18 research outputs found
Flibanserin: a serendipitous story
Female sexual disorders are increasingly being recognized in the population and hypoactive sexual desire disorder (HSDD) is one of the commonest sexual disorders among females. The prevalence of the disease varies between 10-20% in the Caucasian population. Testosterone is the only treatment that is approved by the European Medical Agency. Flibanserin is a drug that has been approved by the US FDA for HSDD among pre-menopausal women in 2015. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist that rebalances the neural circuitry involved in processing sexual desire by reducing serotonin activity and enhancing dopamine and epinephrine activity. The efficacy of the drug was confirmed in three pivotal randomized placebo control trials in premenopausal women who consumed the drug for 24 weeks. There was a significant improvement in the number of sexually satisfying events. The most common safety concerns for flibanserin as seen in clinical trials were somnolence, hypotension and syncope. The drug is prescribed at a dose of 100 mg once daily at bed time. The marginal efficacy of the drug coupled with other safety concerns, such as hypo-tensions have given room for much criticism over the drug’s approval by the FDA. Nevertheless, on a positive note the serendipitous discovery of flibanserin and its repurposing for HSDD is a compelling narrative in its drug development history. It remains to be seen if the long term safety of the molecule and the efficacy of the molecule in non-trial settings could make it an attractive pharmaco-therapeutic option for HSDD
Lesinurad: a novel therapeutic option in the pharmacotherapy of gout
Gout is characterized by painful joint inflammation, most commonly in the first metatarsophalangeal joint, resulting from precipitation of monosodium urate crystals in a joint space. Current therapies for chronic gout include mainly allopurinol and febuxostat. Inspite of the availability of these medications for several years, a significant number of patients do not have adequate control of uric acid levels resulting in acute gout flares. Lesinurad is the most recent drug molecule approved by US FDA & EMA for the treatment of gout in patients with uncontrolled gout along with allopurinol. Lesinurad prevents reabsorption of uric acid from the renal tubules, resulting in uricosuria. The efficacy of the lesinurad was demonstrated in three randomized phase 3 controlled clinical trials where the drug was primarily evaluated in the setting of background therapy with allopurinol or febuxostat. There is a definite risk of nephrotoxicity with monotherapy and when the drug is used in patients who have inadequate renal function. The drug does appear to be relatively safe, though the inconclusive cardiovascular safety of the drug has prompted the regulatory agency to mandate post marketing trials to evaluate the safety of this molecule. Nevertheless, lesinurad does appear to have a lot of promise as a front line drug molecule in the control of hyperuricemia
Association of galectin-3 with high cardiovascular risk in patients with type 2 diabetes attending a multi-specialty hospital in South India
Background: Diabetes mellitus is a chronic hyperglycemic condition that continues to be associated with high mortality and morbidity. Galectin-3 is a β-galactoside binding lectin and is a potential marker for inflammation, immunity and fibrosis. The aim of the study was to evaluate the relationship between Galectin-3 and baseline characteristics and to find the association between Galectin-3 and high cardiovascular risk in a group of Type-2 diabetes patients.Methods: A total of 100 patients with type-2 diabetes mellitus were included in the study after obtaining informed consent. The study participants were divided into two groups; those with diabetes for duration of less than 5 years as Group-1 and diabetes greater than 5 years as Group-2. Patients were also divided into three tertiles based on the Inter heart risk score (IHR). Five ml of blood was withdrawn from the ante-cubital vein and the serum obtained was subjected to analysis for estimating concentration of Galectin-3.Results: There was no significant difference between the Group-1 and Group-2 except gender variation with a significantly higher preponderance of males in Group 2. There was a significant correlation between Galectin-3 and parameters such as systolic blood pressure (r=0.033, p=0.03), creatinine (r=0.20, p=0.03), IHR (r=0.69, p=0.0001). Patients in the high risk category had greater levels of Galectin-3 compared to those with low and intermediate IHR.Conclusions: Galectin-3 concentration is elevated in diabetes patients and correlates with the IHR-Score. Thus Galectin-3 could be a useful biomarker for prediction of cardiovascular risk in diabetic subjects
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Interaction between TCF7L2 polymorphism and dietary fat intake on high density lipoprotein cholesterol
Recent evidence suggests that lifestyle factors influence the association between the Melanocortin 4 receptor (MC4R) and Transcription Factor 7-Like 2 (TCF7L2) gene variants and cardio-metabolic traits in several populations; however, the available research is limited among the Asian Indian population. Hence, the present study examined whether the association between the MC4R single nucleotide polymorphism (SNP) (rs17782313) and two SNPs of the TCF7L2 gene (rs12255372 and rs7903146) and cardio-metabolic traits is modified by dietary factors and physical activity. This cross sectional study included a random sample of normal glucose tolerant (NGT) (n = 821) and participants with type 2 diabetes (T2D) (n = 861) recruited from the urban part of the Chennai Urban Rural Epidemiology Study (CURES). A validated food frequency questionnaire (FFQ) was used for dietary assessment and self-reported physical activity measures were collected. The threshold for significance was set at P = 0.00023 based on Bonferroni correction for multiple testing [(0.05/210 (3 SNPs x 14 outcomes x 5 lifestyle factors)]. After Bonferroni correction, there was a significant interaction between the TCF7L2 rs12255372 SNP and fat intake (g/day) (Pinteraction = 0.0001) on high-density lipoprotein cholesterol (HDL-C), where the 'T' allele carriers in the lowest tertile of total fat intake had higher HDL-C (P = 0.008) and those in the highest tertile (P = 0.017) had lower HDL-C compared to the GG homozygotes. In a secondary analysis of SNPs with the subtypes of fat, there was also a significant interaction between the SNP rs12255372 and polyunsaturated fatty acids (PUFA, g/day) (Pinteraction<0.0001) on HDL-C, where the minor allele carriers had higher HDL-C in the lowest PUFA tertile (P = 0.024) and those in the highest PUFA tertile had lower HDL-C (P = 0.028) than GG homozygotes. In addition, a significant interaction was also seen between TCF7L2 SNP rs12255372 and fibre intake (g/day) on HDL-C (Pinteraction<0.0001). None of the other interactions between the SNPs and lifestyle factors were statistically significant after correction for multiple testing. Our findings indicate that the association between TCF7L2 SNP rs12255372 and HDL-C may be modified by dietary fat intake in this Asian Indian population
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Evidence for the association between FTO gene variants and vitamin B12 concentrations in an Asian Indian population
Background
Low vitamin B12 concentrations have been associated with major clinical outcomes, including adiposity, in Indian populations. The Fat mass and obesity-associated gene (FTO) is an established obesity-susceptibility locus; however, it remains unknown whether it influences vitamin B12 status. Hence, we investigated the association of two previously studied FTO polymorphisms with vitamin B12 concentrations and metabolic disease-related outcomes and examined whether these associations were modified by dietary factors and physical activity.
Methods
A total of 176 individuals with type 2 diabetes, 152 with pre-diabetes, and 220 normal glucose-tolerant individuals were randomly selected from the Chennai Urban Rural Epidemiology Study. Anthropometric, clinical, and biochemical investigations, which included body mass index (BMI), waist circumference, vitamin B12, homocysteine, and folic acid were measured. A validated food frequency questionnaire was used for dietary assessment and self-reported physical activity measures were collected. An unweighted genetic risk score (GRS) was calculated for two FTO single-nucleotide polymorphisms (rs8050136 and rs2388405) by summation of the number of risk alleles for obesity. Interaction analyses were performed by including the interaction terms in the regression model.
Results
The GRS was significantly associated with increased BMI (P = 0.009) and risk of obesity (P = 0.023). Individuals carrying more than one risk allele for the GRS had 13.13% lower vitamin B12 concentrations, compared to individuals carrying zero risk alleles (P = 0.018). No associations between the GRS and folic acid and homocysteine concentrations were observed. Furthermore, no statistically significant GRS-diet or GRS-physical activity interactions with vitamin B12, folic acid, homocysteine or metabolic-disease outcomes were observed.
Conclusion
The study shows for the first time that a genetic risk score using two FTO SNPs is associated with lower vitamin B12 concentrations; however, we did not identify any evidence for the influence of lifestyle factors on this association. Further replication studies in larger cohorts are warranted to investigate the association between the GRS and vitamin B12 concentrations
The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design
Aims Cachexia, the wasting disorder associated with a wide
range of serious illnesses including cancer, is a major cause of morbidity and mortality. There is currently no widely approved therapeutic agent for treating or preventing
cancer-associated cachexia. Colorectal cancer and nonsmall
cell lung cancer have relatively high incidences of cachexia, approximately 28% and 34%, respectively.
Neurohormonal overactivity has been implicated in the
genesis and progression of cachexia and beta receptor
antagonism has been proposed as a potential therapy.
MT-102, a novel anabolic/catabolic transforming agent,
has a multi-functional effect upon three potential pharmacological targets in cancer cachexia, namely reduced
catabolism through non-selective β-blockade, reduced
fatigue, and thermogenesis through central 5-HT1a
antagonism and increased anabolism through partial β-2
receptor agonism.
Methods At least 132 male and female patients, aged
between 25 and 80 years with a confirmed diagnosis of
late-stage non-small cell lung cancer or colorectal cancer,
with cachexia will be randomised to either one of the two
MT-102 doses or placebo in a 3:1:2 ratio (MT-102
10 mg BD−1/MT-102 2.5 mg BD/placebo). Patients will
continue on study treatment for maximally 16 weeks. The
primary endpoint, to be analysed by assigned treatment
group, will be body weight change over 16 weeks. For this
endpoint, the study has 85% power (0.05% significance
level) to detect per 4-week period a mean change of −0.8 kg
in the placebo group and 0 kg in the high-dose MT-102
arm. The first patient was randomised in February 2011 and
patient recruitment is expected to continue until mid-2012.
Perspective The ACT-ONE trial is designed to test whether
the anabolic/catabolic transforming agent MT-102 will
positively impact on the rate of change of body weight in
cancer cachexia, thereby evaluating a novel therapeutic
strategy in this hitherto poorly treatable condition. A
separate ACT-TWO trial will recruit patients who complete
the ACT-ONE trial and remain on randomised double-blind
medication. Participants in ACT-TWO will be followed for
an additional period with a separate primary endpoint
Formation of Trans-Activation Competent HIV-1 Rev:RRE Complexes Requires the Recruitment of Multiple Protein Activation Domains
The HIV-1 Rev trans-activator is a nucleocytoplasmic shuttle protein that is essential for virus replication. Rev directly binds to unspliced and incompletely spliced viral RNA via the cis-acting Rev Response Element (RRE) sequence. Subsequently, Rev oligomerizes cooperatively and interacts with the cellular nuclear export receptor CRM1. In addition to mediating nuclear RNA export, Rev also affects the stability, translation and packaging of Rev-bound viral transcripts. Although it is established that Rev function requires the multimeric assembly of Rev molecules on the RRE, relatively little is known about how many Rev monomers are sufficient to form a trans-activation competent Rev:RRE complex, or which specific activity of Rev is affected by its oligomerization. We here analyzed by functional studies how homooligomer formation of Rev affects the trans-activation capacity of this essential HIV-1 regulatory protein. In a gain-of-function approach, we fused various heterologous dimerization domains to an otherwise oligomerization-defective Rev mutant and were able to demonstrate that oligomerization of Rev is not required per se for the nuclear export of this viral trans-activator. In contrast, however, the formation of Rev oligomers on the RRE is a precondition to trans-activation by directly affecting the nuclear export of Rev-regulated mRNA. Moreover, experimental evidence is provided showing that at least two protein activation domains are required for the formation of trans-activation competent Rev:RRE complexes. The presented data further refine the model of Rev trans-activation by directly demonstrating that Rev oligomerization on the RRE, thereby recruiting at least two protein activation domains, is required for nuclear export of unspliced and incompletely spliced viral RNA
Lesinurad: a novel therapeutic option in the pharmacotherapy of gout
Gout is characterized by painful joint inflammation, most commonly in the first metatarsophalangeal joint, resulting from precipitation of monosodium urate crystals in a joint space. Current therapies for chronic gout include mainly allopurinol and febuxostat. Inspite of the availability of these medications for several years, a significant number of patients do not have adequate control of uric acid levels resulting in acute gout flares. Lesinurad is the most recent drug molecule approved by US FDA & EMA for the treatment of gout in patients with uncontrolled gout along with allopurinol. Lesinurad prevents reabsorption of uric acid from the renal tubules, resulting in uricosuria. The efficacy of the lesinurad was demonstrated in three randomized phase 3 controlled clinical trials where the drug was primarily evaluated in the setting of background therapy with allopurinol or febuxostat. There is a definite risk of nephrotoxicity with monotherapy and when the drug is used in patients who have inadequate renal function. The drug does appear to be relatively safe, though the inconclusive cardiovascular safety of the drug has prompted the regulatory agency to mandate post marketing trials to evaluate the safety of this molecule. Nevertheless, lesinurad does appear to have a lot of promise as a front line drug molecule in the control of hyperuricemia
Association of galectin-3 with high cardiovascular risk in patients with type 2 diabetes attending a multi-specialty hospital in South India
Background: Diabetes mellitus is a chronic hyperglycemic condition that continues to be associated with high mortality and morbidity. Galectin-3 is a β-galactoside binding lectin and is a potential marker for inflammation, immunity and fibrosis. The aim of the study was to evaluate the relationship between Galectin-3 and baseline characteristics and to find the association between Galectin-3 and high cardiovascular risk in a group of Type-2 diabetes patients.Methods: A total of 100 patients with type-2 diabetes mellitus were included in the study after obtaining informed consent. The study participants were divided into two groups; those with diabetes for duration of less than 5 years as Group-1 and diabetes greater than 5 years as Group-2. Patients were also divided into three tertiles based on the Inter heart risk score (IHR). Five ml of blood was withdrawn from the ante-cubital vein and the serum obtained was subjected to analysis for estimating concentration of Galectin-3.Results: There was no significant difference between the Group-1 and Group-2 except gender variation with a significantly higher preponderance of males in Group 2. There was a significant correlation between Galectin-3 and parameters such as systolic blood pressure (r=0.033, p=0.03), creatinine (r=0.20, p=0.03), IHR (r=0.69, p=0.0001). Patients in the high risk category had greater levels of Galectin-3 compared to those with low and intermediate IHR.Conclusions: Galectin-3 concentration is elevated in diabetes patients and correlates with the IHR-Score. Thus Galectin-3 could be a useful biomarker for prediction of cardiovascular risk in diabetic subjects