Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score.

OBJECTIVES: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. METHODS: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. RESULTS: Patients were divided into three similarly sized groups (CPE ≤ 1, CPE between 1.5 and 2.5, and CPE ≥ 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. CONCLUSION: These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.

Effects of low density and high density lipoproteins isolated from non-insulin dependent diabetic patients on prostaglandin secretion by mouse macrophage cell line P388D1.

We have previously shown that low-density (LDL) and high-density (HDL) lipoprotein from healthy subjects can promote in vitro prostaglandin (PG) release by murine macrophages. In this pilot study, we have measured PG production induced by lipoproteins of six diabetic patients with poor metabolic control, compared to five healthy controls. Plasma lipoprotein levels were similar in both groups. Lipoprotein fractions were purified by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and PG quantified by HPLC. In presence of LDL, in control subjects, there was an increase in total PG production, mainly due to thromboxane B2 (TxB2). In diabetic patients, the secretion pattern was similar. In presence of HDL, in control subjects, total PG secretion was also increased, but it was balanced between TxB2 and prostacyclin. In diabetic patients, at low HDL concentration (10 mg/l) the secretion was mainly due to TxB2, while at higher HDL concentrations (100 mg/l). the secretion was balanced between TxB2 and prostacyclin. Comparison of means of areas under curve for the two groups studied showed that LDL increased all PG secretion in diabetic patients compared to controls (P < 0.05 for PGF2alpha), while HDL increased all PG secretion in controls compared to diabetic patients, except PGF2alpha. Our work suggests a key role of LDL in TxB2 secretion in diabetic patients, which is a major proaggregant and vasoconstrictive agent. There was also an increased secretion of all PG in diabetic patients.

Distribution of salicylate in pigmented rabbit ocular tissues after application of a prodrug, sodium monomethyl trisilanol orthohydroxybenzoate: in vivo and ex vivo studies.

SMB (sodium monomethyl trisilanol orthohydroxybenzoate) is an organic complex of silicium and salicylate and the main component of a collyrium used in lens transparency abnormalities. Biotransformation and penetration of salicylate in the whole eyeball have been investigated in vivo after repeated instillations of those 14C-radiolabeled eyedrops. We also studied more accurately the salicylate diffusion within the lens under ex vivo conditions. In vivo experiments demonstrated that 8 to 48 hours after the last instillation, radioactivity was detectable in most tissues and remained stable except in the chorioretina. The following gradient of distribution was observed: conjunctiva > cornea > iris-ciliary body > chorioretina > lens > vitreous body > aqueous humor >> plasma and blood. The diffusion of the radiolabeled compound in lens fibres was low, but a more important retention was observed in lens capsule. Though salicylate-metabolizing activities have been demonstrated in ocular tissues, no biotransformation could be detected under our experimental conditions. The lens SA-biotransformation activity was reported to be low and we can most probably consider that, in our ex vivo pharmacokinetic study, the lens metabolite amounts were negligible compared with the salicylate levels. Under such conditions, results showed that the salicylate reached a steady-state between 6 and 12 hours of incubation, characteristic of a passive diffusion mechanism. Quantitative image analysis of lens section autoradiograms revealed a more intense labeling of the anterior part of the lens and suggests that the lens epithelium may facilitate the salicylate diffusion. Furthermore, renal excretion is important since 40% of the administered eyedrops were eliminated during the study period.

Inhibition of preretinal proliferation by free radical scavengers in an experimental model of tractional retinal detachment.

An original model of experimental proliferative vitreoretinopathy consisting of an intravitreal injection of 10(7) human platelets and 1 IU of hyaluronidase was developed in pigmented rabbits. One group of 11 eyes served as non-treated controls. Two other groups of 11 eyes each received Ginkgo Biloba extracts which are known free radical scavengers (EGb761, Ipsen, France), given orally in two doses, 50 mg kg-1 day-1 and 100 mg kg-1 day-1 respectively, from the day after the platelet injection to the end of the first month. The fourth group (11 eyes) was intravenously injected with a unique dose of 15000 U kg-1 of superoxide dismutase the day after platelet injection. All animals were ophthalmoscopically examined in a masked fashion twice a week for 1 month and killed at the end of the experiment for histological analysis. Vitreoretinal proliferation was graded according to a six-stage classification. The non-treated eyes showed a high rate of retinal detachment (11/11 eyes), with a mean final score of 3.91 +/- 0.94. Histologic examinations consistently showed retinal retraction by fibrocellular preretinal membranes spreading to both surfaces of the retina as well as preretinal neovascularization. Many cells positively reacted with anti-cytokeratin or anti-vimentin monoclonal antibodies. All three groups of treated eyes showed significantly lower scores of vitreoretinal proliferation at almost each time point of examination. At the end of the study, five retinal detachments were found in the EGb761 group at 50 mg kg-1 day-1 (mean final score 2.45 +/- 1.37), only one in the group receiving 100 mg kg-1 day-1 (mean score 1.64 +/- 1.03), and one in the SOD treated eyes. The lowest mean score found at day 28 was observed in the group receiving SOD (1.36 +/- 1.43), although this group presented during the first 3 weeks with an intense vitreous and sometimes anterior chamber inflammation. Statistical comparison between treatments did not show significant differences at most time points of the study. These results demonstrate that antioxidants may efficiently prevent preretinal proliferation, in clinicopathological entities where free radicals had not yet been shown to play a direct pathogenetic role. They are also among the first attempts for inhibiting preretinal proliferations with non-cytotoxic agents and using a non-ocular route.

Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir.

PURPOSE: The retinal toxicity of single and repeated intravitreal injections of foscarnet was investigated. In addition, the effects of a combination of foscarnet and ganciclovir were studied, and a pharmacokinetic study to determine the ocular pharmacokinetics of foscarnet after intravitreal injection was carried out. METHODS: Forty rabbits (both albino and pigmented) were used in this study. The electroretinographic (ERG) a-waves and b-waves and oscillatory potentials (OP) were used as as indicators of retinal toxicity. Potential toxicity was also assessed by ophthalmoscopy and histologic studies (light and electron microscopy). RESULTS: The a-wave and b-wave were not deteriorated with 2.4 mg foscarnet after single or repeated injections. The OP remained unchanged. There was no ERG change after intravitreal injection of a combination of both drugs. No evidence of retinal toxicity was observed by indirect ophthalmoscopy in any case. Light and electron microscopy on semithin sections of retina failed to demonstrate any adverse effects, and showed normal organization and cytoarchitecture of all the layers of the retina without evidence of cytopathology. The ocular pharmacokinetics of foscarnet determined by noncompartmental analysis showed a 34-hour terminal elimination half-life and an apparent volume of distribution of 1.9 ml. CONCLUSIONS: Based on these results, high doses of foscarnet were not judged toxic to the rabbit retina, with single or repeated injections. Moreover, concomitant injection of the two drugs did not induce any retinal toxicity. These findings suggest that when systemic treatment is to be stopped in patients with AIDS for toxic side effects, either ganciclovir or foscarnet may be used intravitreally as an alternative. Because a combination of the two drugs has been shown to be synergistic, both ganciclovir and foscarnet might be simultaneously injected into the vitreous cavity to block progression of cytomegalovirus retinitis.

Drugs designed to maintain the transparence of the ocular lens.

Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD-5467, CT-112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti-oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent, in vitro, the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rheumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies are given.

Central nervous system control of intraocular pressure.

Normal intraocular pressure (IOP) is the result of an equilibrium between aqueous humor (AH) production, AH outflow and episcleral venous pressure. Most available antiglaucoma agents produce their effects by interacting with autonomic mechanisms (beta-blockers, epinephrine or parasympathomimetics). In contrast, the role of the central nervous system (brain and nerves) in the regulation of IOP remains unclear in view of the complex haemodynamic, metabolic or hormonal changes which occur under experimental conditions. In this paper, we discuss a basic understanding of the anatomic and physiological relationships between central nervous system and IOP and describe how the brain can affect functions in ciliary body and trabeculum meshwork.

Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: possible implications in pathogenesis of atherosclerosis.

Macrophages have been shown to play a key-role in the development of atherosclerotic lesions. Monocyte attraction and activation in the arterial wall lead to foam cell formation, cholesterol accumulation and secretion of inflammation mediators. Among macrophage secretions, prostacyclin and thromboxane are prostaglandins involved in the regulation of coagulation and vascular permeability. In this study, we have evaluated the effects of human native low-density and high-density lipoproteins on macrophage prostaglandin production (P388D1 mouse cell line). Lipoprotein fractions were purified from venous blood of healthy volunteers by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and prostaglandins quantified by high-performance liquid chromatography. Our technique allows the determination of the main classes of prostaglandins. In the presence of low-density lipoproteins, time-course study showed an increase in total prostaglandin production within 10 min (50 times basal secretion level). This increase was dose-dependent. A steady-state was obtained at 20 mg protein LDL/1. Stimulation of thromboxane B2 and prostacyclin was predominant, with a main effect on the proaggregant thromboxane. Production of the proinflammatory PGF2 alpha and the immunoregulatory PGE2 was lower. In the presence of high-density lipoproteins, P388D1 cells also increased their total prostaglandin secretion at 30 min, in a dose-dependent manner. This increase was directly related to a stimulation of prostacyclin, with no significant effect on thromboxane. Our results demonstrate that normal low-density lipoproteins can stimulate macrophage prostaglandin secretions, with putative deleterious effects on the arterial wall, in particular thrombus formation. On the other hand, high-density lipoproteins, by mainly stimulating prostacyclin, could theoretically have a beneficial influence.

Physiological roles of dopamine and neuropeptides in the retina.

The retina is a highly complex nervous tissue that converts light into patterns of electrical action potentials in order to process visual information. To carry out its function as a transducer and processor of visual information, the retina must be structurally and biochemically organized to send a coherent signal to the visual areas of the brain. In recent years, a number of biologically active substances have been demonstrated to be located within neurons in the retina. Most of them are thought to be involved in the modulation of the signal and its transmission to the brain through the optic nerve. The present paper attempts to summarize the immunocytochemical distribution and physiology of some neuronally localized substances in the mammalian retina, namely dopamine and neuropeptides.

Growth factors in vitreous and subretinal fluid cells from patients with proliferative vitreoretinopathy.

Mechanisms accounting for the development of proliferative vitreoretinopathy (PVR) in patients with rhegmatogenous retinal detachment remain poorly understood. In a previous study, we found the presence of various growth factors in preretinal membranes that were surgically removed from patients with PVR. The present immunohistological study was undertaken in intravitreal and subretinal fluid cells from patients suffering from PVR in various stages of development, in order to seek the presence of 4 growth-promoting factors for retinal pigment epithelial cells: acidic fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor type I (IGF-I) and transforming growth factor-beta (TGF-beta). Results were quite similar in vitreous and subretinal fluid. Acidic FGF was found in all vitreous and subretinal specimens, in 30-100% of the examined cells. Immunoreactivity for EGF could be found in 53% of intravitreal cells and 69% of subretinal fluid cells. Positive cells were seen in all vitreous specimens and in all but 1 of the subretinal fluid specimens. IGF-I-containing cells were present in 13 of 15 vitreous specimens and in 18 of 20 subretinal fluid samples (mean percentages of reactivity in positive specimens 70% and 78%, respectively). In contrast, TGF-beta 1 reactivity was found in only 8 of 15 vitreous specimens and in 11 of 20 subretinal samples. Mean percentages of reactive cells were 30% and 50%, respectively. These results suggest that several growth factors could be involved in the proliferation and migration of retinal pigment epithelial cells during the course of PVR.(ABSTRACT TRUNCATED AT 250 WORDS)

MHC class II antigen expression by ocular cells in proliferative diabetic retinopathy.

An immunohistological study was performed on ciliary biopsies of the pars plana obtained surgically in 10 patients suffering from diabetic retinopathy and on 15 surgical specimens of pre-retinal neovascularized membranes. Using immunofluorescence and immunoperoxidase procedures, linear deposits of IgG, IgA and complement components were found in the 8 pars plana from patients with proliferative diabetic retinopathy, at the basal pole of the pigment epithelial cells and within the stroma. In contrast, these deposits were absent from normal pars plana and from the cases of background retinopathy. Moreover, pigment and non-pigment epithelial cells were found to express HLA DR and DQ determinants, in six of the eight patients with proliferative retinopathy. Immunohistological examination of pre-retinal membranes showed deposition of immunoglobulins and complement components within the connective stroma and along the new blood vessels. Endothelial cells of the newly formed vascular walls strongly expressed class II antigens on their membrane, as well as scattered stromal cells. As neither pigment epithelial cells nor retinal vascular endothelial cells normally express class II determinants, our results suggest the involvement of immunological phenomena in intraocular proliferative diseases and eventual interactions between the immune system and peptide growth factors. However, whether or not this immune reaction plays a role in the initiation or extension of intra-ocular proliferation remains to be determined.

Clinical pharmacology of nicardipine in liver transplant patients.

Slow calcium channel antagonists are widely used among transplanted patients suffering from hypertension, although some of them tend to reduce hepatic blood flow. The aim of our study was to determine the pharmacological properties of nicardipine in transplanted patients with hypertension. Ten hours after liver transplantation, six patients (three men, three women) received 5 mg of intravenous nicardipine to prevent high blood pressure during intensive care. Prior to the administration and during the study (at the completion of the infusion, 3, 5, 10, 15, 20, 30, 45, and 60 min after infusion), the systemic and splanchnic parameters were measured (Swan Ganz catheter). Blood samples were drawn simultaneously from radial artery and free hepatic veins, in order to obtain the hepatic extraction of nicardipine. The hepatic extraction ratio was around 70% for the first 3 min, then decreased and remained stable thereafter, around 45%, showing a non linear first-pass metabolism pattern. Plasma hepatic clearance of nicardipine (699-850 ml/min) was close to total plasma clearance throughout the study (978 +/- 222 ml/min, from 71 to 87%) and half of the estimated hepatic plasma flow values at the same times (1467-1770 ml/min, from 44 to 51%). No statistically significant changes were observed in cardiac output and hepatic blood flow during the study, although there was a decrease in mean arterial blood pressure from 87 +/- 6 mmHg baseline level to 76 +/- 3 mmHg, 60 min after administration. Nicardipine chlorhydrate seems to be appropriate in post operative liver transplant patients when blood pressure must be decreased. Nicardipine safely lowers peripheral resistance, and does not induce changes in hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Is verapamil also a non-selective beta blocker?

Verapamil is a calcium channel blocker widely used as an antihypertensive agent, and its pharmacological effects may partly be due to some degree of beta blockade. In order to evaluate the changes occurring in beta-2 adrenoceptor density, 40 patients with mild to moderate hypertension received verapamil 240 mg (once a day) or captopril 20 mg (twice a day) during 30 days, in a double-blind randomized study, after a placebo run-in period. The lymphocytic membrane beta-2 adrenoceptor density (Bmax) was determined before the administration of active drugs and after a 15-day treatment. After a month of treatment, most patients showed a marked reduction of their diastolic blood pressure: from 98.2 +/- 3.2 mmHg to 81.2 +/- 4.0 mmHg (p < 0.05), in the verapamil group, and from 95.0 +/- 6.0 mmHg to 82.5 +/- 4.8 mmHg (p < 0.05) in the captopril group. After 15 days of treatment, verapamil induced an up-regulation of beta-2 adrenoceptors from 39.5 +/- 8.3 fmol/mg protein to 58.5 +/- 12.0 fmol/mg protein (p < 0.05), whereas the Bmax in the captopril group did not significantly change. No significant change occurred in the two dissociation constants. This up-regulation phenomenon, common among beta-2 blockers, supports the hypothesis of verapamil's beta blockade potency.

[Evaluation of anti-atheromatous properties of calcium channel inhibitors]. / Evaluation des propriétés antiathéromateuses des inhibiteurs calciques.

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

Acute arsenic intoxication: forensic and toxicologic aspects (an observation).

The authors report on an acute suicidal arsenic intoxication (di-arsenic-trioxide). Death can occur one week after ingestion, despite intensive care. The forensic, anatomopathological and toxicologic aspects are reported. Forty titrations are realized at the level of the biologic fluid in viscera, by absorption spectrophotometry. These data are compared with those in standing literature, especially with the rates determined in normal subjects, following simple environmental impregnation.

[Gingival hyperplasia secondary to the use of calcium antagonists: analysis]. / Les hyperplasies gingivales secondaires à la prise d'antagonistes calciques: mise au point.

Calcium antagonists are drugs restricting transmembrane calcium delivery. They possess a wide range of action against vasoconstriction and spastic reactions and were therefore initially recommended for the treatment of angina pectoris. With the increasing number and classes of calcium antagonists new therapeutic indications have emerged. Cases of gingival hyperplasia associated with their use are repeatedly reported, therefore the question deserves to be restated. The aim of the present study was to discuss the clinical, pathologic and pathogenetic features bases on an investigation carried out in a Department of Cardiology, on a case observation and on review of published cases in the international literature.

Retinal dopaminergic receptor affinity and ocular pharmacokinetic profile of piribedil.

Binding studies on retinal dopamine receptors have revealed the existence of both D1 and D2 receptors. Human retina micro-autoradiographs confirm the distribution of dopaminergic receptors in the plexiform layers. Piribedil, a dopaminergic agonist, is able to bind to D2 receptors, while its metabolite (S584) preferentially displaces D1-specific radioligands. These results demonstrate that piribedil has a dopamine-like pharmacological profile including direct interaction with receptors. When instilled into the rabbit eye, piribedil penetrates rapidly and accumulates in the pigmented epithelia--the iris ciliary body and chorioretina--before being rapidly cleared. Macro-autoradiographs confirm this distribution and show the levels to be compatible with the affinity of piribedil for retinal dopaminergic receptors.

Immunohistological study of subretinal membranes in age-related macular degeneration.

An immunohistological study was performed on 6 specimens of subretinal membranes obtained surgically from patients suffering from age-related disciform macular degeneration. using immunoperoxidase procedures, we found in those membranes large amounts of IgG, IgA and IgE as well as C1q, C3c and C3d complement components diffusely distributed in the connective stroma and within the new blood vessel walls. Moreover, subretinal membranes contained numerous isolated HLA-DR- and -DQ-expressing cells, including glial, pigment epithelial and vascular endothelial cells. Monoclonal antibodies to immunocompetent cells disclosed only rare B and natural killer lymphocytes or suppressor-cytotoxic T cells, as well as some monocytes. These results show that immune phenomena are involved in proliferative changes associated with subretinal neovascularization. In addition, they suggest there are interactions between the immune system and peptide growth factors.