Vitamin D as an adjunct to antibiotics for the treatment of acute childhood pneumonia.

BACKGROUND: Children with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases children's risk of developing pneumonia. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries on 28 December 2021. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared vitamin D supplementation with placebo in children (aged one month to five years) hospitalised with acute community-acquired pneumonia, as defined by the World Health Organization (WHO) acute respiratory infection guidelines. For this update, we reappraised eligible trials according to research integrity criteria, excluding RCTs published from April 2018 that were not prospectively registered in a trials registry according to WHO or Clinical Trials Registry - India (CTRI) guidelines (it was not mandatory to register clinical trials in India before April 2018). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with number of participants in each group. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: In this update, we included three new trials involving 468 children, bringing the total number of trials to seven, with 1601 children (631 with pneumonia and 970 with severe or very severe pneumonia). We categorised three previously included studies and three new studies as 'awaiting classification' based on the research integrity screen. Five trials used a single bolus dose of vitamin D (300,000 IU in one trial and 100,000 IU in four trials) at the onset of illness or within 24 hours of hospital admission; one used a daily dose of oral vitamin D (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used variable doses (on day 1, 20,000 IU in children younger than six months, 50,000 IU in children aged six to 12 months, and 100,000 IU in children aged 13 to 59 months; followed by 10,000 IU/day for four days or until discharge). Three trials performed microbiological diagnosis of pneumonia, radiological diagnosis of pneumonia, or both. Vitamin D probably has little or no effect on the time to resolution of acute illness (mean difference (MD) -1.28 hours, 95% confidence interval (CI) -5.47 to 2.91; 5 trials, 1188 children; moderate-certainty evidence). We do not know if vitamin D has an effect on the duration of hospitalisation (MD 4.96 hours, 95% CI -8.28 to 18.21; 5 trials, 1023 children; very low-certainty evidence). We do not know if vitamin D has an effect on mortality rate (risk ratio (RR) 0.69, 95% CI 0.44 to 1.07; 3 trials, 584 children; low-certainty evidence). The trials reported no major adverse events. According to GRADE criteria, the evidence was of very low-to-moderate certainty for all outcomes, owing to serious trial limitations, inconsistency, indirectness, and imprecision. Three trials received funding: one from the New Zealand Aid Corporation, one from an institutional grant, and one from multigovernment organisations (Bangladesh, Sweden, and UK). The remaining four trials were unfunded. AUTHORS' CONCLUSIONS: Based on the available evidence, we are uncertain whether vitamin D supplementation has important effects on outcomes of acute pneumonia when used as an adjunct to antibiotics. The trials reported no major adverse events. Uncertainty in the evidence is due to imprecision, risk of bias, inconsistency, and indirectness.

Positive Outcomes of Comprehensive Exercise Program on Restoration of Functional Level and Quality of Life in a Patient With Rheumatoid Arthritis: A Case Report.

A relatively recurrent inflammatory disease that is autoimmune, affecting the tissue that lines the joints and tendons, is rheumatoid arthritis (RA). Genome-wide association research has discovered additional genetic markers. The cornerstones of current RA care strategies include anti-inflammatory pharmaceuticals, disease-modifying anti-rheumatic drugs, joint protection and energy conservation, exercise, assistive devices, splinting, orthotics, and surgical treatment. Cardiovascular ailment is still the leading cause of mortality, and those with autoimmune diseases are far more likely to have cardiovascular disease. We present a case of RA with a history of hypothyroidism, hypertension, and diabetes mellitus. She has also taken Ayurveda treatment panchakarma for the same. Physiotherapy interventions included resistance training and aerobic exercises, which showed appreciable results on the Numeric Pain Rating Scale and Multidimensional Health Assessment Questionnaire.

Cadmium toxicity in medicinal plants: An overview of the tolerance strategies, biotechnological and omics approaches to alleviate metal stress.

Medicinal plants, an important source of herbal medicine, are gaining more demand with the growing human needs in recent times. However, these medicinal plants have been recognized as one of the possible sources of heavy metal toxicity in humans as these medicinal plants are exposed to cadmium-rich soil and water because of extensive industrial and agricultural operations. Cadmium (Cd) is an extremely hazardous metal that has a deleterious impact on plant development and productivity. These plants uptake Cd by symplastic, apoplastic, or via specialized transporters such as HMA, MTPs, NRAMP, ZIP, and ZRT-IRT-like proteins. Cd exerts its effect by producing reactive oxygen species (ROS) and interfere with a range of metabolic and physiological pathways. Studies have shown that it has detrimental effects on various plant growth stages like germination, vegetative and reproductive stages by analyzing the anatomical, morphological and biochemical changes (changes in photosynthetic machinery and membrane permeability). Also, plants respond to Cd toxicity by using various enzymatic and non-enzymatic antioxidant systems. Furthermore, the ROS generated due to the heavy metal stress alters the genes that are actively involved in signal transduction. Thus, the biosynthetic pathway of the important secondary metabolite is altered thereby affecting the synthesis of secondary metabolites either by enhancing or suppressing the metabolite production. The present review discusses the abundance of Cd and its incorporation, accumulation and translocation by plants, phytotoxic implications, and morphological, physiological, biochemical and molecular responses of medicinal plants to Cd toxicity. It explains the Cd detoxification mechanisms exhibited by the medicinal plants and further discusses the omics and biotechnological strategies such as genetic engineering and gene editing CRISPR- Cas 9 approach to ameliorate the Cd stress.

Bioresponsive supramolecular hydrogels for hemostasis, infection control and accelerated dermal wound healing.

Injectable, drug-releasing hydrogel scaffolds with multifunctional properties including hemostasis and anti-bacterial activity are essential for successful wound healing; however, designing ideal materials is still challenging. Herein, we demonstrate the fabrication of a biodegradable, temperature-pH dual responsive supramolecular hydrogel (SHG) scaffold based on sodium alginate/poly(N-vinyl caprolactam) (AG/PVCL) through free radical polymerization and the subsequent chemical and ionic cross-linking. A natural therapeutic molecule, tannic acid (TA)-incorporated SHG (AG/PVCL-TA), was also fabricated and its hemostatic and wound healing efficiency were studied. In the AG/PVCL-TA system, TA acts as a therapeutic molecule and also substitutes as an effective gelation binder. Notably, the polyphenol-arm structure and diverse bonding abilities of TA can hold polymer chains through multiple bonding and co-ordinate cross-linking, which were vital in the formation of the mechanically robust AG/PVCL-TA. The SHG formation was successfully balanced by varying the composition of SA, VCL, TA and cross-linkers. The AG/PVCL-TA scaffold was capable of releasing a therapeutic dose of TA in a sustained manner under physiological temperature-pH conditions. AG/PVCL-TA displayed excellent free radical scavenging, anti-inflammatory, anti-bacterial, and cell proliferation activity towards the 3T3 fibroblast cell line. The wound healing performance of AG/PVCL-TA was further confirmed in skin excision wound models, which demonstrated the potential application of AG/PVCL-TA for skin regeneration and rapid wound healing.

Vitamin D as an adjunct to antibiotics for the treatment of acute childhood pneumonia.

BACKGROUND: Children with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases the risk of developing pneumonia in children. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited. OBJECTIVES: To evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia. SEARCH METHODS: We searched CENTRAL (2017, Issue 7), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register; Ovid MEDLINE Epub Ahead of Print; In-Process & Other Non-Indexed Citations; Ovid MEDLINE Daily and Ovid MEDLINE (1946 to July Week 4, 2017); and Embase (2010 to 28 July 2017). We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 28 July 2017. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) including children (aged over one month and up to five years) hospitalised with acute community-acquired pneumonia, as defined by the WHO acute respiratory infection guidelines, that compared vitamin D supplementation with control. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with numbers of participants in each group. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included seven RCTs conducted in low-income countries that involved 1529 children (780 with pneumonia and 749 with severe or very severe pneumonia). Four studies used a single 100,000 IU dose of vitamin D3 at the onset of illness or within 24 hours of hospital admission; two used a daily dose of oral vitamin D3 (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used a daily dose of oral vitamin D3 (50,000 IU) for two days. One study reported microbiological and radiological diagnosis of pneumonia.The effects of vitamin D on outcomes were inconclusive when compared with control: time to resolution of acute illness (hours) (mean difference (MD) -0.95, 95% confidence interval (CI) -6.14 to 4.24; 3 studies; 935 children; low-quality evidence) mortality rate (risk ratio (RR) 0.97, 95% CI 0.06 to 15.28; 1 study; 193 children; very low-quality evidence); duration of hospitalisation (MD 0.49, 95% CI -8.41 to 9.4; 4 studies; 835 children; very low-quality evidence) and time to resolution of fever (MD 1.66, 95% CI -2.44 to 5.76; 4 studies; 584 children; very low-quality evidence).No major adverse events were reported.The GRADE assessment found very low-quality evidence (due to serious study limitations, inconsistencies, indirectness, and imprecision) for all outcomes except time to resolution of acute illness.One study was funded by the New Zealand Aid Corporation; one study was funded by an institutional grant; and five studies were unfunded. AUTHORS' CONCLUSIONS: We are uncertain as to whether vitamin D has an important effect on outcomes because the results were imprecise. No major adverse events were reported. We assessed the quality of the evidence as very low to low. Several trials are ongoing and may provide additional information.

Effect of alcoholic extract of Entada pursaetha DC on monosodium iodoacetate-induced osteoarthritis pain in rats.

BACKGROUND & OBJECTIVES: Osteoarthritis (OA) is a degenerative disease characterized by joint pain and progressive loss of articular cartilage. Entada pursaetha has been traditionally used in the treatment of inflammatory disease, liver ailment, etc. In this study we investigated suppressive effect of ethanolic extract of E. pursaetha (EPE) on monosodium iodoacetate (MIA)-induced osteoarthritis pain and disease progression by histopathological changes in joints in a rat model. METHODS: OA was induced in right knee of rat by intra-articular injection of 3 mg of MIA and characterized by pathological progression of disease and pain of affected joint. Spontaneous movements, mechanical, thermal and cold sensitivity were monitored at days 0 (before drug and MIA injection), 7, 14 and 21 of MIA administration. EPE (30, 100 and 300 mg/kg), vehicle or etoricoxib (10 mg/ kg; reference drug) were administered daily for 21 days by oral route. RESULTS: EPE at various doses significantly reduced mechanical, heat, cold hyperalgesia and increased the horizontal and vertical movements in intra-articular MIA injected rats. EPE prevented the damage to cartilage structure and reduced the cellular abnormalities. Articular cartilage of rats treated with EPE at 300 mg/kg group was almost normal with well-developed smooth surface and chondrocytes were distributed individually or arranged in column. INTERPRETATION & CONCLUSIONS: The present findings showed that the EPE was not only able to mitigate pain and hyperalgesia but also inhibited MIA-induced cartilage degeneration in vivo. EPE may have the potential to become therapeutic modality in the treatment of osteoarthritis. However, further studies need to be done to confirm these findings in other models and clinical trials.

Neonatal hyperbilirubinemia and childhood allergic diseases: a systematic review.

Studies have found a link between neonatal hyperbilirubinemia (NNH) and/or neonatal phototherapy (NPT) and childhood allergic diseases. The present systematic review was conducted to provide updated evidence and to provide direction regarding future research. A systematic search of the published literature was carried out. Observational studies including children up to 12 yr of age were included. Data extraction was carried out using a standardized data extraction form that was designed and pilot tested a priori. The analysis was carried out with the statistical software RevMan (version 5.2) [Protocol is registered at PROSPERO: CRD42014009943]. Of 79 citations retrieved, a total of 7 good quality studies (n = 101,499) were included in the final analysis. There was a significant increase in the odds of asthma and allergic rhinitis (AR) after NNH [asthma, OR 4.26 (95% CI 4.04-4.5); AR, OR 5.37 (95% CI 4.16-6.92)] and after NPT [asthma, OR 3.81 (95% CI 3.53-4.11); AR, OR 3.04(95% CI 2.13-4.32)]. A similar increase in the trend was noted for late onset of asthma after NNH [OR 4.1 (95% CI 2.82-5.94)], and hospitalization due to asthma after NPT [OR 3.56 (95% CI 2.93-4.33)]. The GRADE evidence generated was of 'low quality'. The current evidence finds a significant increase in the odds of childhood allergic diseases after NNH and/or NPT. As observational studies were included, the evidence generated was of 'low quality'. Future studies should try to elucidate the pathophysiologic link between NNH and/or NPT and childhood allergic diseases.

Zinc for the common cold.

BACKGROUND: The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted in high-income countries since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results. OBJECTIVES: To assess whether zinc (irrespective of the zinc salt or formulation used) is efficacious in reducing the incidence, severity and duration of common cold symptoms. In addition, we aimed to identify potential sources of heterogeneity in results obtained and to assess their clinical significance. SEARCH METHODS: In this updated review, we searched CENTRAL (2012, Issue 12), MEDLINE (1966 to January week 2, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013), Web of Science (1985 to January 2013), LILACS (1982 to January 2013), WHO ICTRP and clinicaltrials.gov. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: Five trials were identified in the updated searches in January 2013 and two of them did not meet our inclusion criteria. We included 16 therapeutic trials (1387 participants) and two preventive trials (394 participants). Intake of zinc was associated with a significant reduction in the duration (days) (mean difference (MD) -1.03, 95% confidence interval (CI) -1.72 to -0.34) (P = 0.003) (I(2) statistic = 89%) but not the severity of common cold symptoms (MD -1.06, 95% CI -2.36 to 0.23) (P = 0.11) (I(2) statistic = 84%). The proportion of participants who were symptomatic after seven days of treatment was significantly smaller (odds ratio (OR) 0.45, 95% CI 0.20 to 1.00) (P = 0.05) than those in the control, (I(2 )statistic = 75%). The incidence rate ratio (IRR) of developing a cold (IRR 0.64, 95% CI 0.47 to 0.88) (P = 0.006) (I(2) statistic = 88%), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.58, 95% CI 1.19 to 2.09) (P = 0.002), bad taste (OR 2.31, 95% CI 1.71 to 3.11) (P < 0.00001) and nausea (OR 2.15, 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. The very high heterogeneity means that the averaged estimates must be viewed with caution. AUTHORS' CONCLUSIONS: Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people but some caution is needed due to the heterogeneity of the data. As the zinc lozenges formulation has been widely studied and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. When using zinc lozenges (not as syrup or tablets) the likely benefit has to be balanced against side effects, notably a bad taste and nausea.

Zinc for the common cold.

BACKGROUND: The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results. OBJECTIVES: To assess the effect of zinc on common cold symptoms. SEARCH STRATEGY: We searched CENTRAL (2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: We included 13 therapeutic trials (966 participants) and two preventive trials (394 participants). Intake of zinc is associated with a significant reduction in the duration (standardized mean difference (SMD) -0.97; 95% confidence interval (CI) -1.56 to -0.38) (P = 0.001), and severity of common cold symptoms (SMD -0.39; 95% CI -0.77 to -0.02) (P = 0.04). There was a significant difference between the zinc and control group for the proportion of participants symptomatic after seven days of treatment (OR 0.45; 95% CI 0.2 to 1.00) (P = 0.05). The incidence rate ratio (IRR) of developing a cold (IRR 0.64; 95% CI 0.47 to 0.88) (P = 0.006), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. AUTHORS' CONCLUSIONS: Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.

Diet in dermatology: present perspectives.

Many nutrients are essential for life, and an adequate amount of nutrients in the diet is necessary for providing energy, building and maintaining body organs, and for various metabolic processes. The role of food in the induction of various skin disorders and skin diseases leading to nutritional deficiencies is well known. The photo-protective potential of antioxidants, the effects of micronutrient supplementation on the skin immune system, and the modulating effects of fatty acids on skin disorders are well documented. Skin diseases due to nutritional deficiencies, the dietary role in skin immunity and various skin diseases, and the role of antioxidants and other supplements in skin health have been reviewed.

Long-term response to deferiprone therapy in Asian Indians.

Deferiprone (L1) has been used in several countries for iron chelation therapy for over one decade. Long-term results on the drug are lacking. In the present study, data of 110 patients on deferiprone (L1) for up to 17 years were analyzed. On a mean L1 dose of 70.2 mg/kg/day (range 44-100), serum ferritin level showed a very steady decrease with time from an initial mean (+/-SD) of 3,033.61 +/- 1,468.04 ng/ml to final of 1,665.08 +/- 949.93 ng/ml after a mean (+/-SD) of 6.1 +/- 3.8 years. In total, 13 patients discontinued L1 therapy. Major complications of L1 requiring permanent discontinuation of treatment included arthropathy (n = 8, 7.2%) and neutropenia/agranulocytosis (n = 5, 4.5%). Lesser complications permitting continued L1 treatment included transient mild leucopenia or thrombocytopenia (n = 3) and gastrointestinal problems (n = 5). There were a total of three deaths attributed to agranulocytosis. Although the complications associated with L1 treatment are significant and require close monitoring, they do not preclude effective long-term therapy in the vast majority of patients. A longer duration of therapy is required for effective response in chronically iron-overloaded patients. Further well-controlled prospective studies of L1 are required to identify factors affecting individual response to therapy.

Drug induced shortening of the QT/QTc interval: an emerging safety issue warranting further modelling and evaluation in drug research and development?

INTRODUCTION: A session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh. METHODS: The session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing "for" and "against" QT/QTc shortening being a safety issue and a panel discussion with the audience. RESULTS: Compared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future. DISCUSSION: Currently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.

Refining detection of drug-induced proarrhythmia: QT interval and TRIaD.

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or I(Kr), hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.

Induction of apoptosis by curcumin and its implications for cancer therapy.

Curcumin (diferuloyl methane), the yellow pigment in turmeric (Curcuma longa), is a potent chemopreventive agent that inhibits proliferation of cancer cells by arresting them at various phases of the cell cycle depending upon the cell type. Curcumin-induced apoptosis mainly involves the mitochondria-mediated pathway in various cancer cells of different tissues of origin. In some cell types like thymocytes, curcumin induces apoptosis-like changes whereas in many other normal and primary cells curcumin is either inactive or inhibits proliferation, but does not appear to induce apoptosis. These together with reports that curcumin protects cells against apoptosis induced by other agents, underscore the need for further understanding of the multiple mechanisms of cell death unleashed by curcumin. Tumor cells often evade apoptosis by expressing several antiapoptotic proteins, down-regulation and mutation of proapoptotic genes and alterations in signaling pathways that give them survival advantage and thereby allow them to resist therapy-induced apoptosis. Many researchers including ourselves, have demonstrated the involvement of several pro and antiapoptotic molecules in curcumin-induced apoptosis, and ways to sensitize chemoresistant cancer cells to curcumin treatment. This review describes the mechanisms of curcumin-induced apoptosis currently known, and suggests several potential strategies that include down-regulation of antiapoptotic proteins by antisense oligonucleotides, use of proapoptotic peptides and combination therapy, and other novel approaches against chemoresistant tumors. Several factors including pharmacological safety, scope for improvement of structure and function of curcumin and its ability to attack multiple targets are in favor of curcumin being developed as a drug for prevention and therapy of various cancers.

Drugs, QT interval prolongation and ICH E14: the need to get it right.

Regulatory concerns on the ability of an ever-increasing number of non-cardiovascular drugs to prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in initiatives to harmonise internationally the regulatory guidance on strategies by which to evaluate new drugs for this liability. The International Conference on Harmonisation (ICH) has released consensus texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies as regulatory drafts for wider consultation. Draft ICH E14 calls for a clinical 'thorough QT/QTc study' (typically in healthy volunteers) for new drugs with systemic bioavailability, regardless of the non-clinical data. This indifference to non-clinical data has sparked off a major debate, even among the regulators. The 'thorough QT/QTc study' is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc prolongation, and proposes the use of a positive control to validate the study. The guideline recommends exploration of the effect of concentrations that are higher than those achieved following the anticipated therapeutic doses and, consequently, a negative 'thorough QT/QTc study', even in the presence of non-clinical data of concern, will almost always allow standard collection of on-therapy ECGs. The proposed threshold of a 5 ms increase in mean placebo-corrected QTc interval for designating a study as positive for an effect, with all its implications for subsequent development of the drug and its regulatory assessment and labelling, has also generated a controversy. This paper provides an overview commentary on some contentious or ambiguous aspects of draft ICH E14 with a view to stimulating a debate and inviting scientifically supported comments from stakeholders in order to ensure that the application of the ICH E14 strategy, when finalised and adopted, does not result in either restriction in the use (or even rejection) of a potentially beneficial drug or approval of an otherwise hazardous drug without the restrictions required to promote its safe use.

Drug-induced QT interval prolongation: regulatory perspectives and drug development.

Drug-induced torsade de pointes is a modern, iatrogenic challenge. This potentially fatal tachyarrhythmia is associated with many non-antiarrhythmic (including noncardiovascular) drugs, leading to a number of effective drugs being withdrawn from the market. Others have attracted severe prescribing restrictions while some new chemical entities have experienced difficulties in gaining regulatory approval. Since QT interval prolongation, a surrogate of torsade, is a mechanism-based concentration-dependent pharmacological effect, it is usually possible to characterise a drug for this toxicity during its development. The physicochemical and other pharmacological properties of a QT-prolonging drug modulate its clinical risk of torsade de pointes. Apart from these properties, the torsadogenic potential of a drug is also influenced clinically by a number of genetic and non-genetic factors. The former include polymorphisms of enzymes that metabolise the drug or its pharmacological target. Major non-genetic factors are the dose of the drug, co-medications especially metabolic inhibitors or other QT-prolonging drugs, presence of electrolyte imbalance and co-morbidity especially liver or cardiac disease, including pre-existing prolongation of the QT interval or bradycardia. Drug development programmes should be aimed at characterising the potency of a drug to prolong the OT interval and its interactions with these genetic and non-genetic variables, if valuable drugs are to gain approval and continue to be prescribed effectively and safely. Physicians too have an important role by ensuring that they adhere to prescribing information and monitor the patients as recommended.

Potential role of vitamins in chromium induced spermatogenesis in Swiss mice.

Chromium (Cr) (VI) compounds are known carcinogens and mutagens. The mechanism of carcinogenicity and mutagenicity caused by chromium(VI) compounds remained unclear for several years. However, in the recent past chromium-induced carcinogenicity and/or mutagenicity was known to happen due to the generation of reactive oxygen species (ROS). In the present context, chromic acid (CrO(3)), a potential Cr(VI) compound could be able to generate reactive oxygen radicals in the testes of Swiss mice as evidenced from significantly higher lipid peroxidation compared to untreated controls. The cytotoxic effects of the compound on the testes are depicted in terms of significantly reduced sperm count level accompanied with increased abnormal sperm population in treated mice. Supplementation of vitamins like Vitamin C and Vitamin E (Vit C and Vit E) to CrO(3) injected mice groups could partially prevent the incidence of abnormal sperm population and increased the sperm count. Of the two vitamins, taken for the study, Vit C happens to be more effective in ameliorating germ cells from degeneration and from mutation to abnormal sperm. Possible antioxidative role of both the vitamins have been studied for significant decrease in lipid peroxidation associated with marked elevation in sperm count level and significant decrease in the percentage of abnormal sperm formation in CrO(3)-treated mice.