An in vitro analysis of aminoglycoside corneal epithelial toxicity

We evaluated the cytotoxicity of four aminoglycoside agents (neomycin, gentamicin, tobramycin, and amikacin) using an in vitro confluent rabbit corneal epithelial cell culture model. Primary corneal epithelial cell cultures were established and cells replated at 2 x 10(4) cells/2 cm2 well. After 48 hours either vehicle or an antibiotic was added at varying concentrations, each for 5, 30, or 60 minutes. 3H-thymidine was added immediately after drug removal and incorporation was measured 8 hours after drug or vehicle exposure. Comparisons of each drug to vehicle were expressed as % inhibition of control culture values. At the 5-minute exposure time tobramycin and amikacin showed no significant inhibition at any concentration, whereas neomycin and gentamicin showed significant inhibition at 6 mg/ml and 3.5 mg/ml or greater concentrations, respectively (p less than 0.05). At 30- and 60-minute exposure times all agents demonstrated significant inhibition at all tested concentrations in a non-dose dependent fashion (p less than 0.05). These in vitro data corroborate the animal and limited clinical data available for the aminoglycosides. Based on these toxicity profiles, tobramycin appears to be the topical agent of choice in the treatment of susceptible bacterial keratitis.     

Role of cholinergic inputs to the medial preoptic area in regulation of sleep–wakefulness and body temperature in freely moving rats

The medial preoptico-anterior hypothalamic area receives adrenergic as well as cholinergic inputs. Independent studies showed that both these inputs influence sleep, wakefulness and body temperature. The role of the adrenergic inputs was studied earlier. The role of cholinergic inputs is reported here. The cholinergic agonist, carbachol, and antagonist, scopolamine, were injected into this area during the day and the night in freely moving rats and the effects on sleep–wakefulness and body temperature studied. It was observed that carbachol induced wakefulness accompanied by a fall in body temperature while scopolamine induced an opposite effect, i.e. sleep accompanied by an increase in body temperature. This suggested that the cholinergic input into the medial preoptic area is spontaneously active in regulating sleep–wakefulness and body temperature and this regulation is mediated through muscarinic receptors present in this area. The results also suggest that, contrary to the action of adrenergic inputs (which have a dissociated effect on sleep–wakefulness and body temperature), the cholinergic input is unlikely to have a dissociated effect on those functions. © 1997 Elsevier Science B.V. All rights reserved.     

Multiple Myeloma—Effect of Induction Therapy on Transplant Outcomes

BackgroundPatients with multiple myeloma (MM) aged ≤ 65 to 70 years, with a good Eastern Cooperative Oncology Group performance status and no major comorbid conditions, are considered potential candidates for autologous stem cell transplant (ASCT) and will be treated with novel agent-based induction therapy for 4 to 6 cycles before ASCT.Patients and MethodsWe analyzed the data from 326 patients with MM who had received novel agent-based induction before ASCT at our center to evaluate the effect of induction therapy on ASCT response, stem cell mobilization, engraftment characteristics, and survival. The median age was 52 years (range, 29-72 years), 216 patients were men (66.3%), 32.7% had stage III using the Revised Multiple Myeloma International Staging System, and 15.8% had high-risk cytogenetics. Of the 326 patients, 75 (23.0%) had undergone ASCT in second remission after salvage therapy for relapse. Also, 194 patients (59.5%) had received doublet induction therapy and 132 (40.5%) had received triplet induction therapy.ResultsTriplet-based induction therapy was superior to doublet-based therapy for response (95.4% vs. 84.02%; P < .003), stem cell mobilization (CD34⁺ ≥ 2 × 10⁶/kg; 88.6% vs. 76.8%; P < .005), and lower 100-day transplant-related mortality (P < .001). The ≥100 day post-ASCT overall response (97.4% vs. 91.7%; P = .124) and complete response (72.5% vs. 68.0%; P = .38) rates were similar. At a median follow-up of 62.5 months, the overall survival (97.5 months vs. 100.0 months; P = .606) and progression-free survival (54.5 months vs. 57 months; P = .515) were similar between the triplet and doublet induction groups.ConclusionAn initial response (chemosensitivity) to induction therapy will prepare patients better for subsequent consolidation therapy and ASCT, leading to favorable outcomes.     

Can homeopathic arsenic remedy combat arsenic poisoning in humans exposed to groundwater arsenic contamination?: a preliminary report on first human trial

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans.     

Chemotypical variations in Withania somnifera lead to differentially modulated immune response in BALB/c mice

Withania somnifera (Ashwagandha) is a plant with known ethnomedicinal properties and its use in Ayurvedic medicine in India is well documented. The present investigation reports on immunomodulatory efficacy of aqueous-ethanol extracts of roots of three selected Withania somnifera chemotypes designated as NMITLI 101R, NMITLI 118R and NMITLI 128R. Each chemotype was administered 10-100 mg/kg orally to BALB/c mice once daily for 14 days. The immunomodulatory consequences were recorded by determining the humoral immune response with the help of hemagglutination, plaque forming cell assay and cellular response by measuring delayed type hypersensitivity reaction. Additionally, other immune parameters such as proliferation of T and B cells, intracellular and secreted Th1 and Th2 cytokines along with modulation in ROS production by peritoneal macrophages were monitored after feeding with lower doses (3-30 mg/kg/day) of these three chemotypes individually. NMITLI 101R incited both humoral and cellular immune response in terms of higher number of antibody producing cells and enhanced foot pad swelling at the 10 mg dose as also dose dependent B and T cell proliferations. Levels of intracellular and secreted cytokines post-NMITLI 101R treatment illustrated generation of mixed Th1/Th2 response that remained more polarized towards Th1. This chemotype also generated maximum reactive oxygen species. NMITLI 118R provoked comparatively reduced immune response in all humoral and cellular parameters at lower doses but induced highly polarized Th1 cytokine response. In contrast, NMITLI 128R led to enhanced antibody production with minimal cellular response demonstrating marginally Th2 dominance at a lower dose. Taken together, it may therefore be concluded that there were distinct modulation in the immune response exhibited by the three chemotypes of Withania somnifera and NMITLI 101R appeared to possess a better immunostimulatory activity than the other chemotypes at lower doses.     

The effects of aminophylline and pentoxifylline on multiple organ damage after Escherichia coli sepsis

We studied the effects of the methylxanthines, aminophylline (AMPH) and pentoxifylline (PTXF), on multiple organ damage following Escherichia coli sepsis in guinea pigs. To assess multiple organ damage, 125I-labeled albumin accumulation was measured in bronchoalveolar lavage (BAL) fluid, lung, kidneys, liver, heart, adrenal glands, and spleen and expressed as a ratio of BAL fluid or tissue to 125I-labeled albumin plasma (albumin index: Al). Wet-to-dry lung weight (W/D) ratios were also measured. The methylxanthines were administered by a bolus injection followed by a continuous infusion. The seven experimental groups included: saline-control, AMPH-control, PTXF-control, E. coli septic-control, E. coli septic-AMPH high dose, E coli septic-AMPH low dose, and E. coli septic-PTXF. The AI of the BAL fluid and all examined organs significantly increased in the septic-control group compared to those in the saline-, AMPH-, and PTXF-control groups, In all septic-methylxanthine groups, the AI of the BAL fluid and all organs, except for the spleen, were significantly lower than those of the septic-control group. Compared to the saline-, AMPH-, and PTXF-control groups, the septic-control group revealed a significant increase in lung W/D ratios, whereas the septic-AMPH high and low dose groups and the septic-PTXF group did not. Of importance, the septic-PTXF group did not cause a significant decrease in mean arterial pressure (MAP) as compared to the control groups, whereas the septic-AMPH groups did cause a significant decrease in MAP compared to the septic-control group. Therefore, the data from this experiment demonstrate that both AMPH and PTXF attenuate the multiple organ albumin leak seen in septic guinea pigs. However, PTXF exerted this protective effect with no discernible effect on the MAP whereas the MAP of AMPH-treated guinea pigs was significantly decreased.     

HLA antigens and risk factors for nephropathy in Type 1 (insulin-dependent) diabetes mellitus

Summary This study of risk factors for diabetic nephropathy in juvenile Type 1 (insulin-dependent) diabetes mellitus compares two carefully characterised groups of patients, one with proteinuria (n = 23), the other a control group (n = 24) with no evidence of nephropathy despite more than 25 years of diabetic life. No significant difference was observed between the groups in any HLA-A, -B or -DR antigen or Bf allotype. DR3 was present in 87% of patients with proteinuria and 75% of the diabetic control group; DR4 was present in 48% of patients with proteinuria and 63% of diabetic controls; BfFl was present in 17% of patients with nephropathy and 9% of the diabetic control group. Compared with the control group, patients with proteinuria had significantly higher mean diabetic-clinic blood glucose concentrations before the diagnosis of microvascular disease, a significantly earlier age at diagnosis of diabetes, and had more often been treated with once-daily as opposed to twice-daily insulin regimens. Susceptibility to nephropathy in Type 1 diabetes appears to be determined by the quality of metabolic control and age of onset of diabetes; although the number of subjects studied was relatively small no evidence was found of any influence of HLA or Bf phenotype.