Sohil Khan

Definite, probable or dubious: antioxidants trilogy in clinical dentistry

Recent years have shown the presence of free radicals in causation and progression of various dental diseases and antioxidant usage in dental therapeutics. Antioxidant micronutrients are important not only for limiting oxidative and tissue damage, but also in preventing increased cytokine production, which is a result of prolonged activation of the immune response. There has been a widespread availability and clinical claims on the safety and efficacy of antioxidants. However, lack of randomised controlled trials in dental research limits their usage. There is a substantial gap between these clinical claims and efficacy/safety of antioxidants in dental therapeutics which needs to be addressed. This article highlights the clinical significance of antioxidant therapy in dental practice and touches upon controversial areas and research lacunae. An evidence based approach for making recommendations about antioxidant usage and efficacy in routine dental practice seems to be the need of the hour.

Therapeutic Challenges in Cancer Pain Management: A Systematic Review of Methadone

ABSTRACT The proven therapeutic efficacy of methadone in cancer pain is hindered by a challenging pharmacokinetic-pharmacodynamic profile, considerable interpatient variation, and increasing concern about the complexities of dosing. The objective of this study was to assess the evidence for the use of methadone in cancer pain management. The authors conducted a systematic literature search for randomized controlled trials (RCTs) published post the 2007 Cochrane review of methadone in cancer pain. Trial quality was assessed using the Oxford Quality Scoring System and Cochrane Handbook for Systematic Reviews of Interventions. Of the 152 abstracts found, 4 were RCTs (272 participants). Two RCTs compared the efficacy and safety of methadone with placebo or active control and two investigated rotation to methadone from other opioids. The studies used different routes of administration, dosing, initiation, and titration of methadone and distinct pain scoring tools and did not address the issues raised by the Cochrane review. Methadone has an important role in the management of cancer pain, with many advantages including low cost, high oral bioavailability, rapid onset of action, once-daily dosing, and postulated benefits in difficult pain control scenarios. However, due to limited research in this area, methadone dosing remains a challenge, with vigilant dose initiation, adjustment, and monitoring required. There is a need for further studies using standardized methodology to evaluate the optimal dosing strategy of methadone, the effect on different types of pain, and the role of pharmacokinetics and pharmacogenomics in clinical outcomes.

Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry

Background: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders. Objective: The objective of the study is to develop a liquid chromatography–tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders. Methods: A deuterated internal standard (d7-melatonin) was added to a diluted saliva sample (20 µL) in an autosampler vial insert, and 50 µL were injected. Plasticware was strictly avoided, and all glassware was scrupulously cleaned and then baked at 120°C for at least 48 hours to obtain satisfactory performance. Reverse-phase chromatography was performed on a C8 column using a linear gradient elution profile comprising mobile phases A (0.1% aqueous formic acid) and B (15% methanol in acetonitrile containing 0.1% formic acid), pumped at a total flow rate of 0.8 mL/min. The run time was 8 minutes. After atmospheric pressure chemical ionization, mass spectrometric detection was in positive ion mode. Mass detection was by selected reaction monitoring mode with the following mass transitions used for quantification: melatonin, m/z 233.0 → 173.8 and d7-melatonin, m/z 240.0 → 178.3. Results: Linearity (r > 0.999) was established from 3.9 to 1000 pg/mL. Imprecision (coefficient of variation percent) was less than 11%, and accuracy was 100–105% (7.0–900 pg/mL). The method was selective, and the mean (range) ratio of the slopes of calibrations in water to those in daytime saliva samples collected from 10 healthy adult subjects was 0.989 (0.982–0.997), indicating negligible matrix effects. The application of the assay was demonstrated in healthy adults and in children being clinically investigated for sleep disturbances. Conclusions: A validated liquid chromatography–tandem mass spectrometry method suitable for monitoring salivary melatonin in children with circadian rhythm sleep disorders is reported. The method also has potential application to pediatric population pharmacokinetic studies using sparse sampling of saliva as the biological sample matrix.

Role of high-dose corticosteroid for the treatment of leptospirosis-induced pulmonary hemorrhage.

Leptospirosis is a zoonotic disease of worldwide distribution caused by spirochetes of the genus Leptospira. Leptospirosis is a common disease, highly prevalent in human populations but most often unidentified. The International Leptospirosis Society estimates that disease incidence ranges are 0.1 to 1.0 per 100 000 in temperate climates and 10 to 100 per 100 000 in humid tropics.1 In India, outbreaks have been increasingly reported since 1980s, especially from the states of Gujarat, Kerala, Karnataka, Maharashtra, Orissa, and Tamil Nadu.2 Outbreaks mostly occur as a result of heavy rainfall and consequent flooding, usually during monsoons.3 The clinical manifestation of leptospirosis varies from inapparent infection to fulminant fatal disease. Pulmonary complications for patients with leptospirosis are also relatively common, reported in 17% to 70% of patients in several large studies.4 Although these manifestations are usually mild, recent studies suggest that pulmonary involvement is frequently the most dramatic feature of leptospiral infection. Accordingly, severe pulmonary manifestations of leptospirosis are becoming more prevalent, with pulmonary hemorrhage being the most predominant cause of death in leptospirosis. The hemorrhagic potential of leptospirosis was first reported by Weil in 1886.5 The intense intra-alveolar hemorrhages seem to be unique for leptospirosis. Previous literature on diffuse alveolar hemorrhage heavily emphasizes the causal role of vasculitides.6 Use of steroids is rarely reported in leptospirosis-associated pulmonary hemorrhages. Here, we report a case of leptospirosis with pulmonary hemorrhage that was successfully treated with a high intravenous dose of methylprednisolone.

Therapeutic Options in the Management of Sleep Disorders in Visually Impaired Children: A Systematic Review

BACKGROUND Treatment of sleep disorders in visually impaired children is complicated by a complex pathophysiology, a high incidence of sleep disorders in this population, and a dearth of management options. The significant impact on the health of these children and distress to their caregivers warrant a systematic assessment of the published literature on therapeutic approaches. OBJECTIVE This systematic review aims to assess the current therapeutic options in the management of sleep disorders in visually impaired children to identify knowledge gaps and guide future research. METHODS A search of primary literature was conducted using the bibliographic databases PubMed (1980-August 2010), EMBASE (1990-August 2010), Science Citation Index Expanded (1990-August 2010), and CINHAL (1992-August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL). Additional studies were identified through snowballing search techniques (manually by searching retrieved references and electronically by using citation-tracking software). Search terms included behavioral treatment, children, circadian rhythm, hypnosedatives, intellectual disability, light therapy, melatonin, phototherapy, random allocation, randomized controlled trial (RCT), sleep disorder, and visual impairment. Randomized and quasi-randomized clinical trials of therapeutic options (behavioral treatment, light therapy, melatonin, or hypnosedatives) used in participants aged 3 months to 18 years who had both a visual impairment and a sleep disorder were included. Independent extraction of articles was performed by 2 authors using predefined data fields, including quality of the therapeutic options, based on the Strength of Recommendation Taxonomy evidence-rating system. RESULTS Two RCTs were retrieved for melatonin, with improved effect on sleep latency (P = 0.019 and P < 0.05, respectively). However, separate analysis for visual impairment was not conducted. No RCTs were retrieved for behavioral intervention, light therapy, or hypnosedatives. Three studies using behavioral therapy (2 case reports and 1 case series) anecdotally showed improvement in sleep habit. No improvement in sleep rhythm was observed with a case series applying light therapy as an intervention. CONCLUSIONS Children with visual impairment and sleep disorders are a heterogeneous patient group, making diagnosis and treatment difficult. RCTs on treatment options remain in their infancy, with a lack of evidence for appropriate therapeutic strategies. Trials across a range of selected diagnoses need to be conducted with adequate sample populations to differentiate the efficacy of 4 different treatment modalities (behavioral therapy, light therapy, melatonin, and hypnosedatives) as agents for improving sleep.

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection.

Methadone is a potent lipophilic synthetic opioid that is effective in the treatment of cancer pain and perceived benefit in difficult pain control scenarios (especially in cases of neuropathic pain). The use of methadone in clinical practice is challenging however, due to the narrow therapeutic window and large inter- and intra-individual variability in therapeutic response. Quantitation of the enantiomers d- and l-methadone (d- and l-MTD) in plasma and saliva provides a basis for studying its pharmacokinetics in patients with cancer and for monitoring efficacy, toxicity and side-effects. This assay involves quantitation of the enantiomers of methadone using their respective deuterated internal standards, in plasma and saliva matrices with no impact of ion suppression in either matrix. The analytical recoveries of d- and l-MTD from the saliva collection devices (Salivette®) are optimised in this novel method with an accurate and simple extraction method employing dichloromethane. Optimal enantioselective separations were achieved using an α1-acid glycoprotein chiral stationary phase and triple quadrupole tandem mass spectrometer. Linearity was demonstrated over 0.05-1000µg/L for both enantiomers in plasma and in saliva with correlation coefficients greater than 0.998. The lower limit of quantitation (LLOQ) was determined to be 0.1µg/L in plasma and saliva for d- and l-MTD. Accuracy of the method ranges from 100% to 106% even at the LLOQ and total precision, expressed as the coefficient of variation, was between 0.2% and 4.4% for both analytes in both matrices. A simple one step extraction procedure resulted in recoveries greater than 95% for both analytes, at concentrations as low as 0.5µg/L, from the Salivette®. The validated method was applied successfully in 14 paired plasma and saliva samples obtained from adult patients with cancer pain receiving methadone.

Pharmacovigilance Among Surgeons and in Surgical Wards: Overlooked or Axiomatic?

To review the status of pharmacovigilance system among surgeons and in surgical wards with recommendations. Literature search using MEDLINE, cross-reference of published data and review of World Health Organization—Pharmacovigilance transcripts. Pharmacovigilance system is still in its infancy among surgeons and in surgical wards. No major studies have been published addressing this issue, till date. Surgeons are professionals least likely to report adverse drug reactions. Moreover widespread and irrational antibiotic use is contributing towards high incidence of adverse events apart from multidrug resistance. Lack of interest, funding and knowledge pose challenges in effective post marketing drug surveillance in surgery. A three tier proactive pharmacovigilance system in surgical wards is suggested along with specific recommendations. The pros and cons of adverse drug reporting among the surgeons are discussed. With growing awareness of pharmacovigilance in various fields of medicine, surgery can no longer remain an exception. In the transition from medical school to surgery clinic a subtle shift must occur from emphasizing pharmacokinetics to appreciating pharmacodynamics. This change in philosophy will occur at the level of instruction when the surgeons of tomorrow are motivated through regulatory and institutional means at school level to adopt pharmacovigilance in their clinical practices along with the practicing surgeons.

Pharmacotherapy of conduct disorder: Challenges, options and future directions

There is a critical need for evaluation of the pharmacotherapies used in conduct disorder (CD), due to the high incidence of off-label prescribing. The aim of this review was to identify concerns associated with the safety, efficacy and impact on quality of life (QOL) that pharmacotherapy has in children and adolescents with CD. A systematic review was undertaken using pre-defined search criteria and four databases, including reference searches. We assessed these studies using the Strength of Recommendation Taxonomy, Grading of Recommendations Assessment, Development and Evaluation, and Review Manager Risk of Bias (RevMan®) tools. There were 12 randomised controlled trials that met our inclusion criteria. Studies included: antipsychotics, atomoxetine, lithium, clonidine, divalproex sodium and psychostimulants. The antipsychotics demonstrated efficacy, but were associated with adverse effects. Other agents demonstrated mixed responses, highlighting the lack of clinical significance and increased incidence of adverse effects. The management of related adverse effects was addressed to assist with clinical gaps. Overall, there is limited evidence regarding the role of pharmacotherapy in CD. More research is needed that takes into account the heterogeneity of CD and analysis of pharmacotherapy in pure CD.

Sleeping Pills and Quality of Wake Time: The Missing Link

Background: The rising incidence of insomnia in a 24/7 global society quantifies the burden for the individual, in terms of reduced quality of life (QOL), and for society at large, in terms of work absenteeism, disability, and health care costs. Aim: To evaluate research on hypnosedatives (benzodiazepines, non-benzodiazepines) and complementary medicines in paediatric insomnia where quality of wake time is one of the key efficacy outcomes. Design and setting: Retrospective data analysis of clinical studies in paediatric insomnia Methods: A systematic review of clinical studies of hypnosedatives and complementary medicines in paediatric insomnia was conducted. PubMed and Cochrane Central Register of Controlled Trials (January 2002- August 2013) were searched for studies in children aged 3 to18 years (male or female). Quality of wake time and/or health related QOL parameters were assessed as the outcomes. Results: From 31 potentially relevant studies, only one, involving melatonin, met the inclusion criteria. One hundred and forty six children (aged 3 to15 years 8 months) diagnosed with insomnia were evaluated in a 12 week double masked randomised placebo controlled phase III multi-centre trial. Child behaviour and family functioning showed some improvement and favoured use of melatonin but was not statistically significant. There were no controlled clinical studies evaluating the impact of benzodiazepines and non-benzodiazepines hypnosedatives on quality of wake time in the management of paediatric insomnia. Conclusion: Data on quality of wake time in children with insomnia are scarce. Research has focused on addressing the metrics of sleep, with quality of wake time notably ignored. QOL measurement provides valuable information about the psychological and social impact of treatment on children with insomnia. Complementary medicines such as melatonin appear to improve the quality of wake time in paediatric insomnia where there are comorbid conditions; but further research is needed.

Micronutrient Therapy for Violent and Aggressive Male Youth: An Open-Label Trial

OBJECTIVES Pharmacotherapy for problematic aggressive and violent behavior disorders in male children and adolescents is associated with significant adverse events. Treatments with more acceptable risk-benefit ratios are critically needed. Micronutrient intervention will be investigated as an alternative to bridge the therapeutic gap in the management of these behaviors. METHODS Males aged 4-14 who displayed ongoing violent and aggressive behaviors received micronutrient intervention containing alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), biotin, chromium, pyridoxal-5-phosphate (P5P), pyridoxine (vitamins B6), selenium, and zinc, in a 16-week open-label trial. Plasma zinc, plasma copper, copper/zinc ratio, and urinary hydroxyhemopyrroline-2-one (HPL) tests were conducted at baseline and endpoint. Participants were examined for changes in aggressive and violent behaviors measured using the Childrens Aggression Scale (CAS) and the Modified Overt Aggression Scale (MOAS), improvements in family functioning measured using the Family Functioning Style Scale, improvements in health-related quality of life (HRQoL) measured using the Pediatric Quality of Life Inventory (PedsQL) at baseline, 8 weeks, endpoint, and at 4-6-month follow-up. RESULTS Thirty-two male children and adolescents met inclusion criteria. Thirty-one (mean 8.35 ± standard deviation 2.93 years) completed the study, with one participant lost to follow-up. Micronutrient therapy significantly improved parent-reported aggressive and violent behaviors measured using the CAS for all domains except the use of weapons (p < 0.001 to p = 0.02) with medium to large effect size (Cohens d = 0.72-1.43) and the MOAS (p < 0.001) with large effect size (Cohens d = 1.26). Parent-reported HRQoL (p < 0.001; Cohens d = -1.69) and family functioning (p = 0.03; Cohens d = -0.41) also significantly improved. CONCLUSION Micronutrient therapy appeared well tolerated, with a favorable side effect profile. It appeared effective in the reduction of parent-reported aggressive and violent behaviors, and showed improvement in family functioning and HRQoL in male youth after 16 weeks. Further research in the form of a double-blinded, randomized controlled trial is required to verify these initial positive observations.