Use of natalizumab in multiple sclerosis: current perspectives

ABSTRACT

Introduction: Natalizumab is an efficacious monoclonal antibody approved for use in relapsing-remitting multiple sclerosis (RRMS). Multiple studies have demonstrated reduced relapse rate, decreased disability progression and prolonged disease-free intervals with natalizumab use. However, natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), thus restricting its widespread use with populations at high risk for developing PML. Recently, the effect of natalizumab in secondary-progressive (SPMS) population has been explored.

Areas covered: This review highlights the pathophysiology behind disease progression in MS and summarizes various attributes of natalizumab including: its pharmacological properties and global economic impact, results of clinical efficacy studies, its role in SPMS, pregnancy and its adverse events profile including PML and discontinuation protocols.

Expert opinion: Despite an established role in reducing RRMS disease activity, natalizumab has found limited use in SPMS due to insufficient evidence of efficacy. Current disease-modifying therapies exert modest overall benefit in SPMS owing to its complex pathophysiology, higher prevalence of comorbidities and increased PML risk with age and lack of reliable outcome measures. Finding more appropriate MRI and clinical outcome measures is quintessential for designing future randomized trials and possibly exploring primary neuroprotective agents for treating SPMS.     

Expression of the CA1 determinant by carcinomas and by non-malignant epithelial cells in oral lesions

The expression of the Ca antigen was investigated in 5 groups of oral lesions comprising 7 squamous cell carcinomas, 2 pre-invasive carcinomas, 7 lesions of types believed to predispose to carcinoma, 19 lesions of types that do not predispose to carcinoma and 5 biopsies of normal oral mucosa. Using an indirect immunoperoxidase method, the neoplastic epithelium reacted positively with the Ca1 antibody in only 4 out of 7 oral squamous cell carcinomas and the reaction varied between the specimens as to the intensity and number of positively stained cells. Several benign oral lesions specifically bound the Ca1 antibody in areas of epithelium showing infiltration with inflammatory cells. These lesions comprised 5 fibrous epulides, 1 pyogenic granuloma, 1 denture-induced hyperplasia and 1 non-diagnostic ulcer. We conclude that the Ca1 antibody is not sufficiently specific for the carcinoma to be of value in the diagnosis of malignant and premalignant lesions of the oral mucosa.     

Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners

A library of 52 pentamidine congeners in which the flexible pentyldioxy linker in pentamidine was replaced with various restricted linkers was tested for in-vitro activity against two Plasmodium falciparum strains and Leishmania donovani. The tested compounds were generally more effective against P. falciparum than L. donovani. The most active compounds against the chloroquine-sensitive (D6, Sierra Leone) and -resistant (W2, Indochina) strains of P. falciparum were bisbenzamidines linked with a 1,4-piperazinediyl or 1, 4-homopiperazinediyl moiety, with IC50 values (50% inhibitory concentration, inhibiting parasite growth by 50% in relation to drug-free control) as low as 7 nM based on the parasite lactate dehydrogenase assay. Seven piperazine-linked bisbenzamidines substituted at the amidinium nitrogens with a linear alkyl group of 3-6 carbons (22, 25, 27, 31) or cycloalkyl group of 4, 6 or 7 carbons (26, 32, 34) were more potent (IC50<40 nM) than chloroquine or pentamidine as anti-plasmodial agents. The most active anti-leishmanial agents were 4,4'-[1,4-phenylenebis(methyleneoxy)]bisbenzenecarboximidamide (2, IC50 approximately 0.290 microM) and 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl] piperazine (44, IC50 approximately 0.410 microM), which were 10- and 7-fold more potent than pentamidine (IC50 approximately 2.90 microM). Several of the more active anti-plasmodial agents (e.g. 2, 31, 33, 36-38) were also potent anti-leishmanial agents, indicating broad antiprotozoal properties. However, a number of analogues that showed potent anti-plasmodial activity (1, 18, 21, 22, 25-28, 32, 43, 45) were not significantly active against the Leishmania parasite. This indicates differential modes of anti-plasmodial and anti-leishmanial actions for this class of compounds. These compounds provide important structure-activity relationship data for the design of improved chemotherapeutic agents against parasitic infections.     

Capisterones A and B, which enhance fluconazole activity in Saccharomyces cerevisiae, from the marine green alga Penicillus capitatus

A whole-cell-based assay using Saccharomyces cerevisiae strains that overexpress Candida albicans CDR1 and MDR1 efflux pumps has been employed to screen natural product extracts for reversal of fluconazole resistance. The tropical green alga Penicillus capitatus was selected for bioassay-guided isolation, leading to the identification of capisterones A and B (1 and 2), which were recently isolated from this alga and shown to possess antifungal activity against the marine pathogen Lindra thallasiae. Current work has assigned their absolute configurations using electronic circular dichroism and determined their preferred conformations in solution based on detailed NOE analysis. Compounds 1 and 2 significantly enhanced fluconazole activity in S. cerevisiae, but did not show inherent antifungal activity when tested against several opportunistic pathogens or cytotoxicity to several human cancer and noncancerous cell lines (up to 35 microM). These compounds may have a potential for combination therapy of fungal infections caused by clinically relevant azole-resistant strains.     

Computer simulation and validation of the Archimedes Lever hypothesis as a mechanism for aortic isthmus disruption in a case of lateral impact motor vehicle crash: a Crash Injury Research Engineering Network (CIREN) study

OBJECTIVES: Can aortic isthmus disruption occurring in a lateral motor vehicle crash (LMVC) be explained by the Archimedes Lever Hypothesis, where the intrathoracic aorta, super-pressurized by the thoracic impact force, functions as a rigid lever system? The long arm of this lever system is the proximal aorta-aortic arch, the short arm is the aortic isthmus fixed distally at the descending aorta, and the fulcrum is at the great vessels, especially the left subclavian artery. METHODS: The theory was tested by a simulation technique using a computer-based finite element numerical model system. This simulation model included the dynamics of the crashed vehicles, the direction of force impact, and the structure of the thorax and intrathoracic viscera, including the entire intrathoracic aorta. The specific patient whose data were entered into the model was chosen from a study of 34 LMCV aortic injuries (AIs). The model was constrained by patient and vehicle data from this surviving case. RESULTS: Three sequential lateral thoracic levels impacted by the vehicle side structures were selected. At each level, the maximum mean intra-aortic pressure was 50 to 100 ms after impact, the structure dynamics of the actual crash and the resultant vehicle deformation were simulated; only when the lateral impact was induced in a transverse plane including the first 4 ribs at the level of the aortic arch/isthmus system, with intra-aortic pressures from 200 to 500 mm Hg, were AI-compatible stresses and deformations in the aortic wall achieved at the isthmus. CONCLUSIONS: In LMVC AI, the simulation suggests that the aorta functions as an Archimedes Lever System in which the magnified force mediated by the long lever arm produces sufficient strain on the short lever arm to rupture the aorta at the isthmus.     

Evaluation of Alstonia scholaris leaves for broncho-vasodilatory activity

The present study demonstrates that the ethanol extract of Alstonia scholaris (Apocynaceae) leaves induced pronounced bronchodilatory activity in anaesthetized rats with the probable involvement of prostaglandins. However, in vitro preparations of guinea-pig trachea did not confirm this property, indicating that bronchodilation is not due to the direct tracheal smooth muscle relaxation. The vasodilatory activity of the extract was independent of adrenergic or muscarinic receptors or prostaglandins but was mainly via endothelial-derived relaxing factor, nitric oxide. The extract inhibited the spontaneous movements of rabbit jejunum and contractile effects of acetylcholine and histamine on guinea-pig ileum. Additionally, the extract caused marked reduction of barium chloride-, potassium chloride- and calcium chloride-induced contraction on guinea-pig ileum and pulmonary artery, implying a direct interference of plant extract with the influx of calcium ions into cells. However, the extract has no detectable effect on mobilization of intracellular calcium. These results coupled with the in vivo effects of ethanol extract reveal that the Alstonia scholaris leaves possess broncho-vasodilatory activity mediated presumably by prostaglandins, calcium antagonism and endothelium-derived relaxing factor(s).     

Dead sea water intoxication

ABSTRACT: Near drowning in the Dead Sea is associated with both respiratory manifestations and severe electrolyte abnormalities. It is often difficult to distinguish between the contributions of sea water aspiration or ingestion to clinical manifestations. We present a unique case of accidental ingestion of a large amount of Dead Sea water through a gastrostomy tube in which a patient with familial dysautonomia presented with severe electrolyte disturbances. Forced diuresis with large amounts of intravenous fluids resulted in clinical and biochemical improvement. Full recovery was achieved after 2 days of treatment.