal elimination half-life of 17.6+/-5.5 h. Total clearance was low (91.2+/-24.0 ml/min), with renal clearance having only a minor contribution (0.136+/-0.094 ml/min). This first metabolite-based kinetic approach will allow an advanced understanding of CTHC PKs data obtained in previous studies with THC.
The usefulness of dogs and monkeys in predicting potential qualitative drug toxicity in man was examined retrospectively for twenty-five anticancer compounds of diverse chemical and functional classification. It was found that the large animal screen served to alert the physician to a significant proportion of the total spectrum of drug effects, which were encountered during the clinical use of a new toxic compound. The dog and monkey correctly predicted bone marrow depression, gastrointestinal disturbance, and hepatotoxicity for each drug producing these effects in the clinic; in the case of renal, cardiovascular, and neuromuscular toxicity, however, the large animal screen failed in each instance to predict one drug that produced these toxicities in man. The correct predictions were accomplished at the expense of a high percentage of false positives, which resulted from the necessity of using severely toxic dose levels in order to demonstrate all potential toxicities inherent in any compound. While organ system toxicity observed during an animal study can never be disregarded, it should be viewed with an understanding of certain limitations of animal toxicologic data. While toxicity may develop in man in an organ system predicted susceptible by an animal, a different specific clinical or chemical parameter may be involved. The adverse reaction may appear in man at a greater or lesser dose level or may follow a different order of appearance in relationship to the total spectrum of qualitative toxicity inherent in the compound.
Patient demographics a 
Summary of pharmacokinetic data 
Functional consequences of investigated ABCC2 polymorphisms 
Pharmacokinetic parameters as a function of genotype a 
BACKGROUNDPK variability of the anticancer agent CPT-11 is high. Life-threatening grade 3-4 diarrhea is seen in up to 25% of patients and has been related with CPT-11 PK and UGT1A1-status. Aim of this study was to evaluate the association of ABCC2 polymorphisms and haplotypes with CPT-11 disposition and diarrhea.METHODS105 European Caucasian cancer patients who were previously assessed for CPT-11 PK (90-min infusion; three-weekly), toxicity and UGT1A1*28, were genotyped for ABCC2 using Pyrosequencing (table 1).RESULTSFrequencies of wild type alleles and haplotypes (13 identified in 85 patients) are given in table 1. ABCC2*1 was associated with slower CPT-11 clearance (28.4 vs 33.9 L/h; P=.005). In 67 patients who received the recommended single agent dose (350 mg/m2 or 600 mg), ABCC2*1 was negatively correlated with grade 3-4 diarrhea (P=.040). A 3-fold reduced risk (30% vs 10%) was unrelated to UGT1A1*28 since severe diarrhea manifested itself in particular in patients homozygous for the UGT1A1*1 allele (P=.011).CONCLUSIONS This study suggests that the ABCC2*1 haplotype is associated with CPT-11 related diarrhea, maybe as a consequence of altered CPT-11 excretion via the bile into the gut, and hence less local activation into the active metabolite, SN-38. As its protective effect on diarrhea is seen predominantly in patients not at risk for diarrhea due to UGT1A1*28, additional studies of the relationships of ABCC2 genotypes to CPT-11 PK and toxicity are warranted.Frequencies wild type alleles (p) of 6 ABCC2 polymorphisms, and constructed haplotypes (%; N=85).polymorphismphaplotype%−1549G>A0.60GGCGTC (ABCC2*1)35−1019A>G0.45GGCATC19−24C>T0.84AATGTT151249G>A0.79AACGTT12IVS26 −34T>C0.96AACGTC83972C>T0.67AACGCC5Clinical Pharmacology & Therapeutics (2005) 79, P41-P41; doi: 10.1016/j.clpt.2005.12.145
Background and aim Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9*5, *6, *8, and *11 polymorphisms in vivo has not been investigated previously in humans. A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9*1/*1 (n = 9), *1/*5 (n = 1), *1/*6 (n = 1), *1/*8 (n = 2), *1/*11 (n = 3), *5/*6 (n = 1), *5/*8 (n = 1), and *8/*11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9*1/*1, 14.6 for CYP2C9*1/*5, 4.2 for CYP2C9*1/*6, 188 for CYP2C9*5/*6, 11.6 for CYP2C9*5/*8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9*1/*8, 2.2 for CYP2C9*8/*11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9*1/*11. Compared with the CYP2C9*1/*1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9*5 allele carriers (CYP2C9*1/*5, CYP2C9*5/*8, and CYP2C9*5/*6 genotypes) (P =.01, Mann-Whitney) but was not different in CYP2C9*1/*8 (P =.16) and CYP2C9*1/*11 (P =.11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0-18). The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects.
To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4. In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4. In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1'-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (+/-SD) Michaelis-Menten constant for midazolam 1'-hydroxylation by human liver microsomes was 5.6 +/- 3.3 micromol/L. The formation of 1'-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 +/- 16.6 micromol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1'-hydroxylation by recombinant CYP3A4 were 4.0 micromol/L and 61.0 micromol/L, respectively, consistent with the mean values obtained from human liver microsomes. Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4.
The efficacy and safety of isradipine (PN 200-110), a new dihydropyridine calcium antagonist, was evaluated in 87 hypertensive patients in a placebo-controlled, double-blind, randomized multicenter trial. After a 3-week single-blind washout phase, isradipine (or matching placebo) was administered for 4 weeks, beginning at 2.5 mg b.i.d. with increments of 2.5 mg b.i.d. at weekly intervals if supine diastolic blood pressure remained greater than or equal to 90 mm Hg. At the end of 1 week average supine blood pressure in the isradipine group (n = 45) fell from a baseline of 156 +/- 13/104 +/- 4 mm Hg to 146 +/- 14/97 +/- 7 mm Hg. By week 4 blood pressure was reduced by 19/14 mm Hg compared with 4/5 mm Hg in the placebo group (P less than 0.001 between groups). Supine and standing pulse rates were slightly increased initially with isradipine therapy but returned to baseline with increasing isradipine doses. Blood pressure responses at week 4 were good or excellent (supine diastolic less than or equal to 90 mm Hg or greater than or equal to 10 mm Hg decrease from baseline) in 87% of isradipine-treated patients and in 26% of placebo-treated patients. Headache, edema, abdominal discomfort, and constipation occurred slightly more frequently in isradipine-treated patients than in placebo-treated control subjects. The results indicate that isradipine, administered as monotherapy in doses of 2.5 to 10 mg b.i.d., is safe and effective in patients with mild to moderate essential hypertension.
This study was designed to better understand genetic variation in the cytochrome P450 (CYP) gene CYP1A2 and its impact on CYP1A2 activity in Chinese subjects. CYP1A2 genetic polymorphisms were screened by direct sequencing in 27 selected Chinese subjects. Plasma 1,7-dimethylxanthine/caffeine ratios 5 hours after a 100-mg caffeine administration, used as an index of CYP1A2 in vivo activity, were determined in 422 healthy subjects. Five single-nucleotide polymorphism markers, including G-860A (CYP1A2*1C), T-3594G, G-3113A, A-163C (CYP1A2*1F), and C5347T (CYP1A2*1B), were selected and genotyped by either polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. Thirteen polymorphisms and 2 linkage disequilibrium blocks with a boundary around -2467 were identified at this locus. The allele frequency for -3860A, -3594G, -3113A, -163C, and 5347T was 0.21, 0.15, 0.10, 0.36, and 0.14, respectively, in the CYP1A2-phenotyped cohort. A significant difference in CYP1A2 activity was observed among genotypes of polymorphism G-3113A (P = .038), and CYP1A2 activity in subjects carrying the AA genotype was lower than that in those carrying the GA (P = .096) and GG genotypes (P = .036): -0.45 +/- 0.05 (mean +/- SD), -0.32 +/- 0.16, and -0.29 +/- 0.16, respectively. Further analysis based on haplotype pairs found a 1.92-fold variation (95% confidence interval, 1.13-2.71) in mean CYP1A2 activity between haplotype pairs 13 and 15, and the difference was significant (-0.19 +/- 0.15 versus -0.45 +/- 0.05, P = .016). As compared with haplotype pair 10, haplotype pairs 9 and 15 and most haplotype pairs heterozygous for the haplotype with an A allele at -3113, including pairs 5, 8, and 12, also showed significantly lower CYP1A2 activity (P = .015, .048, .008, .024, and .014 for pairs 5, 8, 9, 12, and 15, respectively). In addition, haplotype pairs 5, 9, and 12 also showed significantly lower CYP1A2 activity than pair 13 (P = .034, .020, and .037 for pairs 5, 9, and 12, respectively). The G-3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.
The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.6+/-15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.
The effects of four single oral doses of ICI 118,551 (a selective beta 2-adrenoceptor blocking agent: doses 10, 20, 50, and 100 mg) have been compared with placebo in five normal, healthy volunteers on some cardiovascular responses to intravenous infusions of dobutamine. Increasing infusions of dobutamine produced reproducible dose-dependent reductions in systolic time intervals and increases in systolic blood pressures, these responses representing positive inotropic effects of dobutamine. These effects of dobutamine were unaffected 2 hours after administration by 10 mg ICI 118,551 and minimally by 20 mg; the 50 mg dose attenuated the systolic time interval effect whereas the 100 mg dose attenuated further the systolic time interval reduction and also the increase in systolic blood pressure. These results allow a conclusion that at unit doses of 50 mg and above, ICI 118,551 will produce demonstrable effects on beta 1-adrenoceptors.
The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied by means of positron emission tomography (PET) in an intrasubject comparison of six healthy smokers using two modes of inhalation: one with shallow, frequent inhalations ("buccal mode") and one with deep inhalations ("pulmonary mode"). An average of 15% of the radioactivity was released from the vapor inhaler after 5 minutes of inhalation. Approximately 45% of the dose released was found in the oral cavity. A significant amount of radioactivity, 10%, was observed in the esophagus, suggesting transfer of a major fraction of the dose to the stomach. Only a minor fraction, 5%, was found in the lungs, followed by 2% in the bronchi and 1% in the trachea. The deposition in the oral cavity closely followed a linear pattern during the 5 minutes of inhalation and was followed by a rapid elimination from the oral cavity, with an average half-life of 18 minutes. Only 8% of the dose released remained in the oral cavity 45 minutes after the end of inhalation. On the other hand, the dose fraction of about 14% distributed into the body tissue compartment at the end of inhalation had risen to 60% at that late time point. No statistically or clinically important differences were observed between the buccal and the pulmonary mode of inhalation in either deposition pattern or elimination rates.
Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.
Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.
The paradigm of individualized drug therapy based on genetics is an ideal that is now potentially possible. However, translation of pharmacogenomics into practice has encountered barriers such as limited availability and the high cost of genetic testing, the delays involved, disagreements about interpretation of results, and even lack of understanding about pharmacogenomics in general. We describe our institutional pharmacogenomics-implementation project, "The 1200 Patients Project," a model designed to overcome these barriers and facilitate the availability of pharmacogenomic information for personalized prescribing.
A thin-layer chromatographic method is described for the quantitation of caffeine and its dimethylxanthine metabolites, theophylline, theobromine, and paraxanthine. The method was used to evaluate the effect of polycyclic aromatic hydrocarbons (PCH), polychlorinated biphenyls (Aroclor 1254), or phenobarbital on the pharmacokinetics of caffeine and its dimethylxanthine metabolites. The oral administration of benzo[a] pyrene (BP) or Aroclor 1254 to rats for 3 days markedly increased the plasma clearance of caffeine and its dimethylxanthine metabolites. Similar results on the plasma clearance of caffeine were obtained with benzanthracene, dibenzanthracene, chrysene, or pyrene. Although the elimination of caffeine from plasma was increased in rats treated with phenobarbital for 3 days, it was less effective in this respect than the PCH or Aroclor 1254. In addition, phenobarbital did not significantly affect the rate of elimination of the dimethylxanthine metabolites from rat plasma following an intravenous dose of caffeine. Following the intravenous administration of caffeine to rats pretreated with Aroclor 1254 or BP, there was a marked increase in the appearance of theophylline, theobromine, and paraxanthine in plasma. The time to achieve peak plasma levels of these metabolites was reduced from 6 to 7 hr in control rats to 1 hr in Aroclor 1254-treated rats and to less than 3 hr in rats treated with BP. Moreover, the plasma elimination of the dimethylxanthine metabolites formed, from caffeine was greatly accelerated after pretreatment with BP or Aroclor 1254. A dose-response study with BP indicated that ay little as 1.0 mg lkg of BP administered orally for 3 days markedly increased the plasma clearance of caffeine; however, pretreatment with BP did not affect the absolute bioavailability of caffeine. The area under the caffeine plasma curve after oral administration was identical to the area when the same dose was administered intravenously. The above studies indicate that the plasma clearance of caffeine is markedly increased in rats pretreated with phenobarbital, PCH, or Aroclor 1254 and suggest that the metabolism and pharmacology of caffeine may be considerably altered in human subjects exposed to these substances.
An example from the literature has been used to demonstrate errors involved in calculating drug clearance by inappropriate use of the apparent drug distribution volume Vdext. The Vdext is always an overestimate of the true volume of distribution in a multicompartment system, and the degree of overestimation in using it to calculate clearance for such a system will increase as renal function increases. Drug dosages calculated on the basis of overestimated clearance values may give rise to overdosage in normal individuals, or therapeutic failure in severely uremic patients. Problems associated with the use of an oversimplified pharmacokinetic model for clearance calculations are discussed, together with the concept of model-independent calculations.
3-Methyl-2-(3-pyridyl)-1-indoleoctanoic acid (CGS-12970) is a reversible thromboxane synthase inhibitor that was noted to lower serum uric acid during preliminary trials in humans. Our clinical research unit studied 20 healthy male volunteers who received two doses of CGS-12970 12 hours apart (100, 200, 300, or 400 mg twice a day). Four subjects received placebo as a control. Serum uric acid concentrations decreased between 34% and 47%. Urinary excretion of uric acid increased between 28% and 134% within 12 hours of the first dose. Urinary excretion of uric acid returned to baseline within 24 hours after the last dose. In vitro study of bovine-creme xanthine oxidase inhibitor activity revealed minimal inhibition of xanthine oxidase by either CGS-12970 or its metabolite, CGS-12961. CGS-12970 appears to be a potent reversible uricosuric agent. We hypothesize that the uricosuric effect may be attributable to the acidic properties of CGS-12970 rather than to its inhibition of thromboxane synthase.
Top-cited authors
Kelly E Caudle
  • St. Jude Children's Research Hospital
Stuart A Scott
  • Stanford University
Jesse J Swen
  • Leiden University Medical Centre
Andrea Gaedigk
  • Children’s Mercy Kansas City
Michelle Whirl-Carrillo
  • Stanford Medicine