Using metabolic markers to identify insulin resistance in premenopausal women with and without polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Quantifying IR is invasive and time-consuming, and thus not routinely used in clinical practice. Simple metabolic markers to predict IR exist, but have not been validated in premenopausal women or women with polycystic ovary syndrome (PCOS). OBJECTIVE: To evaluate the ability of metabolic markers to identify premenopausal women with/without PCOS who are insulin resistant. DESIGN/SETTING: Cross-sectional analysis. PARTICIPANTS: One hundred and seventy-one non-diabetic premenopausal overweight/obese women without PCOS and 71 women with PCOS. METHODS: IR was quantified by the steady-state plasma glucose during the modified insulin-suppression test. Metabolic markers (BMI, lipid/lipoprotein concentrations, and fasting glucose) were evaluated for their discriminative ability to identify IR, using area under the receiver-operating-characteristic curve (AUROC) analysis. Optimal cut-points were evaluated for predictive power. RESULTS: In the non-PCOS group, the triglyceride/HDL cholesterol ratio (TG/HDL-C) was the best marker (AUROC 0.73). Optimal diagnostic cut-point was 1.9. In the PCOS group, the TG/HDL-C ratio, cholesterol/HDL-C ratio (TC/HDL-C), and HDL-C performed well (AUROC > 0.80), with optimal cut-points for TG/HDL-C 1.3, TC/HDL-C 3.4, and HDL-C 52 mg/dL: TG/HDL-C was more sensitive, but HDL-C had a higher PPV for IR. CONCLUSION: TG/HDL-C can identify IR in premenopausal women with and/without PCOS; diagnostic cut-points differ from those of men and postmenopausal women. HDL-C is an alternative predictor in women with PCOS. These simple metabolic markers, which are standardized between labs, inexpensive, and routinely measured, can be used to tailor lifestyle and medical interventions to improve health outcomes in insulin-resistant premenopausal women.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss. METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Antipsychotic prescribing and drug-related readmissions in multimorbid older inpatients: a post-hoc analysis of the OPERAM population.

BACKGROUND: Limited data are available on characteristics associated with antipsychotic use in multimorbid older adults. AIM: Primary: to identify patient characteristics associated with antipsychotic prescribing in a multimorbid population of older inpatients with polypharmacy. Secondary: (1) to observe if antipsychotics use during an index hospitalisation was associated with a drug related admission (DRA) within one year, and (2) to describe these cases of antipsychotic-related readmissions. METHOD: This was a secondary analysis of the OPERAM randomized controlled trial. Multivariate analysis assessed the association between characteristics and comorbidities with antipsychotic use. An expert team assessed DRA occurring during the one-year follow-up. RESULTS: Antipsychotics were prescribed to 5.5% (n = 110) patients upon admission while 7.7% (n = 154) inpatients received antipsychotics at any time (i.e. upon admission, during hospitalisation, and/or at discharge). The most frequently prescribed antipsychotics were quetiapine (n = 152), haloperidol (n = 48) and risperidone (n = 22). Antipsychotic prescribing was associated with dementia (OR = 3.7 95%CI[2.2;6.2]), psychosis (OR = 26.2 [7.4;92.8]), delirium (OR = 6.4 [3.8;10.8]), mood disorders (OR = 2.6 [1.6;4.1]),  ≥ 15 drugs a day (OR = 1.7 [1.1;2.6]), functional dependency (Activities of Daily Living score < 50/100) (OR = 3.9 [2.5;6.1]) and < 2 units of alcohol per week (OR = 2.2 [1.4;3.6]). DRA occurred in 458 patients (22.8%) within one year. Antipsychotic prescribing at any time was not associated with DRA (OR = 1.0 [0.3;3.9]) however contributed to 8 DRAs, including 3 falls. CONCLUSION: In this European multimorbid polymedicated older inpatients, antipsychotics were infrequently prescribed, most often at low dosage. Besides neuro-psychiatric symptoms, risk factors for inhospital antipsychotic prescribing were lower functional status and polymedication.

Pharmacokinetics of emtricitabine/tenofovir disoproxil fumarate and tacrolimus at steady state when administered alone or in combination.

OBJECTIVE: An open-label, randomized, 3-way crossover, drug-drug interaction study of the investigational anti-HBV combination agent, emtricitabine/tenofovir DF and the antirejection agent, tacrolimus was conducted in healthy volunteers to evaluate the potential for a pharmacokinetic interaction between these drugs. METHODS: Subjects received emtricitabine/tenofovir DF (200/300 mg q.d.) and tacrolimus (0.1 mg/kg/day) alone or in combination for 7 days, with a 2-week washout between successive treatments. Drug concentrations were measured by LC/MS/MS and steady state pharmacokinetic parameters were calculated for each drug using noncompartmental methods. RESULTS: The 90% confidence intervals (CIs) of the geometric least-squares mean ratio for AUCtau, Cmax and Ctau for each drug together vs. alone were within the predetermined no-effect boundaries of 80 - 125% (representing a maximum 20% effect), other than the upper limit of the 90% CI for tenofovir Cmax, which was just outside the 125% threshold. CONCLUSIONS: It was concluded that there was no clinically relevant pharmacokinetic interaction between emtricitabine/tenofovir DF and tacrolimus when administered together.

A radioimmunoassay for methotrexate and its comparison with spectrofluorimetric procedures.

A radioimmunoassay procedure has been developed for the direct measurement of methotrexate (MTX) in plasma, serum, cerebrospinal fluid, or urine samples. The assay is sensitive to levels of at least 100 pg of MTX and is highly specific for MTX in the presence of folinic acid (citrovorum factor), folic acid, tetrahydrogolic acid, and other folate analogs and known metabolites. Results from this procedure have been compared with those obtained with a spectrofluorimetric method, utilizing the plasma of cancer patients undergoing high-dose MTX treatment with citrovorum factor rescue. Results indicate that the method should be usful in the future in assisting individualization of dosage regimens and in the study of the pharmacokinetics and metabolism of MTX in cancer patients.

Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR.

Investigations with the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR were carried out to identify patterns of cross-resistance and collateral sensitivity and to define the mechanism(s) mediating melphalan resistance. TE-671 MR was cross-resistant to thio-TEPA, mitomycin, vincristine, and cisplatin, and partially resistant to chlorambucil and cyclophosphamide. TE-671 MR and the parent line TE-671 were both resistant to 1,3-bis(2-chloroethyl)-nitrosourea and expressed similar levels of O6-alkylguanine-DNA alkyltransferase. TE-671 MR retained full sensitivity to actinomycin D and demonstrated enhanced sensitivity to VP-16 compared to TE-671. Treatment of TE-671 MR with melphalan plus VP-16 resulted in greater than additive growth delays. The frequency of hypoxic regions was similar in TE-671 MR and TE-671, respectively. Measurement of tumor-to-plasma levels at 180 min following i.p. administration of melphalan at 0.5 of the 10% lethal dosage showed mean tumor-to-plasma ratios of 3.81 in TE-671 MR and 7.38 in TE-671, respectively. The lower drug levels in TE-671 MR may be contributing to the resistance to melphalan and thus indicate the need for further studies to define the reasons for these differences in tumor drug level.

Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.

Melphalan transport, glutathione levels, and glutathione-S-transferase activity were measured in two continuous human medulloblastoma cell lines and transplantable xenografts in athymic nude mice, TE-671 and Daoy. In vitro mean glutathione levels were 10.06 nmol/10(6) cells in TE-671 and 2.96 nmol/10(6) cells in Daoy. In vitro mean glutathione-S-transferase values were 91.52 nmol/min/mg protein in TE-671 and 50.31 nmol/min/mg protein in Daoy. Transport studies revealed kinetic parameters of Km = 108.3 microM, Vmax = 363.1 pmol/10(6) cells/min in TE-671 and Km = 111.7 microM, Vmax = 180.6 pmol/10(6) cells/min in Daoy. Melphalan transport was inhibited by both DL-alpha-2-aminobicyclo[2.2.1]heptane-2- carboxylic acid and sodium ion depletion in TE-671 and Daoy cells in vitro, indicating that both systems of amino acid transport are functional in these medulloblastoma lines. In vivo s.c. xenograft glutathione values were lower (7.79 nmol/mg protein) in TE-671 than in Daoy (13.68 nmol/mg protein). The mean plasma concentration in mice given a 10% lethal dose (71.3 mg/m2) of melphalan i.p. was 50.3 microM at 10 min, with the half-life of 29.9 min. At this dose, s.c. xenograft levels were 2- to 3-fold higher in TE-671 than in Daoy tumors for the 3-h period measured. These studies demonstrate transport parameters confirming facilitated transport of melphalan in human medulloblastoma, a mean murine plasma melphalan concentration (following treatment with melphalan) above the in vitro drug dose at which there is a 90% reduction in the number of colonies in comparison to controls for TE-671 and Daoy for 2 h, and glutathione and glutathione-S-transferase levels in the same range previously reported in other melphalan-sensitive and melphalan-resistant human tumors. Future work with spontaneous and acquired melphalan-resistant human medulloblastoma cell lines and xenografts will define the role of these mechanisms in mediating drug resistance.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES: To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. Patients Elderly patients with VTE were studied. METHODS: In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L(-1) ), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L(-1) , both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS: Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality. CONCLUSION: In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers.

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

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.

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex.

The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide (GAZT) and is cleared rapidly, resulting in a short half-life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is administered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half-life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Acetylation phenotype, platelet monoamine oxidase inhibition, and the effectiveness of phenelzine in depression.

The authors treated 16 depressed patients with up to 90 mg/day of phenelzine. After acetylation phenotype was determined and platelet monoamine oxidase (MAO) activity measured, no significant relationship was observed between clinical improvement and acetylation phenotype or between MAO inhibition and acetylation. Discrepant findings regarding acetylation phenotype and the effects of phenelzine are discussed. The authors do not recommend a sulfamethazine phenotype test as a predictor of outcome for phenelzine.

Overview of acyclovir pharmacokinetic disposition in adults and children.

The metabolic disposition and pharmacokinetics of acyclovir have been studied as part of the clinical evaluation of the drug in humans. Data from 10 studies have been summarized and, when appropriate, pooled across studies for further analysis. The principal findings are as follows: Renal excretion is the major route of elimination of acyclovir and is dependent, in part, on active tubular secretion. Total body clearance (Cltot) and half-life are dependent on renal function as evaluated by estimated creatinine clearance (Clcr). Cltot is markedly reduced in the anuric patient. Plasma protein binding is low and drug interactions involving binding displacement are not anticipated. Acyclovir levels in cerebrospinal fluid are approximately 50 percent of corresponding plasma levels. Dose-independent pharmacokinetics is observed in the range of 0.5 to 15 mg/kg. Proportionality between dose and plasma levels is seen after single doses or at steady state after multiple dosing. Similar plasma levels are achieved in adults and pediatric patients (greater than 1 year) when equivalent doses are given based on body surface area. Intrasubject variability of acyclovir disposition is low. Much but not all intersubject variability in Cltot can be explained by differences in renal function. Dosage adjustment for various stages of renal impairment are proposed based on the observed relationship between Cltot and Clcr.

Pharmacokinetics of acyclovir in humans following intravenous administration. A model for the development of parenteral antivirals.

Data are reported from three step-wise pharmacokinetic studies in 43 patients who received acyclovir. Dosage regimens began at 0.5 mg/kg administered as a single dose intravenously and were increased to 15 mg/kg per dose given three times daily for five days. All patients evaluated were immunocompromised by underlying disease or received cytolytic and/or cytotoxic therapy. Patients with virologically confirmed herpes simplex or zoster infections were assessed in the multiday, multidose pharmacokinetic trial. Postinfusion plasma concentrations of acyclovir declined in a biphasic manner such that the plasma-concentration time data were fitted by a two-compartment, open-model with zero-order input. The drug's half-life showed little variation with a mean of 3.16 +/- 0.20 hours. In both single-dose and multiple-dose studies there was dose proportionality with peak plasma levels and area under the plasma concentration-time curve indicating dose-independent pharmacokinetics. The kidney was the principal route of drug clearance with a mean recovery of 60 +/- 12 percent. Renal clearance exceeded creatinine clearance indicating renal tubular secretion of drug. No significant clinical or laboratory evidence of toxicity appeared. These studies provide a foundation for the evaluation of acyclovir in controlled trials.

Pharmacokinetics and bioavailability of zidovudine in humans.

The basic pharmacokinetic and bioavailability information on zidovudine was obtained during the initial phase I study. Following intravenous doses of 1.0 mg/kg every eight hours to 7.5 mg/kg every four hours, zidovudine plasma levels decay in a biexponential manner, indicating two-compartment pharmacokinetics. The mean half-life was 1.1 hours over this dose range and the total body clearance was approximately 1,900 ml/minute/70 kg, up to doses of 5 mg/kg. At 7.5 mg/kg, total body clearance decreased by 35 percent. The 5'-O-glucuronide was identified as a major metabolite of zidovudine in plasma and urine. This inactive metabolite is rapidly formed and cleared from plasma, with a half-life of one hour. No other metabolites have been found in humans. Renal clearance of zidovudine was estimated at 350 ml/minute/70 kg. Zidovudine penetrated the blood brain barrier as indicated by a cerebrospinal fluid:plasma ratio averaging 0.5, determined two to four hours after dosing. Following oral administration of zidovudine at doses from 2.0 mg/kg every eight hours to 10 mg/kg every four hours, peak plasma levels increased proportionately with dose; the average bioavailability was 65 percent. Since 90 percent of the drug was recovered in the urine as zidovudine or the 5'-O-glucuronide, the incomplete bioavailability is assumed to be the result of first-pass metabolism rather than incomplete absorption. Pharmacokinetic questions related to optimal use of the drug are currently being addressed.

Neonatal acyclovir pharmacokinetics in patients with herpes virus infections.

A preliminary analysis is presented of the pharmacokinetics of acyclovir in neonatal patients with herpes simplex virus infections. Mean peak acyclovir levels (microM +/- SD) at 5, 10, and 15 mg/kg per dose were 30.0 +/- 9.9, 61.2 +/- 18.3, and 86.1 +/- 23.5, with corresponding mean trough levels (microM +/- SD) of 5.3 +/- 3.4, 10.1 +/- 8.4, and 13.8 +/- 11.1, respectively. The mean half-life (t 1/2 beta) of acyclovir was 3.78 +/- 1.21 hours. The mean percent urinary recovery of acyclovir (+/- SD) at each dosage level was similar, with an overall mean recovery of 65 percent. The mean acyclovir concentration in urine did not exceed the solubility of acyclovir in bladder urine (1,300 micrograms/ml). Generally, neonatal acyclovir pharmacokinetics was consistent with previous reports from studies of adults.

In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents.

141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.08 microM against HIV-1 (strain IIIB) and a mean IC50 of 0.012 microM against six HIV clinical isolates. 141W94 was synergistic on the basis of isobologram analysis with each of the following reverse transcriptase inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl, 141W94 was also synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human alpha 1-acid glycoprotein was relatively weak (Kd = 4 microM) and the off-rate for the drug is very fast (> or = 100 s-1). Only a 2-fold reduction of in vitro antiviral activity was observed in the presence of 45% human plasma. No serious drug associated adverse experiences were reported in a Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 141W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.

Hyperthermia-induced enhancement of melphalan activity against a melphalan-resistant human rhabdomyosarcoma xenograft.

The effects of regional hyperthermia (42 degrees C for 70 min) on the antitumor activity of melphalan were examined in athymic mice bearing melphalan-resistant human rhabdomyosarcoma (TE-671 MR) xenografts growing in the right hind limb, and results were compared with similar studies of melphalan-sensitive (TE-671) parent xenografts. Melphalan alone at a dose of 36 mg/m2 (0.5 of the 10% lethal dose) produced growth delays of 4.1 to 10.2 days in TE-671 MR xenografts and 21.8 to 28.7 days in TE-671, respectively. Hyperthermia alone produced growth delays of 0.9 days in TE-671 MR xenografts and 0.8 days in TE-671. Combination therapy with melphalan and hyperthermia produced growth delays of 7.2 to 13.3 days in TE-671 MR xenografts and 34.3 to 42.8 days in TE-671, respectively, representing a mean thermal enhancement ratio of 1.7 in TE-671 MR and 1.5 in TE-671. Measurement of glutathione levels in TE-671 MR xenografts following treatment with melphalan, hyperthermia, or melphalan plus hyperthermia revealed significant reductions in glutathione content with the nadir (60% of control values) seen 6 h following treatment. Glutathione levels in TE-671 xenografts following identical therapy revealed no differences from control values. Hyperthermia plus melphalan did not result in a higher tumor-to-plasma melphalan ratio compared with treatment with melphalan alone in either TE-671 MR or TE-671 xenografts. These studies suggest that heat-induced alterations in tumor glutathione or melphalan levels are not responsible for the increase in melphalan activity produced by hyperthermia. Combination therapy with melphalan plus regional hyperthermia offers promise for treatment of melphalan-resistant neoplasms.

Relationship of sulfamethazine disposition kinetics to acetylator phenotype in man. A preliminary study.

The relationship between sulfamethazine disposition kinetics and acetylation phenotype was studied in man. Sulfamethazine pharmacokinetic parameters were determined after the administration of the drug as an oral suspension. When the half-life, acetylation rate constant, or per cent available dose excreted in the urine as acetylsulfamethazine of each subject was plotted on frequency distribution histograms, bimodal distribution patterns were observed. However, when acetylation clearance values were plotted in the same manner, an apparent trimodal pattern was seen. The failure to identify the presumed homozygous rapid acetylator using the commonly employed indices of drug metabolism, i.e., half-life, metabolic rate constant, or per cent of the dose metabolized, was attributed to a significant increase in the apparent volume of distribution of this genotype, as well as the low renal clearance of sulfamethazine found in all genotypes. This preliminary study points out the value of using metabolic clearance as an index of drug metabolizing capacity and suggests its application to further pharmacogenetic studies.