Clinical profile of eprosartan

Angiotensin II (AII) receptor blockers offer an alternative means of blocking the renin-angiotensin-aldosterone system (RAAS) to angiotensin converting enzyme (ACE) inhibitors. Being highly selective for the AII receptor subtype AT₁, AII receptor blockers may avoid side-effects associated with ACE inhibitor treatment, such as cough. Eprosartan is a non-biphenyl, non-tetrazole competitive blocker that is chemically distinct from other AII receptor blockers, which may account for differences in its pharmacological properties. It induces dual blockade of AT₁ receptors both presynaptically and postsynaptically, reducing sympathetic nerve activity to a significantly greater degree than other AT₁ receptor blockers.At the recommended dose of 600 mg once daily, eprosartan effectively lowers blood pressure (BP) in hypertensive patients to a similar degree as seen with other AII receptor blockers and ACE inhibitors. However, a greater proportion of patients achieved adequate BP control compared with enalapril. When eprosartan is given in combination with hydrochlorothiazide (HCTZ), it provides a significantly greater BP reduction compared with eprosartan alone.Eprosartan has a side-effect profile that is similar to placebo and to other AII receptor blockers, but is better than that of enalapril because it lacks the propensity to cause dry cough. Eprosartan is not metabolized by the cytochrome P450 enzyme system, and so has no interaction with drugs that affect this system. Eprosartan completely reverses renal vasoconstriction induced by AII and may, therefore, have further applications in situations where stimulation of the RAAS is a problem. In summary, eprosartan, alone or in combination with HCTZ, provides an effective and well-tolerated approach to lowering BP in patients with all grades of hypertension. Further development of eprosartan may offer therapeutic opportunities that go far beyond the current recommendations.     

Disparities in HIV treatment and physician attitudes about delaying protease inhibitors for nonadherent patients

BACKGROUND: Current HIV treatment guidelines recommend delaying antiretroviral therapy for nonadherent patients, which some fear may disproportionately affect certain populations and contribute to disparities in care. OBJECTIVES: To examine the relationship of physician's attitude toward prescribing protease inhibitors (PIs) to nonadherent patients with disparities in PI use and with health outcomes. DESIGN: Prospective cohort study. PATIENTS AND SETTING: A national probability sample of HIV-infected adults in the United States and their health care providers was surveyed between January 1996 and January 1998. We analyzed data on 1717 patients eligible for PI treatment and the 367 providers who cared for them. MEASUREMENTS: Providers' attitude toward prescribing PIs to nonadherent patients, time until patients' first receipt of PIs, mortality, and physical health status. MAIN RESULTS: Eighty-nine percent of providers agreed that patient adherence is important in their decision to prescribe PIs (Selective) while 11% disagreed (Nonselective). Patients who had a Selective provider received PIs later than those with a Nonselective provider (P =.05). Adjusting for patient demographics and health characteristics and provider demographics, HIV knowledge, and experience, Latinos, women, and poor patients received PIs later if their provider had a Selective attitude but as soon as others if their provider had a Nonselective attitude. African-American patients received PIs later than whites, irrespective of their providers' prescribing attitude. Patients with Selective providers had similar odds of mortality than those with Nonselective providers (odds ratio, 1.1; 95% confidence interval, 0.6 to 2.0), but had slightly worse adjusted physical health status at follow-up (49.1 vs 50.4, respectively; P =.04), after controlling for baseline physical health status and other patient and provider covariates. CONCLUSIONS: Most providers consider patient adherence an important factor in their decision to prescribe PIs. This attitude appears to account for the relatively later use of PI treatment among Latinos, women, and the poor. Given the rising HIV infection rates among minorities, women, and the poor, further investigation of this treatment strategy and its impact on HIV resistance and outcomes is warranted.     

Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.     

Effect of estrogens on skin aging and the potential role of SERMs

In humans, structural and functional changes attributable to aging are more visibly evident in the skin than in any other organ. Estrogens have significant effects on skin physiology and modulate epidermal keratinocytes, dermal fibroblasts and melanocytes, in addition to skin appendages including the hair follicle and the sebaceous gland. Importantly, skin aging can be significantly delayed by the administration of estrogen. This paper reviews the effects of estrogens on skin and the mechanisms by which estrogens can alleviate the changes due to aging that occur in human skin. The relevance of estrogen replacement therapy (HRT) in post-menopausal women and the potential value of selective estrogen receptor modulators (SERMs) as a therapy for diminishing skin aging are also highlighted.     

Validation of automated blood cell counter for the determination of polymorphonuclear cell count in the ascitic fluid of cirrhotic patients with or without spontaneous bacterial peritonitis

OBJECTIVES: Polymorphonuclear (PMN) cell count in ascitic fluid is the most useful test for the diagnosis of spontaneous bacterial peritonitis (SBP). We evaluated the validity of an automated blood cell counter for the PMN determination in ascitic fluid by comparing it with the traditional hematologic method with a light microscope in a manual counting chamber. METHODS: A total of 130 ascitic fluid samples were collected from 74 consecutive cirrhotics. The agreement between the two techniques was assessed according to Bland and Altman's method. The sensitivity, specificity, and positive and negative predictive values of the automated blood cell counter were calculated by considering the diagnosis of SBP as a PMN count > or = 250 cells/mm(3), determined by the manual method as the "gold standard." RESULTS: The mean PMN counts assessed by the manual method and the automated blood cell counter were 124 +/- 301 cells/mm(3) and 130 +/- 339 cells/mm(3), respectively (p = 0.89, ns). The mean +/- SD of the difference between manual and automated measurements was 6 +/- 61 cells/mm(3), whereas the limits of agreement were +127 cells/mm(3) (95% CI = +108 to +147) and -115 cells/mm(3) (95%CI = -96 to -135). SBP was diagnosed in 11 patients. All but one were correctly identified with the automated blood cell counter, with a sensitivity of 94% and a specificity of 100%; positive and negative predictive values were 100% and 99.1%, respectively. CONCLUSIONS: The manual method and the automated blood cell counter have a good agreement in the PMN determination in ascitic fluid, and the automated blood cell counter is a reliable tool for rapid diagnosis of SBP.     

Health-related quality of life in patients with human immunodeficiency virus infection in the United States: results from the HIV Cost and Services Utilization Study

PURPOSE: To measure health-related quality of life among adult patients with human immunodeficiency virus (HIV) disease; to compare the health-related quality of life of adults with HIV with that of the general population and with patients with other chronic conditions; and to determine the associations of demographic variables and disease severity with health-related quality of life. SUBJECTS AND METHODS: We studied 2,864 HIV-infected adults participating in the HIV Cost and Services Utilization Study, a probability sample of adults with HIV receiving health care in the contiguous United States (excluding military hospitals, prisons, or emergency rooms). A battery of 28 items covering eight domains of health (physical functioning, emotional well-being, role functioning, pain, general health perceptions, social functioning, energy, disability days) was administered. The eight domains were combined into physical and mental health summary scores. SF-36 physical functioning and emotional well-being scales were compared with the US general population and patients with other chronic diseases on a 0 to 100 scale. RESULTS: Physical functioning was about the same for adults with asymptomatic HIV disease as for the US population [mean (+/- SD) of 92+/-16 versus 90+/-17) but was much worse for those with symptomatic HIV disease (76+/-28) or who met criteria for the acquired immunodeficiency syndrome (AIDS; 58+/-31). Patients with AIDS had worse physical functioning than those with other chronic diseases (epilepsy, gastroesophageal reflux disease, clinically localized prostate cancer, clinical depression, diabetes) for which comparable data were available. Emotional well-being was comparable among patients with various stages of HIV disease (asymptomatic, 62+/-9; symptomatic, 59+/-11; AIDS, 59+/-11), but was significantly worse than the general population and patients with other chronic diseases except depression. In multivariate analyses, HIV-related symptoms were strongly associated with physical and mental health, whereas race, sex, health insurance status, disease stage, and CD4 count were at most weakly associated with physical and mental health. CONCLUSIONS: There is substantial morbidity associated with HIV disease in adults. The variability in health-related quality of life according to disease progression is relevant for health policy and allocation of resources, and merits the attention of clinicians who treat patients with HIV disease.     

Cyclin E, a redundant cyclin in breast cancer

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G₁/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.     

Oxygen‐Mediated Reactions in Photopolymerizable Radical Thin Films: Application to Simultaneous Photocuring Under Air and Nanoparticle Formation

Titanium propoxide, titanium isopropoxide, and titanium (triethanolaminato) isopropoxide are proposed as high‐performance additives to overcome the oxygen inhibition effects in the free radical photopolymerization of a low‐viscosity monomer thin film, under air and upon a low‐intensity UV light activation. Indeed, when added to a Type I photoinitiator such as bis(2,4,6‐trimethylbenzoyl)‐phenylphosphine oxide (BAPO), noticeably higher conversions are achieved under air (48% vs. 30%). The in situ formation of Ti‐based nanoparticles is also observed. The photochemical properties of these types of Ti‐based compounds as well as their interaction with BAPO are investigated by steady‐state photolysis and electron spin resonance. Molecular orbital calculations give an interesting insight into the possible reactions. A chemical mechanism is also proposed.