Clinical course and spectrum of intensive care unit patients reactivating herpes simplex-1 virus: a retrospective analysis.

Background: Herpes simplex-1 virus (HSV-1) reactivation in the respiratory tract is common in intensive care unit (ICU) patients. However, susceptible ICU populations are poorly defined. Clinical recognition of HSV infection of the respiratory tract is difficult and the impact of such reactivation is not understood.

Gonadotropin-releasing hormone functionally antagonizes testosterone activation of the human androgen receptor in prostate cells through focal adhesion complexes involving Hic-5.

Gonadotropin-releasing hormone (GnRH) analogs constitute the most widely employed medical treatment for prostatic cancer. The predominant mechanism of action is presumed to be via the inhibition of gonadotropins and resultant decrease in androgen. However, GnRH analogs have also been shown to directly inhibit prostate cancer cells both in vitro and in vivo through antiproliferative cell cycle arrest and stimulation of apoptosis.

A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans.

Aims: This double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y(12) ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects.

Methods: Thirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded.

Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a multiple-dose study in healthy humans.

This double-blind, placebo-controlled trial evaluated the safety, pharmacodynamics, and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 ADP receptor antagonist, during multiple oral dosing in healthy subjects. Eighteen subjects received placebo, or prasugrel 2.5 or 10 mg, orally, daily for 10 days.

Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans.

We assessed the tolerability, pharmacodynamics as measured by inhibition of platelet aggregation (IPA), and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent in healthy volunteers. Twenty-four subjects were randomized into four groups of six in a double-blind, placebo-controlled trial. One subject in each group received placebo and five subjects received prasugrel orally at single doses of 2.

Differential effects of transforming growth factor-beta1 on cellular proliferation in the developing prostate.

TGFbeta1 plays an important role in the growth of the prostate and has been reported to stimulate or inhibit the proliferation of prostatic epithelia. We show here that Tgfbeta1, Tgfbeta2, and Tgfbeta3 mRNA expression correlated with developmental growth of the prostate. Recombinant TGFbeta1 inhibited the growth of the prostate when added to cultures of ventral prostate (VP) organs grown in vitro.

Gonadotropin-releasing hormone-induced activation of diacylglycerol kinase-zeta and its association with active c-src.

Gonadotropin-releasing hormone (GnRH)-induced receptor activation has been demonstrated to entrain a wide variety of signaling modalities. Most signaling pathways are concerned with the control of serine, threonine, or tyrosine-protein kinases, however, in the current article we demonstrate that in both a model cell line and in gonadotropes, GnRH additionally mediates the activation of lipid-directed kinases. We have shown that there is a functional connection between protein-tyrosine kinase modulation and lipid kinase activation.

Sonic hedgehog regulates prostatic growth and epithelial differentiation.

The Sonic hedgehog (SHH)-signalling pathway mediates epithelial-mesenchymal interactions in several tissues during development and disease, and we have investigated its role in rat ventral prostate (VP) development. We have demonstrated that Shh and Ptc expression correlates with growth and development of the prostate and that their expression is not regulated by androgens in the VP. Prostatic budding was induced in response to testosterone in Shh null mouse urogenital sinus (UGS) explants grown in vitro and in rat UGS explants cultured with cyclopamine, suggesting that SHH-signalling is not critical for prostatic induction.

Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce.

Ritalin, an immediate release form of racemic methylphenidate hydrochloride, has been available in the USA since 1955 and is used for the treatment of ADHD. The objective of this study was to evaluate the pharmacokinetics of modified-release methylphenidate (highest single dose), Ritalin LA, when administered under fasting condition, with a high-fat breakfast, and when sprinkled on applesauce in healthy adult subjects. Blood samples were drawn for 24 h following a 40 mg oral administration.

Frovatriptan: a review of drug-drug interactions.

Objective: To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan.

Background: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans.

Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.

Objectives: The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating over the range of 1.0 mg to 100 mg (free base equivalents).

Methods: This was a randomized, double-blind, single-dose, placebo-controlled, dose-escalation trial, with each dose group (1.

Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels.

Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1.

The sexual phenotype is established in three steps: (1) the sex chromosome constitution; (2) the differentiation of the gonads; and (3) the response of the internal and external genitalia to the hormones produced by the differentiated gonads. Errors that occur at any of these stages can result in defective sexual differentiation. Therefore the investigation of patients with abnormalities of testis development will help elucidate the mechanisms of sex determination and gonadal differentiation.

A comparison of the pharmacokinetics of meropenem after intravenous administration by injection over 2, 3 and 5 minutes.

The pharmacokinetics of meropenem were determined in 9 healthy volunteers after the administration of 1 g dose by injection over 2, 3 or 5 min. Peak plasma concentrations were not significantly different across the three rates of administration and, due to the finite time required for complete mixing of the blood in the central compartment, did not always occur at the end of the injection. Overall exposure to meropenem was unchanged by the more rapid rates of administration.

Effects of frusemide on the urinary excretion of dopamine and 5-hydroxytryptamine in normal man.

The effects of frusemide on the urinary excretion of dopamine and 5-hydroxytryptamine (5-HT) were investigated in eight healthy male subjects in a randomized, placebo-controlled, cross-over study. Frusemide produced the expected rise in urinary dopamine excretion but it did not affect 5-HT excretion when compared with placebo. The lack of an effect on 5-HT excretion in man contrasts with studies in the rat which have reported a marked increase in 5-HT excretion after administration of this loop diuretic.

gamma-L-glutamyl-5-hydroxy-L-tryptophan, but not gamma-L-glutamyl-L-tryptophan, causes sodium retention in normal man.

1. This randomized, placebo-controlled, cross-over study compared the relative effectiveness of gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP) and gamma-L-glutamyl-L-tryptophan (glu-TRP) in terms of their ability to act as substrates for renal 5-hydroxytryptamine (5-HT) synthesis and their actions on urinary sodium excretion. 2.

Renal metabolism and effects of the glutamyl derivatives of L-dopa and 5-hydroxytryptophan in man.

1. Equimolar amounts of gamma-L-glutamyl-L-3,4-dihydroxyphenylalanine (gludopa) and gamma-L-glutamyl-5-hydroxy-L-tryptophan were infused separately and together in eight healthy, salt-replete male subjects in a placebo-controlled, cross-over study to investigate whether the administration of one amine precursor affects the renal metabolism of the other and to determine whether dopamine or 5-hydroxytryptamine would be generated preferentially. The overall effect on sodium excretion was also measured when both precursors were administered simultaneously.

Blood and urine 5-hydroxytryptophan and 5-hydroxytryptamine levels after administration of two 5-hydroxytryptamine precursors in normal man.

Six healthy male subjects received equimolar amounts of two 5-hydroxytryptamine (5-HT) precursors, 5-hydroxy-L-tryptophan (5-HTP) and gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), on two occasions in a randomised cross-over study. There were marked increases in urinary 5-HTP and 5-HT excretion after infusion of both compounds. Mean urinary excretion rate of 5-HT, which was < 0.

Effect of coffee and cigarette smoking on the blood pressure of patients with accelerated (malignant) hypertension.

There is a strong association between cigarette smoking and accelerated hypertension. In mild hypertension smoking cigarettes has a distinct pressor effect and caffeine a small but more prolonged pressor action. Coffee and cigarette smoking together have an additive effect on blood pressure (BP).

Atrial natriuretic peptide levels in the sleep apnoea/hypopnoea syndrome.

Background: Patients with the sleep apnoea/hypopnoea syndrome have increased salt and water excretion at night which has been reported to be associated with an increase in plasma levels of atrial natriuretic peptide (ANP). A study was performed to determine whether any rise in plasma ANP levels was related to nocturnal hypoxaemia.

Methods: Nine patients with sleep apnoea/hypopnoea syndrome were studied on two nights, one breathing air and the other 28% oxygen, the order being randomised.

The antinatriuretic action of gamma-L-glutamyl-5-hydroxy-L-tryptophan is dependent on its decarboxylation to 5-hydroxytryptamine in normal man.

1. The effects of inhibition of peripheral aromatic L-amino acid decarboxylase during infusion of the relatively renally selective 5-hydroxytryptamine (5-HT) prodrug, gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), were examined in eight healthy male subjects in a randomised, placebo-controlled, cross-over study. 2.

A comparison of the renal and neuroendocrine effects of two 5-hydroxytryptamine renal prodrugs in normal man.

1. The effects of 1 h intravenous infusions of equimolar amounts (45 nmol min-1 kg-1) of two putative 5-hydroxytryptamine renal prodrugs, 5-hydroxy-L-tryptophan and gamma-L-glutamyl-5-hydroxy-L-tryptophan, were investigated in a randomized, placebo-controlled, cross-over study in nine healthy male subjects. 2.

A comparison of the effects of two putative 5-hydroxytryptamine renal prodrugs in normal man.

1. The effects of 1 h intravenous infusions of equimolar amounts of two putative 5-hydroxytryptamine (5-HT) renal prodrugs, 5-hydroxy-L-tryptophan (5-HTP, 10 micrograms kg-1 min-1) and gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP, 16.6 micrograms kg-1 min-1) were examined in five healthy male volunteers in a randomised, placebo-controlled, cross-over study.