Increased Cortical Cerebral Blood Flow in Asymptomatic Human Immunodeficiency Virus-Infected Subjects.

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. To investigate the physiological basis for this risk, we used magnetic resonance imaging (MRI) to measure oxygen extraction fraction (OEF) and cerebral blood flow (CBF) in treatment-naive asymptomatic HIV-infected subjects and controls. METHODS: In treatment-naive asymptomatic HIV-infected subjects and age-, gender-, and race-matched controls, OEF was measured by MRI asymmetric spin-echo echo-planar imaging sequences and CBF was measured by MRI pseudocontinuous arterial spin labeling. RESULTS: Twenty-six treatment-naive HIV-infected subjects and 27 age-, gender-, race-matched controls participated. Whole-brain, gray matter (GM), and white matter OEF were not different between the groups (all P > .70). Unexpectedly, HIV-infected subjects had significantly higher CBF in cortical GM (72.9 ± 16.2 mL/100 g/min versus 63.9 ± 9.9 mL/100 g/min; P = .01) but not in subcortical GM (P = .25). CONCLUSIONS: The observed increase in cortical GM CBF in treatment-naive HIV-infected subjects is unexpected, contrary to CBF decreases reported in HIV-infected subjects on treatment, and may represent an initial increase in metabolic activity due to an HIV-mediated inflammation.

Influence of agents affecting voltage-dependent calcium channels and dantrolene on the anticonvulsant action of the AMPA/kainate receptor antagonist LY 300164 in mice.

It was previously documented that calcium (Ca(2+)) channel inhibitors intensified the protective effects of conventional antiepileptics against electroconvulsions in mice. The aim of this study was to evaluate the effects of Ca(2+) channel inhibitors (nifedipine, nicardipine and flunarizine) on the anticonvulsant action of the new AMPA/kainate receptor antagonist, 7-acetyl-3-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxazolo[4,5-h][2,3]-benzodiazepine (LY 300164), against maximal electroshock (MES)-induced seizures in mice. Dantrolene (an inhibitor of Ca(2+)release from intracellular stores) was also included. Nifedipine (30 mg/kg) and flunarizine (15 mg/kg) raised the threshold for electroconvulsions, being ineffective at lower doses. Nicardipine (up to 30 mg/kg) and dantrolene (up to 20 mg/kg) did not affect this parameter. Flunarizine (10 mg/kg), nicardipine (20 mg/kg) and dantrolene (20 mg/kg) potentiated the efficacy of LY 300164 against MES. However, nicardipine (at 20 mg/kg) raised the free plasma concentration of LY 300164. Nifedipine (30 mg/kg), given even in a dose raising the electroconvulsive threshold, did not significantly alter the protective effect of LY 300164 against MES. Furthermore, the Ca(2+) channel agonist-BAY k-8644 (at 5 mg/kg) did not influence the protection offered by LY 300164 against MES. Finally, this Ca(2+) channel activator did not affect the enhanced efficacy of LY 300164 by Ca(2+) channel modulators. The only exception was the combination of LY 300164 with flunarizine. Combined treatment with LY 300164 and dantrolene (20 mg/kg), compared to LY 300164 alone, resulted in an impairment of motor performance in mice. Ca(2+) channel inhibitors were without effect upon this parameter evaluated in the chimney test. As shown in the passive avoidance task, LY 300164 alone (at its ED(50)) or combined with agents affecting neuronal Ca(2+) concentration did not disturb long-term memory. The present results suggest that agents preventing influx of Ca(2+) ions into neurons may enhance the protective action of LY 300164.

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers.

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.

Binding of two anthranilic acid derivatives to human albumin, erythrocytes, and lipoproteins: evidence for glafenic acid high affinity binding.

The binding of two anthranilic acid derivatives, glafenic and floctafenic acids, to human erythrocytes and plasma proteins has been investigated in vitro by equilibrium dialysis. Despite their close chemical structures it was shown that the binding of the two compounds to serum albumin, lipoproteins, and erythrocytes was dramatically different both in quality and quantity. Using various techniques including fluorometry and circular dichroism, it was shown that glafenic acid binds to the human serum albumin (HSA) warfarin/azapropazone site and that floctafenic acid binds to both warfarin/azapropazone and benzodiazepine sites. Glafenic acid is strongly bound to HSA with n = 1, k = 2.4 X 10(6) liters/mol and to erythrocytes with N = 12.4 mumol/liter, K = 1.7 X 10(6) liters/mol. Floctafenic acid is bound with a weaker affinity to HSA, n = 2, k = 0.3 X 10(6) liters/mol and to erythrocytes, N = 2900 mumol/liter and K = 0.007 X 10(6) liters/mol.

[Renal pelvis stones made of glafenic acid in two patients under prolonged treatment with analgesics (author's transl)]. / Calculs pyéliques d'acide glafénique chez deux patientes traitées de façon prolongée par des analgésiques.

Two women aged 62 and 69 years who had been taking glafenine at normal dosage over a period of 4 years developed a renal calculus. In the first case, 6 small slightly radioopaque stones were extracted by pyelotomy, presenting a crystalline surface and yellow, soft, and amorphous section. They consisted of 50% calcium oxalate, 33% glafenic acid, and 10% proteins. In the second case, pyelography showed a sizable round and radiotransparent defect in the renal pelvis. At pyelotomy, a large, soft, and greenish stone was extracted, presenting a yellow and amorphous section, without calcium, but consisting of 75% glafenic acid, and 25% proteins. Through IR spectrography, glafenine metabolites found in the stones represented 33% in our first case and 75% in our second case. Through other methods, such as UV spectrophotometry and chromatography, 26% and 61% are respectively found. The metabolites are glafenic acid and hydroglafenic acid, in an identical proportion of 9 to 1 in both cases.

Nicafenine, a new analgesic. I. Synthesis and physicochemical properties.

The synthesis of 2-[(7-chloro-4-quinolyl)-amino] benzoic acid 3-pyridine carboxamide-N-ethyl ester (nicafenine) was carried out by a new method using isatoic anhydride. The IR, NMR, MS and UV spectrophotometric studies are described, together with the characteristics of this compound.