chmidt S

Hydrochlorothiazide and atenolol combination antihypertensive therapy: Effects of drug initiation order

For combination antihypertensive therapy with thiazide diuretics and β‐blockers, the effect of the order of initiation of the drugs on the outcome has not been tested. Patients with uncomplicated hypertension were randomized to receive either hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by addition of the alternative drug. Blood pressure (BP) responses were evaluated by race and order of drug initiation. A total of 368 participants received combination therapy. Among the participants, blacks showed a greater BP‐lowering effect than whites did with HCTZ monotherapy (−13.0/−7.4 mm Hg vs. −8.0/−4.2 mm Hg, P < 0.001) but a smaller BP‐lowering effect than did whites with atenolol monotherapy (−1.1/−2.9 mm Hg vs. −9.9/−9.2 mm Hg, P < 0.0001). These differences were not evident during combination therapy. However, both groups showed greater response to HCTZ + atenolol than to atenolol + HCTZ (−19.1/−14.2 mm Hg vs. −15.6/−11.3 mm Hg, P < 0.0001). Despite optimal dosing of HCTZ + atenolol, only two‐thirds of the participants achieved BP control. In HCTZ/atenolol combination antihypertensive therapy, the order in which the drugs are initiated affects total BP lowering during the first 4–6 months of therapy.

Characteristics of sensitization associated with chronic pain conditions

Objectives:To describe and understand varieties and characteristics of sensitization contributing to hyperalgesia in participants with chronic pain conditions. Methods:Thermal stimulation was delivered to the face, forearm, and calf of pain-free participants and individuals with irritable bowel syndrome, temporomandibular pain disorder (TMD), and fibromyalgia syndrome (FM). Three-second contacts by a preheated thermode occurred at 30-second intervals in ascending and then in descending series (0.7°C steps). Results:Thermal pain ratings during ascending series were greater at each site in individuals diagnosed with chronic pain. Intense pain at the time of testing further enhanced the ratings at all sites, but mild or moderate clinical pain did not have this effect. Thermal pain in all participants was greater during descending series compared with the ascending series of arm and leg stimulation. The hypersensitivity during the descending series was comparable in pain-free, FM and TMD participants but was increased in duration for arm or leg stimulation of FM participants. Discussion:The widespread sensitization for irritable bowel syndrome and TMD participants does not rely on mechanisms of spatial and temporal summation often invoked to explain widespread hyperalgesia associated with chronic pain. Increased sensitivity during descending series of stimulation of an arm or leg but not the face indicates a propensity for sensitization of nociceptive input to the spinal cord. Abnormally prolonged sensitization for FM participants reveals a unique influence of widespread chronic pain referred to deep somatic tissues.

PTPRD gene associated with blood pressure response to atenolol and resistant hypertension.

Objective: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the &bgr;-blocker atenolol. Methods: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10−5 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114). Results: In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10−6 and P = 5.9 × 10−6, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 × 10−6). rs12346562 had a similar trend in association with response to bisoprolol (a different &bgr;-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10−5). Conclusion: PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.

Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to &bgr;-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10–8 and suggestive variants with P<5×10–7 were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: −9.3 versus −4.6, −9.6 versus −4.8, and −9.7 versus −6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10–8, &bgr;=−4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to &bgr;-blocker therapy with 3-group meta-analysis P=7.2×10–8 and &bgr;=−3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to &bgr;-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

Systems Approaches in Risk Assessment

Adverse drug events (ADEs) remain a universal problem in drug development, regulatory review, and clinical practice with a substantial financial burden on the global health‐care system. Recent advances in molecular and “omics” technologies, along with online databases and bioinformatics, have enabled a more integrative approach to understanding drug‐target (protein) interactions, both desirable and undesirable, within a biological system. This has led to the development of systems approaches to risk assessment in an attempt to complement and improve on contemporary observational and predictive strategies for assessing risk. Although still in an evolutionary phase, systems approaches have the potential to markedly advance our understanding of ADEs and ability to predict them. Systems approaches will also move personalized medicine forward by enabling better identification of individual and subgroup risk factors.

Atenolol exposure and risk for development of adverse metabolic effects: A pilot study

Study Objective. To evaluate whether the level of systemic exposure to atenolol explains observed interindividual differences in adverse metabolic responses.

Predictors for Glucose Change in Hypertensive Participants Following Short-term Treatment with Atenolol or Hydrochlorothiazide

To develop and validate a predictive model for glucose change and risk for new‐onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide (HCTZ).

Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress.

Extreme Thermal Sensitivity and Pain-Induced Sensitization in a Fibromyalgia Patient

During the course of a psychophysical study of fibromyalgia syndrome (FMS), one of the subjects with a long history of headache and facial pain displayed an extraordinarily severe thermal allodynia. Her stimulus-response function for ratings of cutaneous heat pain revealed a sensitivity clearly beyond that of normal controls and most FMS subjects. Specially designed psychophysical methods showed that heat sensitivity sometimes increased dramatically within a series of stimuli. Prior exposure to moderate heat pain served as a trigger for allodynic ratings of series of normally neutral thermal stimulation. These observations document a case of breakthrough pain sensitivity with implications for mechanisms of FMS pain.

The Effect of Topical Local Anesthetics on Thermal Pain Sensitivity in Patients with Irritable Bowel Syndrome

Generalized hypersensitivity that extends into somatic areas is common in patients with irritable bowel syndrome (IBS). The sensitized state, particularly assessed by experimental methods, is known to persist even during remissions of clinical pain. It was hypothesized that disease-related nociceptive activity in the gut maintains a systemic-sensitized state. The present study evaluated responses to prolonged thermal stimuli maintained at constant temperature or constant pain intensity during stimulation. The effect of topically applied rectal lidocaine on heat sensitivity was also evaluated. The question is whether silencing potential intestinal neural activity (which may not always lead to a conscious pain experience) with lidocaine attenuates sensitization of somatic areas. Tests were also performed where lidocaine was applied orally to control for systemic or placebo effects of the drug. The IBS subjects exhibited a greater sensitivity to somatic heat stimuli compared to controls; however, lidocaine had no discernible effect on sensitization in this sample of IBS patients, where most of the individuals did not have clinical pain on the day of testing.