Memory recuperative potential of rifampicin in aluminum chloride-induced dementia: role of pregnane X receptors.

The present study has been designed to investigate the potential of rifampicin [Pregnane X receptors (PXR) agonist] in experimental dementia. Aluminum chloride (AlCl3) [100mg/kg, p.o. for 42days] was administered to Wistar rats (n=6) to induce dementia. Morris water maze (MWM) test was used to assess learning and memory and rota rod test was used to assess locomotor activity of the animals. A battery of biochemical tests and histopathological evaluation using hematoxylin and eosin (H&E) and Congo Red stains were performed at the end of the study. AlCl3-treated rats demonstrated impaired cognition and locomotor activity on MWM apparatus and rota rod test, respectively. These animals exhibited a significant rise in acetylcholinesterase (AChE) activity (138±3.6), thiobarbituric acid reactive species (TBARS) level (15±1.6), nitrite (56±2.4) level and myeloperoxidase (MPO) activity (4.1±0.9) along with decline in reduced glutathione (GSH) level (22±1.3) in comparison to the control group (p<0.05). Further the H&E and Congo Red-stained cerebral cortex sections of AlCl3-treated rats indicated severe neutrophilic infiltration and amyloid deposition. Rifampicin-treated AlCl3-rats exhibited significant attenuation in memory deficits, biochemical parameters like AChE activity (33±1.4), TBARS level (4.1±1.0), nitrite level (64±2.6), MPO activity (3.6±1.0) and GSH level (53±2.4) along with improved histopathological alterations and locomotor activity when compared with AlCl3-treated rats (p<0.05). Combined administration of ketoconazole (a PXR antagonist) and rifampicin to AlCl3-treated animals reversed the rifampicin-induced protective effects. Therefore the results obtained from the study indicate a defensive role of rifampicin in memory dysfunction which may probably be due to its anti-cholinesterase, anti-oxidative, anti-inflammatory and amyloid lowering effects. Moreover the study speculates the potential of PXR in the pathophysiology of dementia which is subject to further evaluation.

An update on non-peptide angiotensin receptor antagonists and related RAAS modulators.

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.

Retrospective validation of a surveillance system for unexplained illness and death: New Haven County, Connecticut.

OBJECTIVES: This study investigated retrospective validation of a prospective surveillance system for unexplained illness and death due to possibly infectious causes. METHODS: A computerized search of hospital discharge data identified patients with potential unexplained illness and death due to possibly infectious causes. Medical records for such patients were reviewed for satisfaction of study criteria. Cases identified retrospectively were combined with prospectively identified cases to form a reference population against which sensitivity could be measured. RESULTS: Retrospective validation was 41% sensitive, whereas prospective surveillance was 73% sensitive. The annual incidence of unexplained illness and death due to possibly infectious causes during 1995 and 1996 in the study county was conservatively estimated to range from 2.7 to 6.2 per 100,000 residents aged 1 to 49 years. CONCLUSIONS: Active prospective surveillance for unexplained illness and death due to possibly infectious causes is more sensitive than retrospective surveillance conducted through a published list of indicator codes. However, retrospective surveillance can be a feasible and much less labor-intensive alternative to active prospective surveillance when the latter is not possible or desired.