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Akopian A.N.,UTHSCSA
Current Pharmaceutical Biotechnology | Year: 2011

TRPV1 and TRPA1 have traditionally been considered to function independently from each other as homomers, but their extensive co-expression in sensory neurons and recent evidence suggest that these channels can functionally interact and may form a complex as part of their normal function. Although TRPA1 and TRPV1 do not absolutely require interaction to maintain function in expression systems or even sensory neurons, their heteromerization may still result in dramatic effects on channel biophysical properties, pharmacology, signaling, regulation, and ultimately function. Understanding the regulation and functional significance of TRPA1-TRPV1 interaction is of tremendous clinical importance since first, both channels are the potential molecular targets for numerous therapeutic drugs; and second, TRPA1-TRPV1 co-expression is far more specific for nociceptive sensory neurons than expression patterns of TRPA1 or TRPV1 considered separately. © 2011 Bentham Science Publishers Ltd.

Dobie R.A.,UTHSCSA | Dobie R.A.,University of California at Davis | Agrawal Y.,Johns Hopkins University
Audiology and Neurotology | Year: 2011

One can study occupational noise exposure by comparing hearing thresholds of exposed people to control data from national or international standards. ANSI S3.44 (1996) offers Annex C - thresholds for people without occupational noise exposure - as appropriate control data for such comparisons. Annex C is based on the false assumption that people who have had occupational noise exposure are similar in all other important ways to those without such exposures. In fact, people with noisy jobs are more likely than others to be smokers, diabetics, poorly educated, white and exposed to non-occupational noise. Taking these other risk factors into account, the appropriate thresholds for comparison to industrial study populations are closer to those of the unscreened population than to an 'Annex C' population that simply excludes occupationally noise-exposed persons. Copyright © 2010 S. Karger AG, Basel.

DeFronzo R.A.,UTHSCSA | Stonehouse A.H.,Amylin Pharmaceuticals Inc. | Han J.,Amylin Pharmaceuticals Inc. | Wintle M.E.,Amylin Pharmaceuticals Inc.
Diabetic Medicine | Year: 2010

Aims: Baseline glycated haemoglobin (HbA1c) concentrations vary between clinical trials of glucose-lowering agents and this may affect interpretation of clinical efficacy. The objective of this study is to quantify the relationship between baseline HbA1c and reduction of HbA 1c in clinical trials. Methods: PubMed literature searches from 1991 to 2007. Randomized controlled studies with placebo-controlled or comparator arms [≥ 9 patients in the intent-to-treat (ITT) population] ranging in duration from 23 to 52 weeks, in which baseline and change in glycated haemoglobin (HbA1c) were reported. The relationship between baseline HbA1c and change in HbA1c was analysed by a weighted least-squared regression model accounting for ITT population and variance of HbA1c change. Fourteen per cent of independently abstracted studies met the selection criteria. Results: Meta-analysis from 59 clinical trials (8479 patients) produced weighted R2 of 0.35 (P < 0.0001) for the association of baseline HbA1c and absolute change in HbA 1c. Subanalysis of eight metformin clinical trials demonstrated a stronger association [weighted R2 of 0.67 (P = 0.0130)]. Exclusion of metformin clinical trials from the overall meta-analysis (n = 51) yielded a weighted R2 of 0.31 (P < 0.0001). Subanalyses of clinical trials of glucose-lowering therapies predominantly targeting fasting (n = 37) or postprandial (n = 22) blood glucose produced weighted R2 values of 0.27 (P < 0.001) and 0.42 (P < 0.005), respectively. Conclusions: These data demonstrate a positive relationship between baseline HbA1c and the magnitude of HbA1c change across 10 categories of glucose-lowering therapies, irrespective of class or mode of action. These observations should be considered when assessing clinical efficacy of diabetes therapies derived from clinical trials. © 2010 The Authors.

Schwartz S.,University of Pennsylvania | Defronzo R.A.,UTHSCSA
Current Diabetes Reports | Year: 2014

Patients with hyperglycemia in hospital have increased adverse outcomes compared with patients with normoglycemia, and the pathophysiological causes seem relatively well understood. Thus, a rationale for excellent glycemic control exists. Benefits of control with intensive insulin regimes are highly likely based on multiple published studies. However, hypoglycemia frequency increases and adverse outcomes of hypoglycemia accrue. This has resulted in a 'push' for therapeutic nihilism, accepting higher glycemic levels to avoid hypoglycemia. One would ideally prefer to optimize glycemia, treating hyperglycemia while minimizing or avoiding hypoglycemia. Thus, one would welcome therapies and processes of care to optimize this benefit/ risk ratio. We review the logic and early studies that suggest that incretin therapy use in-hospital can achieve this ideal. We strongly urge randomized prospective controlled studies to test our proposal and we offer a process of care to facilitate this research and their use in our hospitalized patients. © 2014 Springer Science+Business Media New York.

Seillier A.,UTHSCSA | Advani T.,UTHSCSA | Cassano T.,University of Foggia | Hensler J.G.,UTHSCSA | Giuffrida A.,UTHSCSA
International Journal of Neuropsychopharmacology | Year: 2010

The cannabinoid hypothesis of schizophrenia tulates that over-activity of the endocannabinoid system might contribute to the aetiology of schizophrenia. In keeping with this hypothesis, increased expression of CB1 receptors, elevation of the endocannabinoid anandamide (AEA) and cannabinoid-induced cognitive changes have been reported in animal models of schizophrenia and psychotic patients. In this study we measured brain endocannabinoid levels and [35S]GTPS binding stimulated by the CB receptor agonist CP55,940 in rats undergoing withdrawal from subchronic administration of phencyclidine (PCP), a well-established pharmacological model of schizophrenia. We also investigated whether systemic application of the fatty-acid amide hydrolase (FAAH) inhibitor URB597 or CB1 receptor blockade by AM251 affected the following PCP-induced behavioural deficits reminiscent of schizophrenia-like symptoms: (1) working-memory impairment (cognitive deficit), (2) social withdrawal (negative symptom), and (3) hyperactivity in response to d-amphetamine challenge (positive symptoms). PCP-treated rats showed increased endocannabinoid levels in the nucleus accumbens and ventral tegmental area, whereas CB1 receptor expression and CP55,940-stimulated [35S]GTPS binding were unaltered. URB597 reversed the PCP-induced social withdrawal but caused social withdrawal and working-memory deficits in saline-treated rats that were comparable to those observed after PCP treatment. Administration of AM251 ameliorated the working-memory deficit in PCP-treated rats, but impaired working memory in saline-injected controls. Taken together, these results suggest that FAAH inhibition may improve negative symptoms in PCP-treated rats but produce deleterious effects in untreated animals, possibly by disturbing endocannabinoid tone. A similar pattern (beneficial for schizophrenia-related cognitive deficits, but detrimental under normal conditions) accompanies CB1 receptor blockade. © 2009 CINP.

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