Archive of Medical Research

[Antihypertensive drugs prescribed to patients before their first consultation in a hypertension unit: Comparison between 2001 and 2006.]

PURPOSE: To determine if trends in antihypertensive drug prescriptions by non-specialist physicians reflect evidence from clinical research. METHODS: Comparison of antihypertensive drugs prescribed to patients before they attended a hypertension clinic in 2001 and 2006, with a special consideration for thiazide diuretics in drug combinations and angiotensin converting enzyme inhibitors (ACEI) in hypertensive patients at high cardiovascular risk (diabetes or secondary prevention). RESULTS: Overall, 1072 hypertensive patients attended the hypertension clinic in 2001 (mean age 53.9 years) and 1040 in 2006 (mean age 55.6 years); both genders were equally represented. Patients already treated when they came at the consultation received a mean number of 2.24 antihypertensive drug classes in 2001 and 2.44 in 2006 (p=0.002). The prescription of three antihypertensive drug classes increased between 2001 and 2006: Calcium channel blockers from 49 % of treated patients in 2001 to 56 % in 2006 (p=0.007), angiotensin receptor antagonists from 28 to 42 % (p<0.001) and thiazide diuretics from 31 to 39 % (p=0.001). Thiazide diuretics were included in 48 % of the antihypertensive combinations in 2001 and 55 % in 2006 (p=0.02). The prescription of ACEI in patients at high cardiovascular risk remained stable around 31 %. CONCLUSION: Antihypertensive treatments were more intensive in 2006 than 2001, but thiazide diuretics remained underused in drug combinations. The prescription of ACEI did not increase in patients at high cardiovascular risk despite convincing evidence of their benefit.

Steichen O, Plouin PF.

Inserm, U872, équipe 20/laboratoire de santé publique et informatique médicale, 15, rue de l’école de médecine, 75006 Paris, France; UMR S 872, université Pierre-et-Marie-Curie-Paris-6, 75006 Paris, France; UMR S 872, université Paris-Descartes, 75006 Paris, France; Service de médecine interne, hôpital Tenon, AP–HP, 4, rue de la Chine, 75020 Paris, France; Faculté de médecine, université Pierre-et-Marie-Curie-Paris-6, 75006 Paris, France.

[Skeletal manifestations in Behçet\’s disease. A report of 79 cases.]

PURPOSE: Our aim is to describe the skeletal manifestations of Behcet\’s disease (BD) among young adults in a military population. METHODS: We conducted a retrospective study of 176 patients with BD who were followed between 1980 and 2005. All the patients fulfilled the international study group on Behcet\’s disease diagnostic criteria. RESULTS: Rheumatic manifestations were noticed in 79 out of 176 patients (45%), ranking second after the skin and mucosal manifestations of the disease. Articular manifestations were the first disease manifestation in 16.5% of the patients. Inflammatory arthralgias were the most common manifestation and observed in 81%, interesting mainly the large lower limb joints. Disease course was acute in most of the patients. Arthritis was less common: oligoarthritis (7.5%), monoarthritis (6.5%) and polyarthritis (5%). Axial involvement was also noted: spine pain in 29%, isolated sacroiliitis in 7.5%, and definite ankylosing spondylitis in 5%. CONCLUSION: Joint involvement is common in BD and could be the first manifestation of the disease. Most of the patients present with inflammatory arthralgias of the large lower limb joints. Disease course is usually favourable, spontaneously or with treatment. However, in our study population, skeletal manifestations were responsible for significant disability.

Ait Badi MA, Zyani M, Kaddouri S, Niamane R, Hda A, Algayres JP.

Service de médecine interne, hôpital militaire Avicenne, 74, boulevard de Pont-Royal, B.P. 100446, 40000 Marrakech, Maroc.

[Pseudoxanthoma elastic like syndrome associated with hemoglobinopathy: A case report?]

INTRODUCTION: We report a case of hemoglobinopathy which could be associated with a pseudoxanthoma elastic-like syndrome. EXEGESIS: We report the case of a 26-year-old male patient with sickle cell anemia for which the supra-aortic-doppler ultrasonography suggested an asymptomatic left carotid artery of 70% stenosis. The magnetic resonance imaging and angiography showed a left megadolichocarotid with plicature suggestive of pseudoxanthoma elastic or a dilatation relative to a high rate of blood explaining the acceleration speed. There was a cutaneous infiltration but other vasculopathies of neither carotide, nor cerebral, nor ocular have been discovered while they were sometimes found in pseudoxanthoma elastic-like syndrome. This acquired form is different of rare hereditary disease by a later diagnosis, a clinical expression often very incomplete and a frequent association with hemoglobinopathies. CONCLUSION: This observation shows that RMA could be necessary to perform in adults, when cervical and transcranial Doppler ultrasonography is abnormal, particularly before deciding to start long term blood transfusions. The hemoglobinopathy and pseudoxanthoma elastic-like syndrome must not be ignored because the control of cardiovascular factors reduce the risks of arterial complications.

Vuotto F, Chevrier E, Bourgeois E, Cambier N, Chevalier J, Rose C.

Service d’hématologie, université catholique de Lille, hôpital Saint-Vincent-de-Paul, groupe hospitalier de l’institut catholique de Lille, boulevard de Belfort, 59020 Lille, France.

Thiazolyl/oxazolyl formazanyl indoles as potent anti-inflammatory agents.

A series of 3-(2\’-substituted indolidene aminothiazol-4\’-yl)-2-(4-chlorophenyl) indoles (3a-3d), 3-(2\’-substituted indolidene amino oxazol-4\’-yl)-2-(4-chlorophenyl) indoles (3a\’-3d\’) and 3-[2\’-(1\’-substituted phenyl-3\’-substituted indolyl formazan-4\’-yl) thiazol-4\’-yl]-2-(4-chlorophenyl) indoles (4a-4h), 3-[2\’-(1\’-substituted phenyl-3\’-substituted indolyl formazan-4\’-yl) oxazol-4\’-yl]-2-(4-chlorophenyl) indoles (4a\’-4h\’) were synthesized and evaluated for their anti-inflammatory activity against carrageenan induced oedema in albino rats at a dose of 50mg/kg p.o. The structure of all these compounds were established on the basis of elemental and spectral (IR, (1)H NMR and mass spectral data) studies. All the compounds of this series show moderate to good activity. The most active compound of this series 3-(2\’-methyl indolidene aminothiazol-4\’-yl)-2-(4-chlorophenyl) indole (3b) is found to be the most potent and has shown higher percent of inhibition of oedema, lower ulcerogenic liability and acute toxicity than the reference drug phenyl butazone.

Singh N, Bhati SK, Kumar A.

Medicinal Chemistry Division, Department of Pharmacology, L.L.R.M. Medical College, Gargh Road, Meerut 250004, Uttar Pradesh, India.

Synthesis, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles.

The synthesis and antimicrobial activity of a new series of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazole derivatives 3-12 were described. The in vitro antimicrobial activity of the compounds was determined against some Gram-positive, Gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicated that the synthesized compounds possessed a broad spectrum of activity with MIC values 500-15.625mug/ml. In the series, the most active compound against Candida krusei and Candida albicans isolate is 8 with MIC value 31.25mug/ml. However, it is one dilution less potent than the compared fluconazole. Some of the screened compounds exhibit significant activity, having MIC value as 31.25mug/ml in Pseudomonas aeruginosa having same activity as Rifampicin. Furthermore, considering the worth of developing new antibacterial agents against drug-resistant P. aeruginosa the present study explores the structure-activity relationship analysis of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles using 3D-common features pharmacophore hypotheses approach.

Alper-Hayta S, Arisoy M, Temiz-Arpaci O, Yildiz I, Aki E, Ozkan S, Kaynak F.

Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Tandogan, Ankara, Turkey.

Specific N-terminal mutations in the human androgen receptor induce cytotoxicity.

Polyglutamine (polyQ) stretch amplification in different proteins causes neurodegenerative disease. These proteins form intracellular aggregates thought to be cytotoxic but differ in pathology and tissue specificity. Here, we demonstrate that specific sequences outside the polyQ stretch of the human androgen receptor contribute to polyQ pathology. An exchange of two N-terminal serine phosphorylation residues to alanine in the wild type androgen receptor (ARQ22dm) resulted in cytoplasmic accumulation and increased early hormone-dependent aggregation of the receptor. In a Drosophila model, the ARQ22dm was cytotoxic, and developing larvae expressing this receptor showed behavioral abnormalities and severely impaired locomotion. In contrast, the same double mutation in an androgen receptor with an extended polyQ stretch was less toxic. The response of the receptors to inhibitors of polyglutamine toxicity is altered by the amino acid exchanges suggesting that careful consideration is needed in the choice of potential therapies of disorders involving toxic polyQ species.

Funderburk SF, Shatkina L, Mink S, Weis Q, Weg-Remers S, Cato AC.

Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany.

Linking vascular disorders and Alzheimer\’s disease: Potential involvement of BACE1.

The etiology of Alzheimer\’s disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Abeta), are hallmark lesions in AD and evidence indicates that Abeta plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Abeta generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Abeta and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation.

Cole SL, Vassar R.

Northwestern University, The Feinberg School of Medicine, Department of Cell and Molecular Biology, 303 E. Chicago Avenue, Chicago, IL 60611, USA.

Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.

We have shown that immunostimulated astrocytes produce excess nitric oxide (NO) and eventually peroxynitrite (ONOO(-)) that was closely associated with the glucose deprivation-potentiated death of astrocytes. The present study shows that activated p38 MAPK regulates ONOO(-) generation from lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma)-stimulated astrocytes. LPS+IFN-gamma-induced p38 MAPK activation and ONOO(-) generation were attenuated by SB203580 or SKF-86002, specific inhibitors of p38 MAPK. ONOO(-) generation was blocked by NADPH oxidase inhibitor, diphenyleneiodonium chloride, and nitric oxide synthase (NOS) inhibitor, Nomega-nitro-l-arginine methyl ester, suggesting both enzymes are involved in ONOO(-) generation. Inhibition of p38 MAPK suppressed LPS+IFN-gamma-induced NO production through down-regulating inducible form of NOS expression. It also suppressed LPS+IFN-gamma-induced NADPH oxidase activation and eventually, the inducible form of superoxide production. Transfection with dominant negative vector of p38alpha reduced LPS+IFN-gamma-induced ONOO(-) generation through blocking both iNOS-derived NO production and NADPH oxidase-derived O(2)(-) production. Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.

Yoo BK, Choi JW, Shin CY, Jeon SJ, Park SJ, Cheong JH, Han SY, Ryu JR, Song MR, Ko KH.

Department of Pharmacology, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.

The endogenous CCK mediation of electroacupuncture stimulation-induced satiety in rats.

A major satiety hormone, cholecystokinin (CCK) is well known to be released by electroacupuncture (EA) stimulation at certain body sites which elicits profound psychophysiological responses. Previous clinical and animal studies have shown that EA stimulation reduces food intake and body weight in both normal and obese subjects. The aim of the present study was to elucidate the satiety effect of EA stimulation and its mechanism related to CCK in rats. Here we show that EA stimulation at \”Zusanli\” (ST36) acupoint significantly reduced 30-min and 60-min food intake in 48-h fasted Sprague-Dawley rats, and such effect was reversed by a lorglumide (CCK-1 receptor antagonist, 10mg/kg, i.p.) pretreatment. The ST36 EA stimulation-induced satiety was not observed in CCK-1 receptor knockout, Otsuka Long-Evans Tokushima Fatty rats, but in their controls, Long-Evans Tokushima Otsuka rats. Subdiaphragmatic vagotomy also blocked the satiety effect of ST36 EA stimulation in Sprague-Dawley rats. These results suggest that ST36 EA stimulation elicits satiety in rats and this is mediated by the endogenous CCK signaling pathway.

Kim SK, Bae H, Lee G, Jeong H, Woo HS, Han JB, Kim Y, Lee H, Shin MK, Hong MC, Jin YH, Min BI.

Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; BK21 Oriental Medical Science Center, Kyung Hee University, Seoul 130-701, Republic of Korea.

Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5.

The UII and urotensin II-related peptide (URP) genes belong to the same superfamily as the somatostatin gene. It has been previously shown that somatostatin activates the UII-receptor (UTR). In contrast, the possible interaction between UII and URP and somatostatin receptors has remained scarcely analyzed. Herein, we have investigated the effects of UII and URP on cell proliferation and free cytosolic Ca(2+) concentration ([Ca(2+)](i)) in CHO-K1 cells stably expressing the porcine somatostatin receptor subtypes sst2 and sst5. Results show that both UII and URP induce stimulation of cell proliferation mediated by sst2 receptors and UII provokes inhibition of cell proliferation mediated by sst5 receptors. UII and URP also provoked an increase of [Ca(2+)](i) in both sst2- and sst5-transfected cells. Together, our present data demonstrate that UII and URP directly activate sst2 and sst5 and thus mimic the effect of somatostatin on its cognate receptors.

Malagon MM, Molina M, Gahete MD, Duran-Prado M, Martinez-Fuentes AJ, Alcain FJ, Tonon MC, Leprince J, Vaudry H, Castaño JP, Vazquez-Martinez R.

Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14014 Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición CB06/03, Instituto de Salud Carlos III, Spain.