Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. METHOD: A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. RESULTS: In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. CONCLUSIONS: Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Development and Validation of a Simple High-Pressure Liquid Chromatography-Ultraviolet Detection Method for Simultaneous Quantitation of First-Line Anti-Tuberculosis Drugs in Formulations of Fixed-Dose Combination.

The current treatment protocol for drug-sensitive tuberculosis involves all four first-line anti-tuberculosis drugs: rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride in a single tablet, known as fixed-dose combination tablets. However, the analytical methods are scanty to test all these drugs simultaneously in a single run without any pre-sample process or using a simple method suitable for resource-limited settings. In this method, 50 mM potassium phosphate buffer containing 0.2% triethylamine (without pH adjustment) added with acetonitrile (98:2, v/v) was served as mobile phase A, while mobile phase B was 100% acetonitrile. All four drugs were separated within 10.3 min using a gradient mobile phase program in a C18 column (150 mm × 4.6 mm; 5 µm) and detected at two ultraviolet wavelengths (238 nm for rifampicin, isoniazid and pyrazinamide, and 210 nm for ethambutol hydrochloride). The method was selective, sensitive and linear with a correlation coefficient >0.999 with the acceptable precision and accuracy (<2% relative standard deviation) for all four drugs. In conclusion, the method is simple and it does not require any pH adjustment of the buffer/mobile phase, and within 11 min, the separation of all four drugs can be achieved. Overall, the method is suitable for quality testing of fixed-dose combination tablets in limited-resource settings.

Assessment of virgin coconut oil in a balanced diet on indicators of cardiovascular health in non-obese volunteers: A human metabolic study.

BACKGROUND AND AIMS: Consumption of coconut oil is implicated in cardiovascular disease risk. On the contrary, virgin coconut oil (VCO) is believed to offer better health benefits, however, the evidence to support such claims is lacking, particularly in humans. Therefore, this study aimed at assessing the impact of VCO in a balanced diet on HDL-C and some of the anthropometric and biochemical parameters associated with human cardiovascular health before and after the feeding experiment. METHODS: In a crossover observational study, apparently healthy non-obese male volunteers (n = 22) aged between 28 and 50years with a mean body weight of 67.5 kg were inducted into a two-arm controlled feeding experiment one after another for eight weeks with a six-week washout period. In the first arm, the diets were prepared with VCO, whereas peanut oil was used in the second arm (∼35g/day) as the control. RESULTS: Compared to baseline, the consumption of VCO did not affect HDL-C and anthropometric measures at the end of the 8th week, whereas plasma total cholesterol (TC) and LDL-C levels (Means±standard error; 172 ± 5.6 mg/dL versus 186 ± 5.9 mg/dL and 113 ± 4.29 mg/dL versus 126 ± 4.17 mg/dL respectively) increased significantly. However, plasma triglycerides and some of the cardiovascular risk markers (namely, vascular cell-adhesion molecules, serum amyloid proteins and C-reactive protein) remained unaltered. Further, most of the changes in the VCO arm were comparable to the peanut oil regimen. CONCLUSION: The consumption of VCO in a balanced diet displayed neutral effects on most parameters related to cardiovascular risk. However, the rise in TC and LDL-C must be tested in a larger sample size over longer periods.

Long-Term Intake of Linezolid Elevates Drug Exposure and Reduces Drug Clearance and Elimination in Adults With Drug-Resistant Pulmonary Tuberculosis.

PURPOSE: Pharmacokinetic (PK) studies are critical for dose optimization, and there is a paucity of linezolid (LZD) PK data for prolonged use in drug-resistant tuberculosis (DR-TB). Therefore, the authors evaluated the pharmacokinetics of LZD at two-time intervals in DR-TB during long-term use. METHODS: PK evaluation of LZD was performed at the end of the 8th and 16th weeks of treatment in a randomly selected subset of adult pre-extensively drug-resistant pulmonary tuberculosis patients (n = 18) from a multicentric interventional study (Building Evidence to Advance Treatment of TB/BEAT study; CTRI/2019/01/017310), wherein a daily dose of 600 mg LZD was used for 24 weeks. Plasma LZD levels were measured using a validated high-pressure liquid chromatography (HPLC) method. RESULTS: The LZD median plasma C max was comparable between the 8th and 16th weeks [18.3 mg/L, interquartile range (IQR: 15.5-20.8 and 18.8 mg/L, IQR: 16.0-22.7, respectively)]. However, the trough concentration increased significantly in the 16th week (3.16 mg/L, IQR: 2.30-4.76), compared with the 8th week (1.98 mg/L, IQR: 0.93-2.75). Furthermore, compared with the 8th week, in the 16th week, there was a significant increase in drug exposure (AUC 0-24 = 184.2 mg*h/L, IQR: 156.4-215.8 versus 233.2 mg*h/L, IQR: 187.9-277.2), which corroborated with a longer elimination half-life (6.94 hours, IQR: 5.55-7.99 versus 8.47 hours, IQR:7.36-11.35) and decreased clearance (2.91 L/h, IQR: 2.45-3.33 versus 2.19 L/h, IQR: 1.49-2.78). CONCLUSIONS: Long-term daily intake of 600 mg LZD resulted in a significant elevation in trough concentration (>2.0 mg/L) in 83% of the study participants. Furthermore, increased LZD drug exposure may be partly because of decreased clearance and elimination. Overall, the PK data underscore the need for dose adjustment when LZDs are intended for long-term treatment.

Stearoyl-CoA desaturase 1: A potential target for non-alcoholic fatty liver disease?-perspective on emerging experimental evidence.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease and one of the leading causes of death. An unnamed disease has become a global epidemic disease of public health concern. This spectrum of diseases manifests itself with initial accumulation of excessive triglycerides (due to de novo lipogenesis) in the hepatocytes, leading to simple steatosis. Although its aetiology is multi-factorial, lifestyle changes (diet and physical activity) are considered to be the key thriving factors. In this context, high fructose consumption is associated with an increased risk for developing NAFLD in humans, while high-fructose feeding to experimental animals results in hepatic steatosis and non-alcoholic steatohepatitis, by increasing hepatic lipogenesis. Among several lipogenic genes, the endoplasmic reticulum-bound stearoyl-CoA desaturase 1 (SCD1) is the key determinant of triglycerides biosynthesis pathway, by providing monounsaturated fatty acids, through the incorporation of a double bond at the delta-9 position of saturated fatty acids, specifically, palmitic (C16:0) and stearic (C18:0) acids, yielding palmitoleic (C16:1) and oleic (C18:1) acids, respectively. Various experimental studies involving SCD1 gene knockout and diet-induced rodent models have demonstrated that SCD1 plays a key role in the development of NAFLD, by modulating hepatic lipogenesis and thus triglyceride accumulation in the liver. Several pharmacological and dietary intervention studies have shown the benefits of inhibiting hepatic SCD1 in the pathogenesis of NAFLD. In this review, we give an overview of SCD1 in NAFLD, based on the current experimental evidence and the translational applicability of SCD1 inhibition in human NAFLD conditions, besides discussing the limitations and way-forward.

Consumption of vitamin A-deficient diet elevates endoplasmic reticulum stress marker and suppresses high fructose-induced orexigenic gene expression in the brain of male Wistar rats.

OBJECTIVE: Here, we assessed the impact of vitamin A deficiency (both alone and in combination with fructose) on the retinol status, phospholipids fatty acid composition and pathways associated with the endoplasmic reticulum (ER) stress and energy homeostasis of the brain. For this purpose, weanling male Wistar rats were divided into four groups consisting of 8 rats each, except 16 for the second group and they received one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and HFr with VAD for 16 weeks, except half of the VAD diet-fed rats, were shifted to HFr diet, after 8 weeks period. RESULTS: The retinol content of the whole brain remained comparable across the groups, despite a significant reduction in the plasma at the end of VAD diet feeding. However, it suppressed the HFr-induced neuropeptide Y and agouti-related peptide, while rescuing the leptin receptor mRNA. Among ER stress markers, CCAAT/Enhancer-binding protein homologues protein levels were elevated significantly in the VAD diet-fed group. Further, the long-chain polyunsaturated fatty acid levels showed an increase in the brain phospholipids across the experimental groups, compared to that of the control. CONCLUSION: Vitamin A deficiency causes ER stress in the brain, and retinol seems to play a regulatory role in the fructose-mediated transcriptional regulation of the genes involved in energy homeostasis.

Micronutrient Deficiency in Pulmonary Tuberculosis - Perspective on Hepatic Drug Metabolism and Pharmacokinetic Variability of First-line Anti- Tuberculosis Drugs: Special Reference to Fat-soluble Vitamins A, D, & E and Nutri-epigenetics.

The liver plays a crucial role in endogenous metabolic activity and homeostasis of macro and micronutrients. Further, it acts as a metabolic hub in mammals, where the ingested food-derived nutrients and xenobiotics or drugs are metabolized for utilization and/or excretion through its enzymatic and non-enzymatic machinery. Nutritional deficiency, one of the major public health problems, is associated with global disease burden, including pulmonary tuberculosis (PTB) caused by Mycobacterium tuberculosis (Mtb) infection. Though it is a curable and preventable infectious disease, millions of people succumb to death, and people in numbers larger than this are still suffering. This scenario is further complicated by the addition of new cases, disease recurrence, and the emergence of drug-resistant, all of which contribute to the spread of this epidemic. Though the manifestation of TB disease has multiple aetiologies, poor nutritional status and sub-optimal therapeutic concentrations of first-line anti-TB drugs are considered as potential contributors to its widespread prevalence. Among various factors, the pharmacokinetic variability of anti-TB drugs is one of the main causes for sub-optimal therapeutic drug concentration in TB patients, which is influenced by the host's genetic make-up and nutritional status, besides several others. However, the role of epigenetic changes in hepatic drug metabolic pathways and their transcript levels is largely unexplored. Therefore, in this review, an attempt has been made to understand the role of micronutrient deficiencies with special reference to fat-soluble vitamins, namely vitamin A, D, & E in pulmonary TB, their possible impact on epigenetic changes on the drug-metabolizing pathway genes, thus their expression levels and plausible influence on pharmacokinetic variability of anti-TB drugs, besides discussing the limitations and emerging potential opportunities. Eventually, this would help in developing the host-directed/personalized therapeutic strategies for the elimination of pulmonary tuberculosis (PTB).

Carrot Juice Consumption Reduces High Fructose-Induced Adiposity in Rats and Body Weight and BMI in Type 2 Diabetic Subjects.

Nutritional intervention is a key strategy in the control and management of non-communicable diseases. Here, initially, we evaluated the effects of carrot juice (CJ) on some of the physical and biochemical parameters in rats fed with high-fructose diet, then in type 2 diabetic subjects. For the animal study, weanling male Wistar rats were given control (n = 6) or high fructose (HFr; n = 24) diet for 8 weeks. Then, the HFr group rats were subdivided into 4 groups (n = 6 in each) and continued either on HFr diet or shifted to control diet, with or without CJ (0.3 mg ß-carotene) ingestion orally for 8 weeks. At the end, the ingestion of CJ reversed the HFr-induced adiposity (23 ± 1.6 vs 18 ± 1.1, P = .038), hypertriglyceridemia (182 ± 18.2 vs 90 ± 10.5 mg/dL, P<0.001), and hyperinsulinemia (81 ± 14.7 vs 40 ± 7.5 µU/mL, P = .014), while increased the retinol levels in liver (240 ± 38.4 vs 492 ± 61.2 µg/g, P = .002) and adipose tissue (1.8 ± 0.09 vs 2.5 ± 0.18 µg/g, P = .026). On the other hand, in the diabetic subjects (7 males and females each, n = 14) compared to their baseline, the daily consumption of 50 mL CJ (~2400 µg ß-carotene) for 6 weeks significantly reduced the body weight (69.4 ± 4.13 vs 69.0 ± 4.09 kg, P = .014), BMI (27.4 ± 1.07 vs 27.2 ± 1.06 kg/m2, P = .007), and fat% (33.4 ± 1.87 vs 31.9 ± 2.13, P = .029) with an increase in plasma ß-carotene levels (0.21 ± 0.045 vs 0.45 ± 0.089 µmol/L, P = .044). Although CJ increased the glucose (145 ± 10.4 vs 165 ± 11.4 mg/dL, P = .039), insulin, and glycated hemoglobin levels remained unaltered. In conclusion, the consumption of carrot juice reversed the HFr-induced metabolic abnormalities in a rat model and decreased body weight and BMI of diabetic subjects.

Coconut oil consumption improves fat-free mass, plasma HDL-cholesterol and insulin sensitivity in healthy men with normal BMI compared to peanut oil.

BACKGROUND & AIMS: The existing scientific evidence on coconut oil consumption and its health effects remains inconclusive due to varied reasons. In this context, we conducted a well-controlled metabolic study, eliminating some of the confounding factors and assessed the effects of the consumption of coconut oil-based diet on various anthropometric, biochemical and inflammatory markers and compared with peanut oil-diet. METHODS: Nine healthy male volunteers with BMI ≤25 kg/m2 were enrolled for this study and given balanced diets prepared with coconut oil (CO; ~35 g) for a period of eight weeks. After a wash-out period of six weeks, the same subjects were provided with diets prepared with peanut oil (~35 g) for eight weeks. Except fat source, the composition of the diets was identical in all aspects. RESULTS: Compared to basal values, there were significant increases in fat-free mass (p ≤ 0.022), plasma HDL-cholesterol (HDL-C) (p ≤ 0.047) and insulin sensitivity of the subjects at the end of CO-consumption. Further, compared to peanut oil, increase in plasma HDL-C was significant (p = 0.004) in CO treatment. On the other hand, plasma inflammatory markers-associated with cardiovascular diseases (CVD), namely soluble vascular cell adhesion molecule 1 (sVCAM1) and matrix metalloproteinase levels were reduced significantly by CO-intake. Further, these subjects displayed elevated levels of myristic acid (14:0) in plasma phospholipids at the end of CO-consumption, which correlated positively with HDL-C and negatively with sVCAM1. However, no such changes were observed after peanut oil diet consumption. CONCLUSIONS: In conclusion, compared to peanut oil, the consumption of coconut oil in a balanced diet resulted in increased fat-free mass, plasma HDL-C, elicited favourable changes on insulin sensitivity and CVD risk-associated parameters in healthy men with normal BMI.

Vitamin A deficiency increases the oleic acid (C18:1) levels in the kidney of high fructose diet-fed rats.

Background & objectives: Stearoyl-CoA desaturase 1 (SCD1) is a key lipogenic enzyme responsible for endogenous synthesis of monounsaturated fatty acids (MUFA) and plays a key role in various pathophysiology, including fatty liver diseases. In this experimental study the impact of vitamin A deficiency was assessed on SCD1 regulation in relation to kidney biology, under high fructose (HFr) diet-fed condition in rats. Methods: Forty male weanling (21 day old) Wistar rats were divided into four groups control, vitamin A-deficient (VAD), HFr, VAD with HFr consisting of eight rats each, except 16 for the VAD group. The groups received one of the following diets: control, VAD, HFr and VAD with HFr for 16 wk, except half of the VAD diet-fed rats were shifted to HFr diet, after eight week period. Results: Feeding of VAD diet (alone or with HFr) significantly reduced the kidney retinol (0.51, 0.44 µg/g vs. 2.1 µg/g; P < 0.05), while increased oleic (C18:1) and total MUFA levels (23.3, 22.2% and 27.3, 25.4% respectively vs. 14.7 and 16.6%; P < 0.05) without affecting the SCD1, both at protein and mRNA levels, when compared with HFr. Comparable, immunohistological staining for SCD1 was observed in the distal convoluted tubules. Despite an increase in MUFA, morphology, triglyceride content and markers of kidney function were not affected by VAD diet feeding. Interpretation & conclusions: Feeding of VAD diet either alone or under HFr condition increased the kidney oleic acid (C18:1) levels and thus total MUFA, which corroborated with elevated SCD1 activity index, without affecting its expression status. However, these changes did not alter the kidney morphology and function. Thus, nutrient-gene regulation in kidney biology seems to be divergent.

Development of Low Glycemic Index Foods and Their Glucose Response in Young Healthy Non-Diabetic Subjects.

Development of low glycemic-foods is important in the prevention and management of type 2 diabetes. In this context, we prepared four test foods (TFs) (two mixed mini-meals and two breakfast items) with low glycemic-components and assessed their glycemic index (GI) in young healthy non-diabetic volunteers with mean age of 29 yr, body mass index of 24 kg/m2, and fasting plasma glucose levels less than 4.62 mmol/L. Volunteers were given 50 g of glucose, as a reference food (RF) on the first day, and TFs, i.e. TF1 (mixed mini meal: roti made of wheat flour and chana dal+ curd), TF2 [mixed mini meal made of wheat, pearl barley, and Bengal gram flour (besan) mix with chana whole (unhusked chana+curd)], TF3 (pearl barley rawa upma), and TF4 (wheat rawa upma) were given 2-day intervals in the same order. Glucose levels at fasting conditions and after the consumption of RF and TFs at different time intervals (15, 30, 45, 60, 90, and 120 min) were measured, and the incremental area under curve (IAUC) for glucose and GI of the TFs were calculated. The glucose IAUC values at different time points were highest for TF2 (GI=71.9±7.4), while all other TFs had comparable GI in the range of 53.7~54.9. Among the various TFs, TF1, TF3, and TF4 exerted low to moderate glycemic response, and thus can be classified as low glycemic-foods. Nevertheless, these foods need to be tested for their efficacy in controlling and/or managing hyperglycemia and glucose over-load in diabetic subjects.