Tacrolimus-associated eosinophilic gastroenterocolitis in pediatric liver transplant recipients: role of potential food allergies in pathogenesis

Tacrolimus is a macrolide agent that is now the primary immunosuppressant used in prevention of graft rejection in transplant recipients. It has been found to be superior to cyclosporine (CSA) for rescue therapy as well as for earlier weaning of steroids. Both tacrolimus and CSA share similar toxicity profiles; however, their gastrointestinal side effects have received little attention. We report three cases of eosinophilic colitis in liver transplant recipients, maintained on tacrolimus as immunosuppressive medication post-liver transplantation. These patients also had high serum immunoglobulin (Ig)E levels, eosinophilia and IgE-positive radioallergosorbent test for milk proteins. The colitis appeared to be mediated by food allergies. Each patient had symptomatic improvement following reduced immunosuppression and an appropriately restricted diet. We conclude that tacrolimus may play a role in the initiation of food allergies, leading to eosinophilic colitis. More studies are needed in a controlled setting to identify the prevalence of similar findings among other pediatric liver transplant recipients.     

Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies

Introduction: Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection. Given the role of microglia in neuroinflammation, recent studies have attempted to unravel the mechanisms that aid to establish microglial cell-based therapy.

Areas covered: While total suppression of microglial activation may compromise its beneficial role in tissue repair in the aftermath of an insult, the benefits of modulating microglial activation and promoting microglia polarization to a neuroprotective phenotype have been highlighted recently.

Expert opinion: So far, the therapeutic strategy focussed on neutralizing microglia-mediated neuroinflammation using drugs that block the release of pro-inflammatory mediators has limitations, such as unwarranted side effects. Recent advances reveal several alternative molecular targets and potential epi-drugs that are capable of modulating microglial function and promoting neuroprotection. This review discusses the recent progress made in understanding the mechanisms of microglia-mediated neuroinflammation in various neuropathologies, and the emerging anti-inflammatory therapeutic strategies in this field.     

A randomized,double blind,placebo controlled,cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model

Objective:

Experimental pain models in human healthy volunteers are advantageous for early evaluation of analgesics. All efforts to develop nonsteroidal anti-inflammatory drugs (NSAIDs) which are devoid of gastrointestinal and cardiovascular system effects are still far from achieving a breakthrough. Hence we evaluated the analgesic activity of an ayurvedic drug, Boswellia serrata by using validated human pain models which has shown its analgesic activity both in-vitro and preclinical studies to evaluate the analgesic activity of single oral dose (125 mg, 2 capsules) of Boswellia serrata compared to placebo using mechanical pain model in healthy human subjects.

Materials and Methods:

After taking written informed consent, twelve healthy subjects were randomized (1:1) to receive single oral dose of Boswellia serrata (Shallaki^®) 125 mg, 2 capsules or identical placebo in a crossover design. Mechanical pain was assessed using Ugo basile analgesymeter (by Randall Selitto test) at baseline and at 1 hr, 2 hrs and 3 hrs after test drug administration. Pain Threshold force and time and Pain Tolerance force and time were evaluated. Statistical analysis was done by paired t-test.

Results:

Twelve healthy volunteers have completed the study. Mean percentage change from baseline in Pain Threshold force and time with Boswellia serrata when compared to placebo had significantly increased [Force: 9.7 ± 11.0 vs 2.9 ± 3.4 (P = 0.05) and time: 9.7 ± 10.7 vs 2.8 ± 3.4 (P = 0.04)] at third hr. Mean Percentage change from baseline in Pain Tolerance force and time with Boswellia serrata when compared to placebo had significantly (P ≤ 0.01) increased at 1 hr, 2 hrs and 3 hrs.

Conclusion:

In the present study, Boswellia serrata significantly increased the Pain Threshold and Pain Tolerance force and time compared to placebo. Both study medications were well tolerated. Further multiple dose studies may be needed to establish the analgesic efficacy of the drug.KEY WORDS: Boswellia serrata, human pain models, randall selitto test, ugo basile analgesymeter     

The determination of nicotinic acid in plasma by mixed-mode liquid chromatography-tandem mass spectrometry following ion exchange solid phase extraction

An assay for nicotinic acid in plasma samples has been developed using ion exchange solid phase extraction in 96-well format followed by mixed-mode ion exchange/reversed-phase liquid chromatography with positive ion tandem mass spectrometry detection. The assay avoids the need for time-consuming derivatisation procedures or involatile ion-pair chromatography reagents. The assay is linear over the wide range 0.05-20 microg/mL, based on a 100 microL sample (correlation coefficient>0.99). The assay is accurate and precise (bias and coefficient of variation<18%) over this calibration range.     

Ineffective pictorial health warnings on tobacco products: lessons learnt from India

Pictorial warnings are effective in promoting smoking cessation as shown by research in the developed countries. This study aims to determine perceptions of Indians about the effectiveness of pictorial health warnings on tobacco packs which existed from May 31, 2009, to December 1, 2011. A cross-sectional survey was undertaken in five states of India with 1897 participants (56% males; 54% tobacco users). More tobacco users expressed that the pictorial warnings are inadequate to convey the health impact of tobacco use when compared with nonusers (71.50% vs. 62.75%; P < 0.001). More illiterates when compared with literates expressed their concern that the current pictorial warnings will not motivate them to quit (61.17% vs. 51.01%; P < 0.001). The new warnings implemented from December 1, 2011, in India are also not field-tested. Field testing and assessment of effectiveness of health warnings should be a mandatory requirement for Parties reporting on Article 11 of Framework Convention on Tobacco Control (FCTC).     

Effect of cyclodextrins on the complexation and nasal permeation of melatonin

The inclusion complexation of melatonin (MT) with modified cyclodextrins (CDs) was studied with an objective of improving the solubility and nasal absorption of MT. The formation of inclusion complex of MT with Hydroxypropyl beta CD (HPbeta CD) and randomly methylated beta CD (RMbeta CD) was characterized in solution and solid states by phase solubility and differential scanning calorimetry analyses. The phase solubility data indicate a linear increase in the solubility of MT with CDs demonstrating Higuchi's A(L)-type phase solubility profiles. The effect of CDs on the permeation of MT across EpiAirway(TM)-100 cultures was studied using a modified nonstatic diffusion setup. CDs were employed at different concentrations with 1% w/v micronized MT suspension in hydroxypropyl methyl cellulose (HPMC) vehicle. At low CD concentrations (1% w/v), the permeation of MT from HPMC formulation was significantly increased (125%,p < .001). However, the permeation was significantly reduced when CDs were used at relatively high concentrations (5 to 10% w/v concentration for HPbetaCD and 10% w/v concentration for RMbetaCD,p < .001). All the tissues were viable with good tissue integrity at the end of permeation experiments, as measured by methylthiazoletetrazolium assay and transepithelial electrical resistance measurements. In conclusion, formation of inclusion complex of MT with HPbetaCD and RMbetaCD was demonstrated in solution and solid state. Both HPbetaCD and RM betaCD at 1% w/v concentration were found to improve the nasal permeability of MT from HPMC gel formulations.     

Reproducibility and validity of an interviewer-administered semi-quantitative food frequency questionnaire to assess dietary intake of urban adults in southern India

We report on the reproducibility and validity of a food frequency questionnaire (FFQ) developed for southern India. One hundred and two adult subjects aged ≥20 years drawn from the Chennai Urban Rural Epidemiology Study participated. The FFQ was developed based on local foods and habits, and was administered three times at 0, 6 and 12 month periods (called FFQ1, FFQ2 and FFQ3) to assess the reproducibility. To test the validity of the FFQ, multiple 24-h recalls collected at 2-monthly intervals for a period of 1 year and the estimated energy intake/basal metabolic rate (EI/BMR) ratio were used. The ‘EpiNu’ in-house food and nutrient database was used to compile dietary intakes, which were analyzed for statistical analysis. The intraclass correlation coefficient for all three FFQs ranged from 0.72 for carbohydrates to 0.45 for folate. The de-attenuated Pearson correlation for the energy adjusted nutrients between FFQ3 and 24-h recalls ranged from 0.73 for carbohydrates to 0.35 for calcium. Bland and Altman plots for energy intake between the two methods showed the limits of agreement ranged from 768 to ?1358 calories/day (±2 standard deviations). Misclassification was low for most of the nutrients. Under-reporting of the energy intake (EI/BMR ratio<1.2) was higher in females than males. This FFQ appears to be a robust tool to measure dietary intakes in southern India.