Lactose intolerance: genetics of lactase polymorphisms, diagnosis and novel therapy

Lactose intolerance is a common disorder affecting an individual's ability to digest lactose present in milk or any food product. Lactose intolerance is caused by the deficiency of β-galactosidase (lactase) in the digestive tract. Diagnosis of lactose intolerance is not so simple and straightforward clinically. Many biochemical and genetic tests have been developed for the determination of lactose intolerance. Several case reports indicate wherein subjects have self-diagnosed being lactose intolerant. There is an emerging link of this disorder with human gene polymorphism, where genetic basis has been used as a diagnostic tool. The high prevalence of this condition among children and adults has compelled the production of lactose-free foods. Additionally, external enzyme supplementation has been looked at as an alternative protective mechanism in lactose intolerant subjects. This review highlights the genetic variants of lactase polymorphism and theranostic (therapeutic and diagnostic) strategies for lactose intolerance.Biomedical Reviews 2014; 25: 35-44

INVESTIGATION OF CYP1A INTERACTION POTENTIAL OF WITHANIA SOMNIFERA IN RAT AND HUMAN LIVER MICROSOMES

Objective: The aim of this study was to investigate CYP1A interaction of crude extracts (ethanolic, methanolic, hydromethanolic & aqueous) of Withania somnifera and its principal phytoconstituents (withaferin-A and withanolide-A) in rat and human liver microsomes.Methods: In vitro study were carried out in both rat & human liver microsomes while, in vivo CYP1A interaction potential was investigated by administering the methanolic extract of Withania somnifera orally at a dose of 500 mg/kg in male Wistar rats using probe substrate technique.Results: The results of this study revealed that IC50 values of all the crude extracts of Withania somnifera and its principal phytoconstituents (withaferin–A & withanolide–A) were found to be >640 µg/ml and >32 µM respectively, for CYP1A enzyme both in rats and humans. However, in vivo pharmacokinetic study of co-administered methanolic extract of Withania somnifera and phenacetin, revealed that the crude extract lead to an approximate 1.5 fold (31%) decrease in AUC 0-24h (p < 0.05). Elimination rate constant (Ke) increased by 2 fold (48%) and half-life (T1/2) decreased by 1.8 fold (43%).Conclusion: The results of this study suggested that Withania somnifera showed no in vitro CYP1A inhibition in both rats and humans. However, in vivo administration of methanolic extract of Withania somnifera significantly induced CYP1A enzyme & subsequently altered the pharmacokinetics profile of phenacetin in rats; indicating a potential for herb-drug interactions.Â

Therapeutic roles of antioxidant and nutraceuticals in the prevention and management of Alzheimer’s disease: A systematic review

Alzheimer’s disease (AD) has emerged as a serious and challenging neurological disorder in the ageing population worldwide. The progressive decline of mental health in AD patients causes memory loss, cognition decline, and motor impairment, which impacts adversely on the quality of life of afflicted individuls. Health care costs of mental diseases, dementia and AD are escalating globally, because the AD patients need continuous attention either by the family members or by the health care providers. Also, pharmaceutical treatment and hospital cost of AD is very expensive for the society. Therefore,  there is an urgent need to develop cost-effective, affordable, and safe alternative remedies for the prevention/mitigation and management of AD. Plant-derived anti-oxidant/anti-inflammation macromolecules (e.g., curcumin, genistein, melatonin, resveratrol, vanillic acid, caffeic acid, berberine) and nutraceuticals (Gingko Biloba) appear to be the safer and cost-effective promising options for the prevention/progression and management of AD patients. The underlying causes and pathological mechanisms of AD are multiple and complex, which include genetic, epigenetic, non-genetic and environmental risk factors. Lifestyle aspects (e.g., excessive tobacco smoking and alcohol abuse), unhealthy dietary habits, accumulation of heavy metals (arsenic, lead, cobalt, mercury) in CNS, and chronic viral infections are considered some other risk factors in memory loss and AD. Brain has relatively low levels of antioxidants and low repair capacity of neuronal cells. Reduced blood supply and impaired mitochondria promote lesser ATP synthesis and energy support in the brain. Many studies have suggested that excessive oxidative stress in the brain leads to the overproduction of free radicals like reactive oxygen species (ROS) and reactive nitrogen species (RNS) from mitochondrial damage and reduction of ATP synthesis. The unabated over production of ROS/RNS cause insults to brain lipids by intiating lipid peroxidation and damage to cellular molecules, resulting in pathological injury and neuronal death. Antioxidant and anti-inflammation phytomolecules, dietary flavonoids, and nutraceuticals have gained significant importance for scavenging the free radicals and producing neuro-protective and memory-enhancing effects. Systematic searches were done using PUBMED, EMBASE, Scopus, Google Scholar, ResearchGate, and Web of Science databases. Numerous in vitro and in vivo studies have demonstrated that dietary antioxidant/anti-inflammation flavonoids, micronutrients (vitamins, trace metals, amino acids), and plant-derived polyphenols synergistically exhibit neuroprotective activity in AD animal models by stimulating transcription of the endogenous antioxidant system in the brain. The aims and objectives of this review are to recapitulate the current knowledge about the pathophysiology of AD and to shed light on the therapeutic strategies being used for slowing down the progression of dementia and cognitive decline.  We will also provide an overview of the proposed underlying mechanisms of different neutraceuticals and their recommended dosages in the prevention/mitigation of AD along with a summary of the antioxidant/anti-inflammation ingredients present in patented formulations

New insights into molecular targets for urinary incontinence

Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI

Resveratrol and Its Role in the Management of B-Cell Malignancies—A Recent Update

The growing incidence of B cell malignancies globally has prompted research on the pharmacological properties of phytoconstituents in cancer management. Resveratrol, a polyphenolic stilbenoid widely found in nature, has been explored for its anti-inflammatory and antioxidant properties, and promising results from different pre-clinical studies have indicated its potential for management of B cell malignancies. However, these claims must be substantiated by a greater number of clinical trials in diverse populations, in order to establish its safety and efficacy profile. In addition to this, there is a need to explore nanodelivery of this agent, owing to its poor solubility, which in turn may impact its bioavailability. This review aims to offer an overview of the occurrence and pathogenesis of B cell malignancies with a special focus on the inflammatory pathways involved, the mechanism of actions of resveratrol and its pharmacokinetic profile, results from pre-clinical and clinical studies, as well as an overview of the marketed formulations. The authors have also presented their opinion on the various challenges associated with the clinical development of resveratrol and future perspectives regarding therapeutic applications of this agent

Determination of Site of Absorption of Propranolol in Rat Gut Using In Situ Single-Pass Intestinal Perfusion

Previously, permeability and site of intestinal absorption of propranolol have been reported using the Ussing chamber. In the present study, the utility of Single-Pass Intestinal Perfusion to study permeability and site of intestinal absorption of propranolol was evaluated in rats. Drug permeability in different regions of rat intestine viz. duodenum, jejunum, ileum and colon was measured. Propranolol (30 μg/ml) solution was perfused in situ in each intestinal segment of rats. Effective permeability (Peff) of propranolol in each segment was calculated and site of absorption was determined. The Peff of propranolol in rat duodenum, jejunum, ileum and colon was calculated to be 0.3316×10-4 cm/s, 0.4035×10-4cm/s, 0.5092×10-4 cm/s and 0.7167×10-4 cm/s, respectively. The above results suggest that permeability of propranolol was highest through colon compared to other intestinal sites, which is in close agreement to that reported previously. In conclusion, in situ single pass intestinal perfusion can be used effectively to study intestinal permeability as well as site of intestinal absorption of compounds in rats