Cost-effectiveness of using hepatitis C viremic hearts for transplantation into HCV-negative recipients

Outcomes following hepatitis C virus (HCV)-viremic heart transplantation into HCV-negative recipients with HCV treatment are good. We assessed cost-effectiveness between cohorts of transplant recipients willing and unwilling to receive HCV-viremic hearts. Markov model simulated long-term outcomes among HCV-negative patients on the transplant waitlist. We compared costs (2018 USD) and health outcomes (quality-adjusted life-years, QALYs) between cohorts willing to accept any heart and those willing to accept only HCV-negative hearts. We assumed 4.9% HCV-viremic donor prevalence. Patients receiving HCV-viremic hearts were treated, assuming $39 600/treatment with 95% cure. Incremental cost-effectiveness ratios (ICERs) were compared to a $100 000/QALY gained willingness-to-pay threshold. Sensitivity analyses included stratification by blood type or region and potential negative consequences of receipt of HCV-viremic hearts. Compared to accepting only HCV-negative hearts, accepting any heart gained 0.14 life-years and 0.11 QALYs, while increasing costs by $9418/patient. Accepting any heart was cost effective (ICER $85 602/QALY gained). Results were robust to all transplant regions and blood types, except type AB. Accepting any heart remained cost effective provided posttransplant mortality and costs among those receiving HCV-viremic hearts were not >7% higher compared to HCV-negative hearts. Willingness to accept HCV-viremic hearts for transplantation into HCV-negative recipients is cost effective and improves clinical outcomes.     

Development of myasthenia gravis after interferon alpha therapy

Interferon (IFN) alpha is now used in the treatment of some malignant diseases and chronic viral hepatitis. There have been several reports of development of autoantibodies and autoimmune diseases or the deterioration of preexisting disorders in patients under treatment. We enclose a case of myasthenia gravis (MG) which developed after six weeks of treatment as fluctuating bilateral ptosis, intermittent diplopia, and mild weakness of limb and neck muscles. A test dose of edrophonium chloride was administered, resulting in improved muscle strength. Elevated anti acetylcholine receptor (AChR) antibody titer was found. Single fiber electromyography showed an increased jitter from extensor digitorum communis, frequently accompanied by transmission blocking. Repetitive electric 3 Hz stimulation of the abductor pollicis brevis muscle, revealed an abnormal decrement of 28% in compound motor action potential. Myasthenia gravis was diagnosed and the patient was given pyridostigmine, immunoglobulines and prednisone with benefit. Six months latter he developed an acute myasthenic crisis with severe respiratory failure and high anti AChR antibody titer. IFN-alpha can induce MG or simply manifests a preexisting subclinical disease, but otherwise its therapeutic efficacy in MG has been shown in experimental and clinical studies. Autoimmune mechanisms, as the release of different cytokines as IFN, by immunocompetent cells, may be involved in the pathogenesis of both MG and chronic active hepatitis. Autoantibody production against postsynaptic membrane structures by IFN-alpha could be the underlying pathophysiology.     

Cyclic GMP may potentiate lordosis behaviour by progesterone receptor activation

The purpose of this study was to test the hypothesis that cGMP acts as a progesterone substitute to facilitate lordosis in oestrogen-primed rats. Female Sprague-Dawley rats underwent stereotaxic surgery to place a 26-gauge guide cannula into the third ventricle. Bilateral ovariectomy was done at the same time as stereotaxic surgery. Five days later ovariectomized rats were primed with 2 microg estradiol benzoate 24 and 48 h prior to behaviour testing. Some animals were further injected with 200 microg progesterone 4 h before behaviour testing. A nitric oxide synthase inhibitor infused into the third ventricle before progesterone administration significantly reduced lordosis performance. 8-Bromo-cGMP, a cell permeable cGMP analogue, or saline vehicle was infused into the third ventricle of hormone-primed animals approximately 4 h prior to the first of 3-h behaviour tests. This cGMP analogue facilitated lordosis behaviour. We next used KT5823, a highly specific inhibitor of protein kinase G (PKG), to test the hypothesis that cGMP action is mediated by this kinase. In this experiment, KT5823 was infused 15 min before progesterone. KT5823 significantly decreased lordosis behaviour. RU486, a progesterone receptor antagonist, was used to assess whether the stimulatory effects of cGMP are mediated through the progesterone receptor. Oestrogen-primed animals were injected with 5 mg of RU486 or vehicle 60 min before infusion with 8-bromo-cGMP. RU486 significantly attenuated cGMP-facilitated lordosis behaviour. These data show that cGMP facilitates lordosis through activation of PKG and the progesterone receptor.     

Radio-guided surgery with MIBG in a case of abdominal neuroblastoma

Radio-guided surgery is a new technique which can provide benefits for pediatric oncology, as in our patient with neuroblastoma in stage IV, that after a chemotherapy, surgical, radiotherapy and autologous bone marrow transplant treatment kept showing, at 2 years, residual tumoral fragments and increase of catecholamines. Radio-guided surgery allowed an easy and exact location. This technique decreases surgery time and let us find residual tumoral tissue no matter how small. With radio-guided surgery we can obtain higher survival and even cure the patient.     

Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.