Developmental activities of elite junior hockey players: an analysis of early sport specialization.

Early sport specialization is a popular and contentious topic in the scientific literature and popular media. The lure of extrinsic rewards has led to increasing rates of specialization among young athletes, while expert recommendations promote multisport participation. The purpose of this study was to describe and analyze developmental activities of a group of elite junior hockey players in Canada. Within this context, elements of specialization were investigated in accordance with existing theoretical frameworks and long-term athlete development models to enhance the literature. Fifteen participants from the Ontario Hockey League completed quantitative retrospective interviews, detailing past sport and recreational activities. Thirty-one developmental milestones were assessed. Accumulated hours of activity were categorized in accordance with Côté's (1999) Developmental Model of Sports Participation, along with the number and types of sports in which they participated during childhood. Jayanthi et al.'s (2015) continuum was utilized to determine the age at which the athletes became moderately and highly specialized. Accrued hours of deliberate practice reported by participants increased from ages 6 to 16 years, as did competition in organized hockey games. Reported hours of deliberate play peaked at 9 years of age and decreased thereafter. Participants played a combined 16 sports other than hockey, ranging from an average of 2.0 at age 6, to a maximum average of 5.6 at 12 years old, and decreasing each year to 2.3 by age 15. The greatest number of hours in other sports was accumulated at 12 years of age. Using a three-point scale, participants considered themselves "highly specialized" at 14 years old; however, other quantitative indicators suggested this may have occurred at 12 years of age. Relative to previous research on early sport specialization, participants in this study spent more time practicing hockey, while ceasing hockey-specific play and other sports at younger ages. Despite a diverse sport history, hockey competition was initiated earlier than recommended, showing high levels of sport commitment as young as 9 years old. The early specialization path remains a popular trajectory among coaches, parents, and athletes in Canadian ice hockey.

The acceptability of a directly-administered antiretroviral therapy (DAART) intervention among patients in public HIV clinics in Los Angeles, California.

Directly administered antiretroviral therapy (DAART) is an intensive adherence support strategy for highly active antiretroviral therapy (HAART) that requires patient acceptance to be effective. In one arm of a randomized adherence study, community workers (CW) delivered and observed ingestion of one HAART dose to participants five days a week for six months. We evaluated acceptability by study participation, retention, attendance and a satisfaction survey. Chi-square and nonparametric tests were used to examine differences between participants who did and did not complete DAART. Between November 2001 and March 2004, 416 eligible participants were identified; 250 were enrolled and 166 refused to participate (22 of these (13%) because of DAART specifically). Of the 82 randomized to DAART (70% Latino, 20% African American, 27% female and 69% foreign-born), 65 (79%) completed six months of DAART. Participants attended 6,953/7,390 (94%) appointments. Latinos were more likely to complete DAART compared to African Americans (OR=4.76, 95%CI=1.38, 16.44, p=0.01). In addition, foreign-born participants were more likely to complete DAART than US-born participants (OR=3.38, 95%CI=1.11-10.22, p=0.03). Participants completing DAART reported high rates of satisfaction. Retention, attendance and participant satisfaction suggest that DAART is an acceptable adherence support strategy in this public clinic population, particularly among Latino and foreign-born participants.

A pilot study of ranolazine in patients with intermittent claudication.

AIM: This pilot study provides preliminary information regarding safety and changes in exercise performance during treatment with ranolazine extended-release in patients with reproducible claudication during exercise treadmill testing (ETT). METHODS: We enrolled 45 patients with documented peripheral arterial disease, reproducible claudication on ETT, and ankle-brachial indices <0.85 at rest that decreased by at least 0.15% or 20% immediately postexercise. Randomized patients received double-blind treatment with either ranolazine 1 000 mg b.i.d. (n=22) or placebo (n=23) for 4 weeks. RESULTS: Compared with baseline, peak walking time (PWT) increased (mean+/-SEM) by 53+/-34 s with ranolazine (P=0.13) and by 41+/-33 s with placebo (P=0.22). Pain-free walking time during ETT increased by 62+/-18 s with ranolazine (P=0.002) and 36+/-18 s with placebo (P=0.045). Supplemental analyses, excluding patients with baseline exercise duration (16 min and (12 min, showed additional improvement with ranolazine on PWT. CONCLUSIONS: Ranolazine was well tolerated and these data provide a rationale for proceeding with a definitive trial.

Endothelial cell adhesion on RGD-containing methacrylate terpolymers.

Hexyl methacrylate (HMA), methyl methacrylate (MMA), and methacrylic acid (MAA) were used as comonomers to produce a low glass transition temperature material, potentially useful in fabricating a small diameter vascular graft. Because it has been shown that grafts seeded with endothelial cells have better resistance to thrombosis, RGD-based peptide sequences were incorporated into the terpolymer. The two methods used for incorporating peptide sequences were a chain transfer reaction during polymerization, and a coupling reaction between the amine terminus of the peptide and the carboxyl groups of the MAA. Polymers were synthesized using the chain transfer reaction with peptide concentrations ranging from 1.7 to 7.0 micromol/g. Weight-average molecular weights decreased with increasing peptide concentration from 310,000 g/mol for the terpolymer without peptide, to 110,000 g/mol for a peptide concentration of 7.0 micromol/g. As a result, Young's modulus decreased with increasing peptide concentration. Terpolymers with peptides attached through a coupling reaction showed no decrease in molecular weight or mechanical properties. Confocal microscopy showed cells seeded on the RGD surfaces adhered and spread, while terpolymers with RGE sequences showed cells that were rounded and not spreading. Cell density on RGD surfaces increased with increasing peptide concentration up to a bulk peptide concentration of approximately 5 micromol/g and reached a plateau, which indicated the minimum peptide concentration necessary for maximum cell adhesion.

Synthesis and characterization of acrylic terpolymers with RGD peptides for biomedical applications.

The goal of this research was to design a biomaterial, using acrylic terpolymers, which could support endothelial cells and function in small diameter vascular graft applications. Hexyl methacrylate (HMA) and octyl methacrylate (OMA) were used as comonomers to produce a material with a low glass transition temperature (T(g)). Methacrylic acid (MAA) was used to provide ionic character, and methyl methacrylate (MMA) was selected because of its wide usage in biomedical applications. Cation neutralization was employed to modify the mechanical properties. RGD-based peptide sequences were attached to promote endothelial cell adhesion, because vascular grafts seeded with endothelial cells have fewer problems with thrombosis. The two methods used to incorporate peptide sequences were a chain transfer reaction during polymerization, and a coupling reaction attaching the peptides to carboxyl groups on the polymer after polymerization. The compositions that produced T(g)s of approximately 0 degrees C were 75 mol% OMA and 92 mol% HMA. The Young's modulus of the HMA copolymer was approximately 0.37 MPa, well below the desired value of 0.9 MPa. Likewise, the Young's modulus of approximately 0.50 MPa for the OMA copolymer was also below the desired value. After partial neutralization with sodium cations, the Young's moduli increased to approximately 0.93 and 0.99 MPa, respectively. The chain transfer reaction lowered the molecular weights and mechanical properties of the copolymers, while the coupling reaction method had little effect on these properties. The chain transfer method appears to be a promising one-step method to produce polymers with a wide range of peptide concentrations.

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.

BACKGROUND: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. OBJECTIVE: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. METHODS: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. RESULTS: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. CONCLUSIONS: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.

CPI-1189 attenuates effects of suspected neurotoxins associated with AIDS dementia: a possible role for ERK activation.

Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.

CPI-1189 inhibits interleukin 1beta-induced p38-mitogen-activated protein kinase phosphorylation: an explanation for its neuroprotective properties?

The p38 mitogen-activated protein kinase (p38-MAPK) is a central enzyme in one of the major protein kinase cascades that regulate proapoptotic and proinflammatory signal transduction. p38-MAPK is activated by receptor/ligand recognition events or by exposure to extracellular stressors, including oxidative stress. Activation of p38-MAPK is affected by dual phosphorylation on a specific inhibitory domain. Dual phosphorylation causes a structural change in the p38-MAPK enzyme which allows binding of ATP and target substrate. Agents which block ATP docking to phosphoactivated p38-MAPK are being investigated for treatment of inflammatory diseases and neurodegenerative pathologies. An alternative strategy for p38-MAPK antagonism would be the inhibition of p38-MAPK phosphoactivation. We now report potent inhibition of p38-MAPK phosphorylation by a synthetic benzamide (CPI-1189) which displays protective action against tumor necrosis factor-alpha (TNFalpha)-induced neurodegeneration. In primary astrocytes treated with interleukin 1beta (IL1beta), CPI-1189 inhibits p38-MAPK phosphorylation at concentrations of 10 nM or less. While the precise molecular target of CPI-1189 remains unknown, these findings suggest a novel mechanism for the neuroprotective properties of the compound. These findings also indicate that antagonism of the p38-MAPK may be achieved through pharmacological inhibition of p38-MAPK phosphorylation, a strategy that is conceptually distinct from direct inhibition of ATP binding to the active enzyme.

CPI-1189 prevents apoptosis and reduces glial fibrillary acidic protein immunostaining in a TNF-alpha infusion model for AIDS dementia complex.

AIDS dementia complex (ADC) is characterized by increased apoptosis, gliosis, and oxidative stress in the CNS, as well as a compromised blood-brain barrier. TNF-alpha has been shown to be elevated in AIDS dementia complex brains and may contribute to AIDS dementia complex. To model elevated TNF-alpha in AIDS dementia complex, TNF-alpha was infused ICV bilaterally into rats for 3 days. TNF-alpha treatment increased apoptosis around the infusion site and selectively in the septum and corpus callosum. Co-administration of the synthetic antioxidant CPI-1189 prevented TNF-alpha induced apoptosis. Both TNF-alpha and CPI-1189 treatment suppressed glial fibrillary acidic protein (GFAP) staining at the infusion site. TNF-alpha did not significantly affect the integrity of the blood-brain barrier, but CPI-1189 treatment increased blood-brain barrier integrity at the infusion site. No effect of TNF-alpha or CPI-1189 treatment was found on measures of oxidative stress. These results support TNF-alpha as a key agent for increasing apoptosis in AIDS dementia complex. Additionally, CPI-1189 treatment may protect against TNF-alpha induced apoptosis and astrogliosis in AIDS dementia complex. Lastly, the toxic effect of TNF-alpha and the protective effect of CPI-1189 may not be mediated primarily through manipulation of classic reactive oxygen species.

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial.

BACKGROUND: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE: We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS: Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician's Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION: Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis.

Preventive actions of a synthetic antioxidant in a novel animal model of AIDS dementia.

Accumulating evidence indicates that the mechanism for causing AIDS dementia complex (ADC) involves the release of damaging inflammatory-related agents by HIV-infected microglia in the brain resulting in CNS oxidative damage. One such agent, tumor necrosis factor alpha (TNF-alpha) is consistently elevated in the brains of ADC patients compared to non-demented HIV patients. To model this aspect of ADC in rats, chronic ventricular infusions of TNF-alpha were given and found to induce several aspects of ADC, including weight loss, learning/memory impairment, enlarged lateral ventricles, and increased apoptosis. Concurrent oral treatment with the antioxidant CPI-1189 prevented all of these TNF-alpha induced effects. The results support TNF-alpha as a key toxic agent in ADC and provide the first in vivo evidence that chronic treatment with a synthetic antioxidant may protect HIV-infected patients against ADC. Our findings may also have implications in other neurological diseases where brain TNF-alpha levels are elevated and inflammation/oxidative stress is suspected to be a contributing cause, such as Alzheimer's disease and Parkinson's disease.

Fosinopril: pharmacokinetics and pharmacodynamics in congestive heart failure.

Fosinoprilat, the active product of fosinopril, is eliminated by a hepatic pathway, in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors. Congestive heart failure (CHF) may elevate drug plasma concentrations caused by a reduction in steady-state volume of distribution (Vss) and/or an impairment of clearance. This study compared the pharmacokinetics and pharmacodynamics of fosinopril (intravenous and oral) in 10 patients with established CHF and 10 age-, sex-, and weight-matched normal control subjects. There were no statistically significant differences between the patients with CHF and the control patients with respect to maximum drug concentration (Cmax) or area under the plasma concentration-time curve from 0 to infinity. Absolute bioavailability was approximately 29%. Vss was similar, and protein binding was 99% in both groups. The oral half-life of fosinoprilat was significantly longer than the intravenous half-life for both the patients with CHF and normal subjects, without statistically significant differences between the study groups. Median time to reach Cmax occurred at 4 hours in each group and corresponded to maximum angiotensin converting enzyme inhibition, which was essentially complete through 12 hours and markedly reduced through 24 hours. Thus these data indicate that patients with CHF can receive fosinopril without undue increases in fosinoprilat concentrations. This probably is due to the dual excretory pathways.

A comparison of mass balance, pharmacokinetics and disposition of [14C(U)]- and [125I]recombinant human interleukin-2 in cynomolgus monkeys.

Recombinant human interleukin-2 (rHuIL-2) has been metabolically labeled with 14C amino acids in Escherichia coli and affinity purified on a rHuIL-2 receptor affinity column. The radiolabeled molecule had a specific radioactivity of 238 dpm/unit and the identical amino acid sequence and biological activity as unlabeled rHuIL-2. In this study, we used this labeled [14C(U)]rHuIL-2 and commercially available [125I]rHuIL-2 (identical in sequence to the [14C(U)]rHuIL-2) to compare the mass balance, pharmacokinetics, and disposition in cynomolgus monkeys. After a single intravenous bolus dose of 4 x 10(5) units/kg, serum samples were collected for 7 days and examined for biological activity, total radioactivity, and by molecular size exclusion chromatography. Urine and feces were analyzed for total radioactivity. When analyzed for biological activity, both [14C(U)]- and [125I]rHuIL-2 exhibited the following pharmacokinetic parameters: terminal elimination half-life of 1-2 hr, AUC0-infinity ranged from 2005 to 4659 units x hr/ml, clearance was 90-200 ml/hr/kg, and volume of distribution ranged from 103 to 163 ml/kg. Comparison of the pharmacokinetic profiles of the two radiolabels were very different from bioactivity, in that the elimination half-lives for radioactivity were approximately 8 days and 10 hr for [14C(U)]- and [125I]rHuIL-2, respectively. We conclude that the [14C(U)]rHuIL-2 was metabolized to constituent amino acids and recycled into newly synthesized proteins from our size exclusion chromatography studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Antianginal and antiischemic efficacy of monotherapy extended-release nisoldipine (Coat Core) in chronic stable angina.

A double-blind, randomized, placebo-controlled study was conducted to test the peak and trough antianginal and antiischemic monotherapy efficacy and safety of a new extended-release formulation of nisoldipine (nisoldipine Coat Core [Bayer Corporation], 20 mg, 40 mg, and 60 mg once daily compared to placebo). Study patients had a history of chronic, stable angina pectoris, exercise-induced angina in association with ST segment depression, and exercise test reproducibility. Of the 483 patients enrolled in the study, results were valid for safety analysis for 312 and for efficacy analysis for 284. There was a statistically significant improvement in total exercise time at both peak and trough for patients taking 20 mg and 60 mg of nisoldipine compared with patients taking placebo, but the group taking 60 mg was not better than the group taking 20 mg (33.9 and 33.7 seconds, respectively, at trough). The results were similar for the secondary endpoints (time to onset of angina and time to 1 mm ST segment depression). No correlation was evident between plasma nisoldipine levels and total exercise duration. Headache and peripheral edema were the most frequently reported adverse events and were dose related. There were no discontinuations due to adverse events in patients randomized to the 20-mg nisoldipine group. No deaths occurred while patients were receiving active nisoldipine therapy. Therapy with this extended-release formulation of nisoldipine is an effective once-daily treatment for chronic stable angina pectoris. It represents one of the few dihydropyridine calcium channel antagonists that has shown efficacy when administered as monotherapy to patients with angina.

A 13-week toxicologic and pathologic evaluation of prolonged cytochromes P450 inhibition by 1-aminobenzotriazole in male rats.

The pharmacologic, toxicologic, and microscopic effects of 100 mg/kg/day of 1-Aminobenzotriazole (ABT), a suicide substrate inhibitor of cytochromes P450, were assessed in male Sprague-Dawley rats over a 13-week period. Hepatic cytochromes P450 levels and resorufin dealkylase activity were decreased to less than 30% of control values beginning at Day 2 and from Day 8 to Day 92. These decreases were not accompanied by overt clinical toxicity, e.g., changes in body weight, food consumption, or clinical appearance, during the study. Hemoglobin, hematocrit, and erythrocyte counts were slightly decreased at 8, 29, and 92 days and were accompanied by increased spleen weights and extramedullary hematopoiesis. Additionally, mean corpuscular hemoglobin concentration, mean corpuscular volume, red cell distribution width, and mean corpuscular hemoglobin were slightly increased at 92 days. Increases in liver weights at 8, 29, and 92 days were accompanied by centrilobular hypertrophy and intracytoplasmic vacuolization consistent with lipid accumulation. Thyroid stimulating hormone (TSH) was slightly elevated and triiodothyronine and thyroxine were slightly decreased at 29 days. TSH was also slightly elevated at 8 and 92 days, and thyroid gland weights were increased at 8, 29, and 92 days with microscopic evidence of hyperplasia and hypertrophy of thyroid gland follicular cells. Increased adrenal weights and hypertrophy of the zona fascicularis of the adrenal gland were observed at 8, 29, and 92 days. Kidney weights were also increased at these assessments. Changes in the thyroid gland, the thyroid hormone profile, and the liver may reflect increased synthesis of microsomal enzymes, an effect that is sometimes difficult to demonstrate directly with suicide substrate inhibitors of cytochromes P450. In general, the effects of daily ABT administration to male rats at a dose that significantly reduces oxidative metabolism over a 13-week period were considered to be well-tolerated under controlled laboratory conditions.

Disposition of [14C]acitretin in humans following oral administration.

The disposition of the antipsoriatic agent, acitretin, was investigated in six healthy human volunteers who each received a single, oral 50 mg dose of [14C]acitretin (50 microCi). plasma, urine, and feces were collected for 240 hr after administration. Mean values of 20.9 and 62.6% of the administered dose were recovered in the urine and feces, respectively. The terminal elimination half-life of total radioactivity from the plasma was approximately 120 hr. Extraction of pooled plasma samples followed by separation by HPLC and quantitation by liquid scintillation counting indicated that acitretin and its 13-cis-isomer, isoacitretin, were minor fractions of the total drug-related material in the plasma at most time points up to 72-hr postdose. The structures of acitretin, isoacitretin, and two other metabolites--(5E,7E)-8-(4-methoxy,2,3,6-trimethylphenyl)-2,6 -dimethyl-5,7- octadienoic acid (I) and (5E,7E)-8-(4-hydroxy-2,3,6-trimethylphenyl)-2,6-dimethyl-5,7 -octadienoic acid (II)--were confirmed by MS and cochromatography with authentic standards. I and II were major fractions of the drug-related material in the plasma at all time points. Other compounds, whose structures could not be confirmed, also account for a significant fraction of the circulating radioactivity.

Double-blind evaluation of the dose-response relationship of amlodipine in essential hypertension.

To determine the dose-response efficacy of once-daily administration of placebo or a new long-acting calcium channel blocker amlodipine in patients with mild to moderate hypertension, a randomized, multicenter, placebo-controlled, double-blind trial was conducted. The study included 210 patients with diastolic hypertension (blood pressure 95 to 114 mm Hg) without major hematologic, renal, hepatic, cardiac, or endocrine abnormalities. After a 4-week single-blind placebo run-in period, patients were given placebo or amlodipine (1.25, 2.5, 5, or 10 mg) daily for 4 weeks. To assess the antihypertensive effect of amlodipine over a 24-hour period, blood pressure and pulse rate at weeks 0 and 4 were recorded for 12 hours after the dose and then again at 24 hours. At the end of the study patients treated with all doses of amlodipine greater than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing than 1.25 mg daily had significantly reduced diastolic blood pressure in both supine and standing positions. Amlodipine, 1.25 mg daily, was also associated with a decrease in standing diastolic blood pressure. Response to treatment was greater in all amlodipine-treated patients than in those receiving placebo. Pulse rate in both the supine and standing positions was not significantly affected by amlodipine. At doses of 2.5, 5.0, or 10.0 mg daily, amlodipine maintained blood pressure below values obtained with placebo throughout the 24-hour period. Treatment with amlodipine was well tolerated and the incidence of side effects was low.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of 1-aminobenzotriazole in male rats after administration of an oral dose.

1. 14C-labelled 1-aminobenzotriazole (ABT), a suicide inactivator of cytochrome P450, was synthesized and administered orally to male rats. The rats were killed at 1, 6, 24, 48 or 72 h after dosing and the concentration of total radioactivity in various tissues and organs measured. 2. The compound appears to be absorbed slowly with 50% of the radioactivity remaining in the stomach at 6 h after dosing and maximum plasma and tissue concentrations were observed at 24 h. 3. Approximately 71% of the dose of 14C was excreted in the urine and 12% in the faeces over 72 h, indicating oral absorption of at least 71%. Tissue-to-plasma ratios of 14C were highest in the liver, adrenals and kidneys, which all contain significant amounts of cytochrome P450; the half-lives of elimination for total 14C in liver, adrenals and kidneys were approximately 24, 16 and 12 h, respectively, while the half-life in plasma was approximately 9 h. 4. ABT was metabolized by N-acetylation, with the acetylated product attaining concentrations equal to ABT in the plasma; two other major metabolites were also excreted in the urine namely, the N-glucuronide of 1-aminobenzotriazole and the N-glucuronide of benzotriazole.

The metabolism of acitretin and isoacitretin in the in situ isolated perfused rat liver.

1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers. 2. Acitretin undergoes alpha-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver. 3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver. 4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.