5-HYDROXYTRYPTAMINE-INDUCED CONTRACTION OF THE MARMOSET AORTA IS MEDIATED BY A 5-HT1-LIKE RECEPTOR

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT₂ antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta.
2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A₂ agonist U44069 in order to amplify the responses; or (ii) exposed to N ^ω-nitro- L -arginine (100 μmol/L) plus LY 53857 (0.1 μmol/L; a 5-HT₂ receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated.
3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di- n -propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT_1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT₃ and 5-HT₄ receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase.
4. The above effects fulfil the criteria for a 5-HT₁-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT₁-like receptor.     

Haptoglobulin phenotypes in leprosy

Haptoglobulin phenotyping was carried out in fifty controls and in thirty five leprosy patients. In controls the incidence Hp phenotypes 2-2, 2-1 and 2-1 (Mod) is 76%, 16% and 8% respectively. In leprosy patients, the incidence of phenotypes 2-2, 2-1, 1-1 and 0-0 is 77%, 11%, 3% and 9% respectively. The incidence of phenotype 2-2, 1-1 and 0-0 is more in leprosy patients than in controls and is significant (p less than 0.05). In none of the leprosy patients phenotype 2-1 (Mod) was recorded.     

The effect of N-alkyl chain length of stereochemistry on the absorption, metabolism and during excretion of N-alkylamphetamines in man

Urinary excretion in man, of the unchanged drug and metabolite amphetamine, has been investigated after the (+)- and (-)-isomers of methyl-, ethyl-, n-propyl- and n-butyl- amphetamine had been taken by mouth under acidic urinary pH. The total metabolism of (+)-methyl-, ethyl-, and n-propyl-amphetamine was greater than that of the corresponding (-)-isomers but there was no difference in the total metabolism of the (+)- and (-)-n-butylamphetamine. A direct correlation was obtained for the (+)-but not the (-)-isomers between the partition coefficient of the compounds in an n-heptane/aqueous system, their buccal absorption and the total metabolism. The (+)-isomers of methyl- and ethyl-amphetamine were N-dealkylated more than their (-)-enantiomorphs but (-)-n-propylamphetamine was N-dealkylated more than the (+)-isomer.     

Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation

BACKGROUND: One-year results of a randomized, double-blinded trial of Thymoglobulin versus Atgam for induction therapy in renal transplantation revealed that Thymoglobulin was associated with higher event-free survival (94% vs. 63%), less acute rejection (4% vs. 25%), and better graft survival. This article compares the safety and efficacy of Thymoglobulin versus Atgam induction through 5 years. METHODS: Review and analysis of clinic records and electronic databases. RESULTS: At 5 years, event-free survival (73% vs. 33%, P<0.001), graft survival (77% vs. 55%, P=0.047), and freedom from rejection (92% vs. 66%, P=0.007) were higher with Thymoglobulin versus Atgam. No additional cytomegalovirus (CMV) disease occurred after the first year with Thymoglobulin or Atgam (13% vs. 33%, P=0.056). There were two cases of posttransplant lymphoproliferative disorder (PTLD) with the Atgam arm and none with Thymoglobulin. Thymoglobulin was associated with profound lymphopenia at 2 years after transplantation. CONCLUSIONS: Thymoglobulin was associated with higher event-free survival, graft survival, and freedom from rejection without increased PTLD or CMV disease at 5 years compared with Atgam. The prolonged and profound lymphopenia may contribute to the long-term results associated with Thymoglobulin.     

Induction of CYP3A by 2,3-oxidosqualene:lanosterol cyclase inhibitors is mediated by an endogenous squalene metabolite in primary cultured rat hepatocytes

The effects of inhibitors of 2,3-oxidosqualene:lanosterol cyclase (cyclase) on cytochrome P450 expression were investigated in primary cultures of rat hepatocytes. Treatment of hepatocyte cultures for 24 h with either of the inhibitors [4'-(6-allyl-methyl-amino-hexyloxy)-2'-fluoro-phenyl]-(4-bromophenyl)-methanone fumarate (Ro 48-8071) or trans-N-(4-chlorobenzoyl)-N-methyl-(4-dimethylaminomethylphenyl)-cyclohexylamine (BIBX 79) selectively increased CYP3A mRNA and immunoreactive protein contents, with maximal accumulations occurring at 3 x 10(-5) M Ro 48-8071 and 10(-4) M BIBX 79. The abilities of Ro 48-8071, BIBX 79, and 3beta-(2-diethylaminoethoxy)androst-5-en-17-one.HCl (U18666A) to induce murine CYP3A were abolished in hepatocyte cultures prepared from pregnane X receptor (PXR)-null mice, and cotransfection of primary cultured rat hepatocytes with a dominant-negative PXR prevented cyclase inhibitor-inducible luciferase expression from a PXR-responsive reporter plasmid. Cyclase inhibitor-mediated CYP3A mRNA induction was eliminated when primary cultured rat hepatocytes were cotreated with any of the following agents that inhibit steps upstream of cyclase in the cholesterol biosynthetic pathway: squalestatin 1 (squalene synthase inhibitor), (E)N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzenemethanamine (NB-598, squalene monooxygenase inhibitor), or pravastatin (HMG-CoA reductase inhibitor). Ro 48-8071-inducible CYP3A mRNA expression was restored when pravastatin-treated cultures were incubated with medium containing mevalonate. The concentration-dependence of Ro 48-8071-mediated CYP3A mRNA induction corresponded to the cellular contents of metabolically labeled squalene 2,3-oxide and squalene 2,3:22,23-dioxide, but not 24(S),25-epoxycholesterol. These results indicate that cyclase inhibitors are capable of inducing CYP3A expression in primary cultured rat and mouse hepatocytes and that the effect is mediated as a consequence of cyclase blockade through the evoked accumulation of one or more squalene metabolites that activate the PXR.