Evaluation of Stress and Associated Biochemical Changes in Patients with Type 2 Diabetes Mellitus and Obesity.

PURPOSE: Type 2 diabetes mellitus (T2DM), a metabolic disorder, remains associated with a physiological impairment affecting large populations worldwide. Onset of T2DM is multifactorial where obesity and abnormal basal metabolic rate are considered most critical. Of people diagnosed with T2DM, about 80% are also obese. It is also reported that obese individuals have an increased odds of developing depression, whereas T2DM is estimated to increase the incidence by two-fold. The preponderance of research data demonstrates that T2DM alters the serum level of cortisol and adiponectin which are known to be associated with neuronal physiology. The study explored, how a metabolic disorder like T2DM is linked with the altered plasma level of cortisol and adiponectin, the risk factors for stress and depression. PATIENTS AND METHODS: A cross-sectional population study was conducted in T2DM patients using a bimodal approach. First approach used questionnaires, (1) Patient Health Questionnaire (PHQ-9) and (2) Stress Coping Inventory Questionnaire (SCQ) to assess signs and symptoms of depression and stress, respectively, in T2DM patients. In the second approach, robust biochemical analysis was conducted for serum adiponectin and cortisol levels. RESULTS: An association of T2DM in stress and depression was evaluated in 158 subjects (105 T2DM obese patients and 53 healthy controls). A lower PHQ-9 score and adiponectin levels were seen in T2DM obese patients compared to healthy controls (p<0.05). Further, results also depicted a lower adiponectin levels in T2DM obese patients with depression compared to T2DM obese patients without depression (p<0.05). The study did not find a significant difference in cortisol serum levels among the T2DM and control groups. However, a higher level of serum cortisol was reported in T2DM obese patients with depression over those T2DM obese patients who lacked depression (p<0.05). CONCLUSION: The findings suggest that T2DM obese patients might have a higher risk of developing stress and depression. Further, biochemical parameters, adiponectin and cortisol, might be the potential biomarkers for T2DM and may help in early diagnosis of these comorbid conditions.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study.

BACKGROUND & OBJECTIVES: In India, the burden of Plasmodium vivax malaria has been projected to be highest in some areas. This study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate (AM) 37.5 mg and piperaquine phosphate 187.5 mg (PQP) dispersible tablets and (not with) chloroquine in the treatment of uncomplicated vivax malaria in pediatric patients. METHODS: This multicentric, open-label trial was carried out at 12 sites in India. A total of 164 patients aged 6 months to 12 years with P. vivax malaria were randomized in a ratio of 2:1 to AM-PQP (111 patients) or chloroquine (53 patients) arms. The duration of follow up was 42 days. RESULTS: At 72 hours, the proportion of a parasitaemic and afebrile patients was 100% in both treatment arms in per protocol (PP) population, and 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively, in intent to treat (ITT) population. The efficacy and safety of AM-PQP was found to be comparable to chloroquine in the treatment of uncomplicated P. vivax malaria in pediatric patients. Overall, the cure rate at Day 28 and 42 was >95% for both AM-PQP or CQ. The commonly reported clinical adverse event was vomiting. No patient was discontinued for any QTc abnormality. INTERPRETATION & CONCLUSION: The efficacy and safety of FDC of arterolane maleate and piperaquine phosphate was found to be comparable to chloroquine for treatment of uncomplicated P. vivax malaria in pediatric patients.

Atherosclerosis risk assessment in patients with chronic obstructive pulmonary disease: a case-control study.

PURPOSE: Chronic Obstructive Pulmonary Disease (COPD) is considered as a risk factor for atherosclerosis and a leading cause of mortality due to cardiovascular disease (CVD). The study assessed the association of COPD with atherosclerotic risk factors and compared the predictor role of various cardiovascular (CV) risk score calculators in Indian subjects with COPD. PATIENTS AND METHODS: Forty subjects with stable COPD and forty age, gender and body mass index (BMI)-matched healthy controls were included in the case-control study conducted in a tertiary care hospital. Atherogenic indices were calculated by using the values of lipid parameters. CV risk calculators were utilized to assess the 10-year CV risk for the COPD group. RESULTS: The study subjects had a mean age of 60.83±12.40 years in COPD group and 57.73±9.49 years in control group (p=0.213). Gender distribution was similar in both the groups. The mean High sensitivity C-reactive protein (hs-CRP) levels were 3.70±2.37 mg/L in COPD group and 2.39±2.23 mg/L in control group. The hs-CRP levels were significantly higher in COPD than in control subjects (p=0.012). Using bivariate correlations, we found significant positive correlations between hs-CRP and atherogenesis indices-atherogenic index of plasma, cardiogenic risk ratio, atherogenic coefficient in COPD patients [(r=0.4265, p<0.006); (r=0.7034, p<0.001) and (r=0.7034, p<0.001), respectively]. Framingham risk score-cardiovascular disease (FRS-CVD) has identified maximum number of COPD subjects (45%) to be in high CVD risk category. CONCLUSION: The study concluded that hs-CRP levels in COPD subjects were significantly higher than in control subjects. FRS-CVD was most useful for identifying high CV risk subjects in COPD subjects.

Review of the Literature Examining the Association of Serum Uric Acid with Osteoporosis and Mechanistic Insights into Its Effect on Bone Metabolism.

BACKGROUND AND OBJECTIVE: Osteoporosis is a common bone disorder that increases susceptibility to fragility bone fractures. The clinical and public health repercussions of osteoporosis are huge due to the morbidity, mortality, and cost of medical care linked with fragility fractures. Clinical assessment of osteoporotic risk factors can help to identify candidates at an early stage that will benefit from medical intervention and potentially lowering the morbidity and mortality seen with fractures and complications. Given this, research is ongoing to evaluate the association of osteoporosis with some novel or less well-studied risk factors/bio-markers such as uric acid (UA). DISCUSSION: Uric acid's antioxidant activity has been proposed to be one of the factors responsible for increasing longevity and lowering rates of age-related cancers during primate evolution, the level of which increased markedly due to loss of uricase enzyme activity (mutational silencing). Accumulated evidence shows that oxidative stress is the fundamental mechanism of age-related bone loss and acts via enhancing osteoclastic activity and increasing bone resorption. Antioxidant substances such as ascorbic acid scavenge free radicals are positively related to bone health. Thus, it is hypothesized that uric acid holds bone-protective potential owing to its potent antioxidative property. Several correlation studies have been conducted globally to investigate the relationship between serum uric acid with bone mineral density and osteoporosis. Few pre-clinical studies have tried to investigate the interaction between uric acid and bone mineral density and reported important role played via Runt-related transcription factor 2 (RUNX2)/core-binding factor subunit alpha-1 (CBF-alpha-1), Wingless-related integration site (Wnt)-3a/ß-catenin signaling pathway and 11ß Hydroxysteroid Dehydrogenase type 1. CONCLUSION: In this review, the authors provided a comprehensive summary of the literature related to association studies reported in humans as well work done until date to understand the potential cellular and molecular mechanisms that interplay between uric acid and bone metabolism.

Raised serum uric acid is associated with higher bone mineral density in a cross-sectional study of a healthy Indian population.

PURPOSE: Oxidative stress has been implicated as a fundamental mechanism in the decline of bone mass. Reactive oxygen species are reported to suppress osteoblast generation and differentiation and enhance osteoclast development and activity. Increasing evidence suggests favorable effect of serum uric acid (UA) on bone metabolism due to its antioxidant properties. Therefore, we investigated the association between serum UA levels and bone mineral density (BMD) in healthy adult Indian subjects. MATERIALS AND METHODS: We reviewed the medical records of 524 subjects who had undergone preventive health check-ups in a tertiary care hospital that included UA and BMD measurements at femur neck, total femur, and lumbar spine. Subjects concomitantly taking drugs or having a medical condition that would affect the bone metabolism or UA levels were excluded. RESULTS: The final analysis included 310 subjects (mean age: 47.2±12.2 years; females: 43.5%; males: 56.5%). Study population was categorized into two groups based on the group median value for UA (ie, 5.4 mg/dL). BMD was significantly higher at all skeletal sites in subjects with UA >5.4 mg/dL compared to subjects with UA ≤5.4 mg/dL (p<0.001). On correlation analysis, UA was positively associated with BMD at all skeletal sites (r=0.211-0.277; p<0.05). The correlation remained significant after controlling for age (p<0.05) and lifestyle factors (smoking, alcohol use, physical activity, and diet; p<0.05) independently. UA significantly (p<0.001) accounted for 4.5%-7.7% of the variance in BMD (r2=0.045-0.077) in unadjusted model and 1.6%-3.2% of the variance (p<0.05) when adjusted for age and body mass index combined at lumbar spine and right femur neck, respectively. CONCLUSION: We conclude that raised UA levels are associated with higher BMD at all skeletal sites and UA may have a protective role in bone metabolism owing to its antioxidant effect.

Prevalence of osteoporosis and osteopenia in an apparently healthy Indian population - a cross-sectional retrospective study.

OBJECTIVES: An understanding of bone mineral density (BMD) pattern in a population is crucial for prevention and diagnosis of osteoporosis and management of its complications in later life. This study aimed to screen the bone health status and factors associated with osteoporosis in an apparently healthy Indian population. METHODS: A retrospective review of medical records was done in a tertiary-care hospital for the subjects who had undergone preventive health-check-ups that included BMD measurements at femur-neck, total-femur, and lumbar-spine. RESULTS: We evaluated 524 subjects (age, 50.0 ±â€¯12.4 years) including 41.2% female and 58.8% male subjects. Osteoporosis was present in 6.9% subjects (female, 11.1%; male, 4.2%) and osteopenia in 34% subjects (female, 40.3%; male, 29.9%). Absolute BMD was higher in male subjects (P < 0.001) compared to female subjects at all bone sites. Prevalence of osteoporosis increased with age in female subjects, but not in male subjects. Osteoporosis rates in the age-groups of 30-39, 40-49, 50-59, 60-69, and ≥70 years were 3%, 3.4%, 14.3%, 18.6%, and 36.4%, respectively in female subjects while prevalence in male subjects was 0%, 4%, 6.5%, 4.3%, and 5.6%, respectively, at lumbar spine. Height (r = 0.234-0.358), weight (r = 0.305-0.388), body mass index (r = 0.143-0.285) and physical activity (r = 0.136-0.153) were positively; and alkaline phosphatase (r = -0.133 to -0.203) was negatively correlated with BMD (all P < 0.01) at all sites. These parameters retained significant correlation after controlling for age and sex. No correlation of serum 25-hydroxy-vitamin-D and calcium was noted with BMD (P > 0.05) at any site. CONCLUSIONS: Further data on absolute BMD, T scores, and prevalence rates of osteoporosis/osteopenia on multiple bone sites have been presented in this article.

Relevance of the Weber effect in contemporary pharmacovigilance of oncology drugs.

BACKGROUND: Numerous reporting biases have been known to affect spontaneous reporting databases. The Weber effect, which constitutes a peak in adverse event (AE) reporting of a drug at the end of second year after regulatory approval followed by a continuous decline thereafter, has been considered an important bias for a long time. The existence of this bias in AE reporting of oncology drugs remains an underevaluated area, prompting a targeted examination. METHODS: The US Food and Drug Administration (USFDA) Adverse Event Reporting System (FAERS) was studied for AE reporting patterns of 5 years of 15 new molecular entities (NMEs) and biologics used in oncology. This 5-year period started from the USFDA date of approval for the NMEs and biologics. The number of AEs reported for each of the drugs was plotted against time (years). The AE reporting patterns were specifically examined for the existence of the Weber effect. In addition, AE reporting rate patterns of 5 years of seven NMEs and biologics used in oncology were examined. RESULTS: A total of 50,630 AE reports were logged in to the FAERS for all 15 drugs examined for AE reporting patterns. We observed five distinct AE reporting patterns for 15 drugs; however, none of the AE patterns were identical to the Weber effect. We did not observe a consistent AE reporting rate pattern for the seven drugs examined for AE reporting rates. With the exception of one drug (cetuximab), none of the drugs exhibited a second-year peak in AE reporting rates. This peak was not followed by continuous decline in AE reporting rate thereafter. CONCLUSION: This study does not support the existence of the Weber effect in AE reporting of oncology drugs. The contemporary AE reporting of oncology drugs does not exhibit a consistent pattern.

Assessment of Efficacy and Safety of Arterolane Maleate-Piperaquine Phosphate Dispersible Tablets in Comparison With Artemether-Lumefantrine Dispersible Tablets in Pediatric Patients With Acute Uncomplicated Plasmodium falciparum Malaria: A Phase 3, Randomized, Multicenter Trial in India and Africa.

BACKGROUND: Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children. METHODS: This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days. RESULTS: The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar. CONCLUSIONS: The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients. CLINICAL TRIALS REGISTRATION: CTRI/2014/07/004764.

A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate-Piperaquine Phosphate vs Artemether-Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa.

BACKGROUND: Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria. METHODS: In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. RESULTS: Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. CONCLUSIONS: AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. CLINICAL TRIALS REGISTRATION: India. CTRI/2009/091/000101.

Comparison of the safety and efficacy of fixed-dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax malaria: a phase III, multicentric, open-label study.

BACKGROUND: Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria. METHODS: Patients aged 13-65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days. RESULTS: In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100% (140/140) in the FDC of arterolane maleate and PQP group, and 99.3% (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9% (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95% CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4% in the FDC of arterolane maleate and PQP group and 85.4% in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1%), headache (1.3 vs 3.2%) and prolonged QT (1.9 vs 3.2%). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h. CONCLUSIONS: The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study.

BACKGROUND: The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years. METHODS: Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph. RESULTS: A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study. CONCLUSION: The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets. TRIAL REGISTRATION: Clinical Trial Registry India: CTRI/2009/091/000531.