Microanalysis of the antiretroviral nevirapine in human hair from HIV-infected patients by liquid chromatography-tandem mass spectrometry.

Sufficient drug exposure is crucial for maintaining durable responses to HIV treatments. However, monitoring drug exposure using single blood samples only provides short-term information and is highly subject to intra-individual pharmacokinetic variation. Drugs can accumulate in hair over a long period of time, so hair drug levels can provide drug exposure information over prolonged periods.

A phase 1 trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion.

Background: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.

Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice.

Huntington disease (HD) is a devastating, untreatable, dominantly inherited neurodegenerative disease. It is caused by an expanded CAG codon repeat that leads to an elongated polyglutamine tract in the N-terminus of the huntingtin (Htt) protein. Few mechanism-based therapeutic leads have been developed.

Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry.

A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode.

Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days.

Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multicenter, randomized, controlled trial.

Objective: We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure.

Study Design: Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.

Risk factors for persistent ductus arteriosus patency during indomethacin treatment.

Objective: To test the hypothesis that patent ductus arteriosus that fail to close with prostaglandin inhibition may be regulated by mechanisms that act independently of prostaglandin production.

Study Design: We examined a cohort of 446 infants who were treated with indomethacin (within 15 hours of birth) to inhibit prostaglandin production. We used multiple logistic regression modeling to determine which perinatal/neonatal variables were most closely associated with the persistence of ductus patency in the presence of diminished prostaglandin production.

Cytochrome P450 eicosanoids are activators of peroxisome proliferator-activated receptor alpha.

Cytochrome P450 (P450) eicosanoids regulate vascular tone, renal tubular transport, cellular proliferation, and inflammation. Both the CYP4A omega-hydroxylases, which catalyze 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and soluble epoxide hydrolase (sEH), which catalyzes epoxyeicosatrienoic acid (EET) degradation to the dihydroxyeicosatrienoic acids (DHETs), are induced upon activation of peroxisome proliferator-activated receptor alpha (PPARalpha) by fatty acids and fibrates. In contrast, the CYP2C epoxygenases, which are responsible for EET formation, are repressed after fibrate treatment.

Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by P-glycoprotein.

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound.

Induction of renal cytochrome P450 arachidonic acid epoxygenase activity by dietary gamma-linolenic acid.

Dietary gamma-linolenic acid (GLA), a omega-6 polyunsaturated fatty acid found in borage oil (BOR), lowers systolic blood pressure in spontaneously hypertensive rats (SHRs). GLA is converted into arachidonic acid (AA) by elongation and desaturation steps. Epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are cytochrome P450 (P450)-derived AA eicosanoids with important roles in regulating blood pressure.

Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation.

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF).

Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1).

Objectives: The organic anion transporter, OAT1 (SLC22A6), plays a role in the renal elimination of many drugs and environmental toxins. The goal of this study was to identify and functionally characterize OAT1 variants as a first step towards understanding whether genetic variation in OAT1 may contribute to interindividual differences in renal elimination of xenobiotics.

Methods: As part of a larger study, 276 DNA samples from an ethnically diverse population were screened and 12 coding region variants of OAT1 were identified.

Relative bioavailability of ketoprofen 20% in a poloxamer-lecithin organogel.

Purpose: The bioavailability of a single, topically applied, 200-mg dose of ketoprofen (delivered in a ketoprofen 20% gel) relative to a single 50-mg oral dose in healthy volunteers was studied.

Methods: This was an open-label crossover study. The subjects were randomized to receive an oral 50-mg ketoprofen capsule or a single topical dose of ketoprofen 20% in a poloxamer-lecithin organogel (PLO).

Pharmacokinetics of quinacrine in the treatment of prion disease.

Background: Prion diseases are caused by the accumulation of an aberrantly folded isoform of the prion protein, designated PrPSc. In a cell-based assay, quinacrine inhibits the conversion of normal host prion protein (PrPC) to PrPSc at a half-maximal concentration of 300 nM. While these data suggest that quinacrine may be beneficial in the treatment of prion disease, its penetration into brain tissue has not been extensively studied.

3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone.

Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology.

Effect of sex and AIDS status on the plasma and intrapulmonary pharmacokinetics of rifampicin.

Objective: To compare the steady-state plasma and intrapulmonary concentrations of oral rifampicin (rifampin) in men and women with and without AIDS.

Design: Prospective nonblinded pharmacokinetic study.

Participants: Ten men with AIDS, ten men without AIDS, ten women with AIDS, and ten women without AIDS.

Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality.

Objective: Buprenorphine and buprenorphine/naloxone combinations are effective pharmacotherapies for opioid dependence, but doses are considerably greater than analgesic doses. Because dose-related buprenorphine opioid agonist effects may plateau at higher doses, we evaluated the pharmacokinetics and pharmacodynamics of expected therapeutic doses.

Design: The first experiment examined a range of sublingual buprenorphine solution doses with an ascending dose design (n = 12).

Liquid chromatographic-tandem mass spectrometric assay for the simultaneous determination of didanosine and stavudine in human plasma, bronchoalveolar lavage fluid, alveolar cells, peripheral blood mononuclear cells, seminal plasma, cerebrospinal fluid and tonsil tissue.

We have developed a sensitive, high-pressure liquid chromatographic-tandem mass spectrometric (LC/MS/MS) method for the simultaneous determination of didanosine (ddI) and stavudine (d4T) in human plasma, bronchoalveolar lavage fluid (BALF), alveolar cells (AC), peripheral blood mononuclear cells (PBMC), seminal plasma, cerebrospinal fluid (CSF), and tonsil tissue. Plasma, AC, PBMC and CSF were run with an isocratic HPLC method, while BALF supernatant, semen, and tonsil tissue utilized a gradient elution. Samples were prepared by solid phase extraction.

Basal signaling activity of mu opioid receptor in mouse brain: role in narcotic dependence.

Narcotic analgesics cause addiction by poorly understood mechanisms, involving mu opoid receptor (MOR). Previous cell culture studies have demonstrated significant basal, spontaneous MOR signaling activity, but its relevance to narcotic addiction remained unclear. In this study, we tested basal MOR-signaling activity in brain tissue from untreated and morphine-pretreated mice, in comparison to antagonist-induced withdrawal in morphine-dependent mice.

A high-performance liquid chromatographic-tandem mass spectrometric method for the determination of cethromycin (ABT-773) in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A method is developed for the specific and sensitive determination of cethromycin concentrations in plasma, bronchoalveolar lavage (BAL), and alveolar cells (AC), using a high-performance liquid chromatographic-tandem mass spectrometry (MS) method. The mobile phase consists of 50% acetonitrile-0.05% acetic acid-5mM ammonium acetate; the column used is a C(8) reversed-phase stationary phase.

No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects.

Background: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highly expressed in the small intestine and in the blood-brain barrier. A major function of P-glycoprotein is to limit the absorption and central nervous system exposure of numerous xenobiotics. A genetic polymorphism in the MDR1 gene (C3435T) has been associated with changes in the intestinal expression level and function of P-glycoprotein.

Intra- and interindividual variabilities of valacyclovir oral bioavailability and effect of coadministration of an hPEPT1 inhibitor.

Variability in valacyclovir bioavailability and the potential for cephalexin-valacyclovir interaction were evaluated. The intraindividual acyclovir area under the concentration-time curve (AUC) varied minimally, whereas interindividual differences were substantial. Coadministration of the human peptide transporter 1 (hPEPT1) substrates valacyclovir and cephalexin minimally reduced the acyclovir AUC.

A high-pressure liquid chromatographic-tandem mass spectrometric method for the determination of ethambutol in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A technique is presented for the specific and sensitive determination of ethambutol concentrations in plasma, bronchoalveolar lavage (BAL), and alveolar cells (AC) using a high-pressure liquid chromatographic (HPLC)-tandem mass spectrometric (MS-MS) method. The preparation of samples requires a deproteinization step with acetonitrile. The retention times for ethambutol, neostigmine bromide, and propranolol are 2.