Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁-adrenoceptors (β₂-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂-adrenoceptors (β₁-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from –logEC₅₀s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β₂-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β₂-adrenoceptors compared to β₁-adrenoceptors. The β₂-adrenoceptor-selectivity of carvedilol may provide protection against β₂-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β₁- and β₂-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.     

Differential up-regulation of striatal dopamine transporter and alpha-synuclein by the pyrethroid insecticide permethrin

The effects of permethrin on striatal dopaminergic biomarkers were assessed in this study. Retired breeder male C57 B1/6 mice were given an ip dose of permethrin (0.1-200 mg/kg) at 7-day intervals, over a 2-week period (Days 0, 7, and 14). Animals were then sacrificed 1 day (t = 1), 14 days (t = 14), or 28 days after the last treatment (t = 28). Dopamine transporter (DAT) protein as assayed by Western blotting was increased to 115% in the 0.8 mg/kg group over that of control mice at t = 1 (P < 0.05). At t = 14, this value increased to 140% of control, and declined slightly to 133% of control at t = 28. The mice given the 1.5 mg/kg dose displayed a significant increase in DAT protein only at t = 28, to 145% of controls. Thus, upregulation of the DAT at low doses of PM is variable 24 h after treatment, and seems to stabilize by t = 28. The threshold dose for increasing DAT expression in Western blots by t = 28 was 0.2 mg/kg permethrin. [(3)H]GBR 12935, used to assay DAT binding, followed the same trend as that for the Western blotting data for 0.8 and 1.5 mg/kg doses of permethrin over the 4 weeks posttreatment. At 200 mg/kg permethrin, DAT protein was unchanged vs controls (t = 1), but had significantly increased by t = 14 and continued to increase at t = 28, suggesting that the reduced dopamine transport at this dose was due to nerve terminal stress and that recovery had occurred. The protein alpha-synuclein was also significantly induced at the 1.5 mg/kg dose at t = 1; however, unlike DAT up-regulation, this effect had declined to control values by t = 14. Maximal induction of alpha-synuclein protein occurred at a dose of 50 mg/kg permethrin. These data provide evidence that the pyrethroid class of insecticides can modulate the dopaminergic system at low doses, in a persistent manner, which may render neurons more vulnerable to toxicant injury.     

End-of-life care for persons with advanced Alzheimer disease: Design and baseline data from the ALFINE study

Context

Alzheimer disease (AD) is the most common cause of dementia. Most affected individuals survive to an advanced stage of dementia, which is under-recognized as a terminal illness.

Objectives

Our objectives were to better understand the clinical trajectory of advanced AD and to identify the palliative care needs of these patients.

Methods

This was an observational prospective study of AD patients in severe stage of disease included after a hospitalization in geriatric wards. They were followed up every three months during 2 years. At each visit, interviews provided data regarding: pain (Elderly Pain Caring Assessment scale), pressure ulcers, eating patterns, daily medications and use of health services. This paper describes the design of the ALFINE study and the characteristics of the recruited cohort.

Results

112 patients were recruited (mean age: 84.03 + 6.96) years; 76.79% were women. Mean time since diagnosis of AD was 5.28 years. Pressure ulcers were observed in 42 patients. Pain assessment with the EPCA showed a mean score of 8.58. One third of patients with an EPCA score of more than 7 (median) had no analgesics. More than half of patients had been treated with antibiotics during the three months before inclusion in the study and 33 patients were still receiving antibiotics at inclusion. Two third of patients had been hospitalized in the month before inclusion.

Conclusion

End-of-life care for individuals with end-stage AD is increasingly important because of the rising number of patients with this disease. Health care systems and clinicians should make efforts to ameliorate the suffering of patients and their caregivers.