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Biomedical subjects

K H Moore

Publications and source records attributed to K H Moore.

At least 55 records · Page 3Linked to original sources
PubMed1999

Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials.

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4(+) cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4(+) cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.

Adult↗
PubMed1999

Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption.

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand-name components administered concurrently and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 5- to 7-day washout period: one lamivudine/zidovudine combination tablet after an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet simultaneously after an overnight fast, or one lamivudine/zidovudine combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for the determination of lamivudine and zidovudine plasma concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals for the ratio of least squares (LS) means for the lamivudine and zidovudine area under the plasma concentration-time curve (AUC infinity) and maximum observed plasma concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC infinity) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC infinity and Cmax were 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent of absorption of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of lamivudine and zidovudine. These changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.

Absorption↗
PubMed1999

Clinical pharmacokinetics of lamivudine.

Lamivudine (3TC), the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and as monotherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5'-triphosphate, the active anabolite which prevents HIV-1 and HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension. The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose. The absolute bioavailability is approximately 82 and 68% in adults and children, respectively. Lamivudine systemic exposure, as measured by the area under the serum drug concentration-time curve (AUC), is not altered when it is administered with food. Lamivudine is widely distributed into total body fluid, the mean apparent volume of distribution (Vd) being approximately 1.3 L/kg following intravenous administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, indicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivudine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum concentrations in adults and 9 to 17% of serum concentrations in children measured at 2 to 4 hours after the dose. In patients with normal renal function, about 5% of the parent compound is metabolised to the trans-sulphoxide metabolite, which is pharmacologically inactive. In patients with renal impairment, the amount of trans-sulphoxide metabolite recovered in the urine increases, presumably as a function of the decreased lamivudine elimination. As approximately 70% of an oral dose is eliminated renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokinetics of lamivudine. Systemic clearance following single intravenous doses averages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination half-life of lamivudine is approximately 5 to 7 hours, and the in vitro intracellular half-life of its active 5'-triphosphate anabolite is 10.5 to 15.5 hours and 17 to 19 hours in HIV-1 and HBV cell lines, respectively. Drug interaction studies have shown that trimethoprim increases the AUC and decreases the renal clearance of lamivudine, although lamivudine does not affect the disposition of trimethoprim. Other studies have demonstrated no significant interaction between lamivudine and zidovudine or between lamivudine and interferon-alpha-2b. There is limited potential for drug-drug interactions with compounds that are metabolised and/or highly protein bound.

Absorption↗
PubMed1999

Efficacy and user acceptability of the urethral occlusive device in women with urinary incontinence.

PURPOSE: We determine the efficacy and user acceptability of the urethral occlusive device (FemAssist) for incontinence for 1 month and identify factors that may predict successful use of the device. MATERIALS AND METHODS: Baseline and posttreatment outcome measures included a 1-hour pad test, frequency volume chart (leakage, voiding and number of pads per 24 hour), visual analog scale for incontinence impact and quality of life (Urogenital Distress Inventory). The last 36 consecutive women also completed a linear analog scale about attitudes toward touching the genitalia. RESULTS: The device was offered to 100 consecutive incontinent women of whom 3 did not enroll in the study and 57 (57%) completed the 1-month trial. Age, incontinence type or severity and attitudes about touching the genitalia were not significantly different between dropouts and participants. Only 13% of recruits were disinclined to place the device on the urethra. Significant reduction of incontinence was observed for all outcome measures with the device in situ. Pad testing revealed that 47% of the patients became continent and 33% had more than 50% benefit, while 9% had worse leakage. Those with severe baseline leakage were equally likely to respond as those with mild or moderate pad test loss. Women with stress, urge or mixed incontinence appeared to respond equally well. CONCLUSIONS: The urethral occlusive device provides a further nonsurgical treatment option which is useful for a range of incontinence types.

Aged↗
PubMed1998

Adrenomedullin concentrations in umbilical cord plasma of uncomplicated term pregnancies.

OBJECTIVE: The study's objective was to determine whether there is a difference in the plasma concentration of adrenomedullin, a hypotensive peptide, between arterial and venous umbilical cord blood of uncomplicated gestations with vaginal delivery. STUDY DESIGN: Arterial and venous umbilical cord blood was obtained immediately after vaginal delivery of 44 term infants with uncomplicated antepartum and intrapartum courses. Radioimmunoassay was performed to assess adrenomedullin concentrations in the plasma. The paired t test was used to compare arterial and venous concentrations. Significance was set at P < .05. RESULTS: Mean +/- SE adrenomedullin concentrations were 178.7 +/- 4.7 pg/mL and 190.6 +/- 6.3 pg/mL for arterial and venous cord plasma, respectively. The difference between the 2 concentrations was not significant (11.8 pg/mL, P = .09). CONCLUSION: Arterial and venous umbilical plasma concentrations of adrenomedullin do not differ significantly in uncomplicated gestations terminating with uncomplicated vaginal deliveries. This suggests that in the normal state there is neither net production nor net clearance of adrenomedullin in the placenta.

Adrenomedullin↗
PubMed1998

Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring.

The safety, pharmacokinetics, and antiretroviral activity of lamivudine alone and in combination with zidovudine was studied in pregnant women infected with human immunodeficiency virus type 1 (HIV-1) and their neonates. Women received the drugs orally from week 38 of pregnancy to 1 week after delivery. Neonate therapy began 12 h after delivery and continued for 1 week. Both treatment regimens were well-tolerated in women and newborns. Lamivudine and zidovudine pharmacokinetics in pregnant women were similar to those in nonpregnant adults. Lamivudine and zidovudine freely crossed the placenta and were secreted in breast milk. Neonatal lamivudine clearance was about half that in pediatric patients; zidovudine clearance was consistent with previous reports. HIV-1 RNA could be quantified in 17 of the 20 women. At the onset of labor/delivery, mean virus load had decreased by approximately 1.5 log10 copies/mL in both treatment cohorts. Although not definitive for HIV-1 infection status, all neonates had HIV-1 RNA levels below the limit of quantification at birth and at ages 1 and 2 weeks.

Administration, Oral↗
PubMed1998

A urodynamic study of surface neuromodulation versus sham in detrusor instability and sensory urgency.

PURPOSE: We studied the effect of surface neuromodulation on cystometric pressure and volume parameters in women with detrusor instability or sensory urgency. Electrical current was delivered to the suprapubic region and third sacral foramina via a transcutaneous electrical nerve stimulator with sham neuromodulation control. MATERIALS AND METHODS: A consecutive series of women with proved detrusor instability or sensory urgency were randomized to 3 surface neuromodulation groups. Volume and pressure parameters were the main outcomes of transcutaneous electrical nerve stimulation applied during second cystometric fill. RESULTS: Sham transcutaneous electrical nerve stimulation did not alter the outcome measures. However, neuromodulation delivered across the suprapubic and sacral skin effected a reduction in mean maximum height of detrusor contraction. A current which inhibits motor activity was not superior to that which inhibits sensory perception in reducing detrusor pressure. Response in sensory urgency was poor. CONCLUSIONS: Results from our sham controlled study suggest that short-term surface neuromodulation via transcutaneous electrical nerve stimulation may have a role in the treatment of detrusor instability. Future studies must examine the clinical effect of long-term surface neuromodulation.

Adult↗
PubMed1997

Fetoplacental vascular tone during fetal circuit acidosis and acidosis with hypoxia in the ex vivo perfused human placental cotyledon.

OBJECTIVES: Our purpose was to determine the effects of acidosis and acidosis-hypoxia on fetoplacental perfusion pressure and its response to angiotensin II. STUDY DESIGN: Perfused cotyledons from 14 placentas were studied with either an acidotic fetal circuit perfusate (n = 7) or an acidotic-hypoxic fetal circuit perfusate (n = 7). Each cotyledon's fetal vasculature was initially perfused under standard conditions and bolus injected with 1 x 10(-10) moles of angiotensin II. Fetoplacental perfusate was then replaced with either an acidotic medium (pH 6.90 to 7.00 and Po2 516 to 613 mm Hg) or an acidotic-hypoxic medium (pH 6.90 to 7.00 and Po2 20 to 25 mm Hg) followed by an angiotensin II injection. The vasculature was subsequently recovered with standard perfusate and again injected with angiotensin II. Perfusion pressures within each group were compared by one-way analysis of variance, and results were expressed as mean pressure +/- SEM. RESULTS: Resting fetoplacental perfusion pressure did not change when the fetal circuit perfusate was made acidotic (28 +/- 1 mm Hg vs 25 +/- 2 mm Hg) or acidotic-hypoxic (26 +/- 2 mm Hg vs 25 +/- 2 mm Hg). The maximal fetoplacental perfusion pressure achieved in response to angiotensin II did not differ with an acidotic perfusate (41 +/- 2 mm Hg vs 38 +/- 1 mm Hg) or with an acidotic-hypoxic perfusate (39 +/- 2 mm Hg vs 36 +/- 2 mm Hg). CONCLUSIONS: In the perfused placental cotyledon fetoplacental perfusion pressure and pressor response to angiotensin II are not affected by fetal circuit acidosis or acidosis-hypoxia. This suggests that neither fetal acidosis nor fetal acidosis combined with hypoxia has a direct effect on fetoplacental vascular tone.

Acidosis↗
PubMed1997

The fetoplacental pressor effects of low-dose acetylsalicylic acid and angiotensin II in the ex vivo cotyledon model.

OBJECTIVE: Our purpose was to investigate perfusion pressure changes ex vivo induced by angiotensin II on fetoplacental vasculature pretreated with low-dose acetylsalicylic acid. STUDY DESIGN: Two cotyledons from each of 12 placentas were perfused. The intervillous space of one cotyledon was infused with acetylsalicylic acid (5 x 10(-5) mol/L) similar to the serum concentration of women receiving daily low-dose aspirin therapy (60 to 81 mg). The control cotyledon was infused with an equivalent amount of normal saline solution. Two doses of angiotensin II, 1 x 10(-11.5) and 1 x 10(-10) moles, were injected as boluses into the chorionic arteries of each cotyledon. A 3 x 10(-7) mole dose of angiotensin II was also injected into the intervillous space. Statistical analysis was performed with analysis of variance, and results are expressed as mean pressure change in millimeters of mercury +/- SEM. RESULTS: Perfusion pressure response did not vary between cotyledons pretreated with acetylsalicylic acid and control cotyledons when 3 x 10(-7) moles of angiotensin II was injected into the intervillous space (8.0 +/- 1.9 mm Hg vs 9.8 +/- 1.6 mm Hg, p = 0.59). There were no differences between cotyledons in pressure response to 1 x 10(-11.5) moles of angiotensin II injected into the fetal circuit (5.9 +/- 0.8 mm Hg vs 6.7 +/- 0.9 mm Hg, p = 0.51). However, in the cotyledons pretreated with acetylsalicylic acid there was a decrease in the pressor response to 1 x 10(-10) moles of angiotensin II (14.1 +/- 1.4 mm Hg vs 21.5 +/- 3.3 mm Hg, p = 0.05). CONCLUSIONS: Low-dose aspirin infused into the intervillous space decreases vasoconstriction elicited by angiotensin II in the fetoplacental compartment. This suggests that maternal low-dose aspirin therapy has effects in the fetoplacental circulation in addition to its effects in the maternal circulation.

Angiotensin II↗
PubMed1997

Frequency-volume chart data from incontinent children.

OBJECTIVE: To establish the mean and standard deviation about the mean for voiding variables of incontinent children aged 6-11 years as measured on a frequency-volume chart (FVC), and to determine the effect of type of incontinence, gender and age on these values. PATIENTS AND METHODS: All children attending two continence clinics over a 3-year period completed a FVC as a routine part of their assessment. Voided volume and voiding interval data were collected from these charts. The mean maximum, mean minimum and overall mean voided volume and voiding interval were established for the whole group and then for each age, gender and type of incontinence. RESULTS: The voiding patterns of incontinent children were very variable and thus the standard deviation for each voiding parameter was large. Multivariate analysis showed that the only variable that affected any of these apparent storage parameters was the child's age; gender and type of incontinence did not influence bladder storage patterns. Children with day-time incontinence did not have smaller voided volumes than those with nocturnal enuresis. CONCLUSION: Both the mean and the standard deviation about the mean of all voided volumes varied widely amongst incontinent children. Only age appeared to influence trends in voided volumes. Any clinical investigation using the FVC in children should consider the high standard deviation when calculating sample size.

Age Factors↗
PubMed1997

Safety, tolerability, and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses.

The delivery of sumatriptan doses intranasally could add greater flexibility in the treatment of migraine than is possible with the currently available subcutaneous and oral sumatriptan preparations. Two independent double-blind, randomized, placebo-controlled clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of intranasally administered sumatriptan following ascending single doses (three different dose levels) and multiple doses. In the four-way, crossover, ascending-dose study, 20 healthy female subjects were randomized to receive on separate occasions single intranasal spray doses of 5, 10, or 20 mg sumatriptan (as the hemisulphate salt) or placebo into one nostril. Adverse events were mild and consisted mainly of bitter taste at the back of the throat and events typical of sumatriptan administered by other routes (headache, lightheadedness and tingling). Area under the plasma sumatriptan concentration versus time curve (AUC infinity) and peak plasma concentration (Cmax) increased with the dose. Dose proportionality was demonstrated between 5 and 10 mg but not across the dose range 5-20 mg. Time to maximum plasma concentration (tmax) was variable due to multiple peaking. The elimination half-life (t1/2), approximately 2 h, was unaffected by the magnitude of dose. In the two-period, multiple-dose, crossover study, 12 healthy adult male and female subjects were randomized to receive either sumatriptan hemisulphate 20 mg or placebo, administered intranasally as a spray three times a day for 4 days. The two dosing periods were separated by 3 to 14 days. Multiple doses of sumatriptan were well tolerated, with no serious adverse events occurring or withdrawals due to adverse events. All patients reported a mild to moderate drug-related disturbance of taste. Nasal examinations remained normal, and olfactory function was unaffected. The AUC over the first 8 h following dosing (AUC8) and fraction of the dose excreted in the urine (fe; 6.2% vs 3.6%) were similar on Days 1 and 4. Day 4 values were significantly higher (p < or = 0.05) for Cmax (16.9 ng/ml vs 13.1 ng/ml), renal clearance (Clr; 19.0 l/h vs 14.2 l/h), and t1/2 (2.18 h vs 1.93 h), and shorter for tmax (0.88 h vs 1.75 h). Some accumulation (22%) occurred over the 4 days of dosing. Serum concentrations of the pharmacologically inactive indole acetic acid metabolite of sumatriptan were fourfold to fivefold higher than corresponding sumatriptan concentrations. Overall, these studies show that the sumatriptan intranasal spray formulation is well tolerated, allows rapid absorption of sumatriptan, and results in only a clinically insignificant degree of sumatriptan accumulation upon repeated dosing.

Administration, Intranasal↗
PubMed1997

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

BACKGROUND: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. METHODS: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. RESULTS: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. CONCLUSIONS: This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

Adult↗
PubMed1997

The use of the bladder neck support prosthesis in combined genuine stress incontinence and detrusor instability.

The Bladder Neck Support Prosthesis (BNSP) was used in 21 women with combined genuine stress incontinence (GSI) and detrusor instability (DI). Outcomes included frequency volume charts, pad tests, voiding cystometry and quality of life scores, up to the sixth month. Of the 21 recruits, 5 never wore the BNSP home, leaving 16 participants. A further 2 did not reach week 4 because of poor efficacy or inability to fit the device. In the 14 who reached week 4, the median number of leaks/day declined from 4.3 to 1.0 (p = 0.002). Median pad test loss fell from 53 to 7 mL (p = 0.012). Cystometry showed an increase in maximum bladder capacity (p < 0.05) and a modest reduction in severity of detrusor instability, with no evidence of outflow obstruction. Three further women discontinued because of poor efficacy (2) or a poorly fitting device (1), leaving 11 of 16 participants (69%) at week 8, when median pad test loss fell to 2 mL. The BNSP is a useful option in patients with the unfortunate combination of an unstable bladder and an incompetent urethra, but requires careful fitting and attention to detail.

Aged↗
PubMed1997

Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder.

The distribution of nerves containing calcitonin gene-related peptide (CGRP), substance P (SP), neurokinin A (NKA), and vasoactive intestinal peptide (VIP) was examined in the human urinary bladder, using both single- and double-label immunohistochemistry. Nerves containing CGRP and tachykinins were typically present within the subepithelial region, encircling intramural ganglia and around blood vessels. These nerves were sparsely distributed, and only very rarely projected to the smooth muscle bundles of the detrusor. In contrast, VIP-containing nerves formed a dense subepithelial plexus and also projected to the detrusor muscle bundles. The double-label studies revealed that approximately 26% +/- 10% of CGRP-immunoreactive nerves also contained SP and NKA, but that no CGRP fibers coexpressed VIP. Conversely, all SP-immunoreactive fibers also contained CGRP, and many coexpressed NKA. At least three neurochemically distinct populations of nerves can therefore be discerned in the human bladder: VIP/-, CGRP/-, and CGRP/SP/ +/- NKA. The density of CGRP and SP-immunoreactive nerves within the subepithelium of 14 women with urodynamically-proven idiopathic detrusor instability was increased by 82% (p = 0.003) and 94% (p = 0.036), respectively, relative to that of 14 control women with no symptoms of frequency or urgency. This effect was not due to an increase in overall nerve density, because immunoreactivity for the general nerve marker, protein gene product, was not significantly different between the two groups (p = 0.21). The results indicate that at least some patients with detrusor instability demonstrate increases in a specific class of nerve fibers containing CGRP and SP. These peptides are characteristic of sensory neurons in a number of species, suggesting that abnormalities in the afferent arm of the micturition reflex may be associated with detrusor instability.

Adult↗
PubMed1996

Counter modulation of adipocyte mitochondrial processes by insulin and S-oxalylglutathione.

Oxalyl thiolesters, a group of putative intracellular regulators, have been shown to be in vitro inhibitors of some cytosolic enzymes which are stimulated by insulin. In this study, the effects of insulin and oxalyl thiolesters on pyruvate dehydrogenase, beta-oxidation, and acyl-CoA hydrolase activities in mitochondria from rat epididymal adipocytes are compared. Using glutathione, CoASH, cysteine, and cysteamine as thiol sources, oxalyl thioesters were synthesized, purified, and quantitated. Mitochondria were isolated from rat epididymal adipocytes, some of which were incubated with or without insulin. Mitochondrial activities were determined by radioisotopic assay subsequent to control, insulin, or oxalyl thiolester incubation. Under the conditions used in this study, pyruvate dehydrogenase activity was increased 28% subsequent to 10-min incubation of adipocytes with 400 microU/ml insulin; in contrast, preincubation of adipocyte mitochondria with S-oxalylglutathione resulted in a dose-dependent 11-19% inhibition of pyruvate dehydrogenase. S-oxalylglutathione also attenuated the spermine-induced activation of pyruvate dehydrogenase. Insulin treatment resulted in a small but significant increase in beta-oxidation of palmitic acid while 100 microM S-oxalylglutathione mediated a 40% decrease in palmitate oxidation. Palmitoyl-CoA hydrolase activity was decreased 14% by insulin treatment; however, S-oxalylglutathione caused a 14-50% increase in hydrolase activity. The other oxalyl thiolesters were not as effective or as consistent as S-oxalylglutathione in modulation of the mitochondrial activities; free thiols and oxalic acid did not modulate the activities. In summary, pyruvate dehydrogenase, palmitate beta-oxidation, and palmitoyl-CoA hydrolase activities in adipocyte mitochondria were modulated in approximately equal but opposite directions by insulin and S-oxalylglutathione. These findings support the suggestion that oxalyl thiolesters may function as an intracellular signal recruited to return insulin to normal levels.

Adipocytes↗
PubMed1996

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.

OBJECTIVE: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine. METHODS: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations. RESULTS: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC infinity) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432-10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole. CONCLUSIONS: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC infinity and a decreased CLR of lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.

Administration, Oral↗