Pharmacokinetics of apomorphine in parkinsonian patients

Summary— Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa-induced on-off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high-performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the T_max was brief (16 ± 11 min) the drug was rapidly cleared from the plasma and had a short plasma half-life (69.7 ± 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter-subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half-life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.     

Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents

Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue- specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post- BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan- pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.     

Effect of Hospital Volume on Outcomes of Transcatheter Mitral Valve Repair: An Early US Experience

Background

Transcatheter mitral valve repair (TMVR) is a complex procedure for patients with mitral regurgitation who cannot get surgery. However, there is a lack of data on how hospital volumes affect these outcomes.

Methods

We performed a cross sectional study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database of 2012 and identified subjects using the ICD‐9‐CM procedure code of 35.97, which was introduced in October 2010 for percutaneous mitral valve repair if present in the primary or secondary procedure field. Hospital volumes were divided into tertiles. The primary outcome was a composite of in‐hospital mortality and peri‐procedural complications. Length of stay and hospitalization cost were also assessed.

Results

A total of 95 (weighted n = 475) TMVR procedures were identified. The mean age of the overall cohort was 70 years; 43.2% were female and 63.2% had a significant baseline burden of co‐morbidities. The composite of in‐hospital mortality and peri‐procedural complications decreased with increasing TMVR hospital volume: 48.7% in the first tertile, 17.4% in the second tertile, and 9.1% in the third tertile. Additionally, we saw a decrease in the length of stay and a trend in decrease in the hospitalization cost.

Conclusion

In hospitals performing TMVR, higher hospital volumes are associated with a reduction in a composite of in‐hospital mortality and post‐procedural complications, in addition to the shorter length of stay. (J Interven Cardiol 2015;28:464–471)

     

The chronic effects of fish oil with exercise on postprandial lipaemia and chylomicron homeostasis in insulin resistant viscerally obese men

Background

The purpose of this study was to determine the effects of the pre-workout supplement Assault? (MusclePharm, Denver, CO, USA) on upper and lower body muscular endurance, aerobic and anaerobic capacity, and choice reaction time in recreationally-trained males. Subjective feelings of energy, fatigue, alertness, and focus were measured to examine associations between psychological factors and human performance.

Methods

Twelve recreationally-trained males participated in a 3-week investigation (mean +/- SD, age: 28 +/- 5 y, height: 178 +/- 9 cm, weight: 79.2 +/- 15.7 kg, VO_2max: 45.7 +/- 7.6 ml/kg/min). Subjects reported to the human performance laboratory on three separate occasions. All participants completed a baseline/familiarization day of testing that included a maximal graded exercise test for the determination of aerobic capacity (VO_2max), one-rep maximum (1-RM) for bench and leg press to determine 75% of 1-RM, choice reaction tests, and intermittent critical velocity familiarization. Choice reaction tests included the following: single-step audio and visual, one-tower stationary protocol, two-tower lateral protocol, three-tower multi-directional protocol, and three-tower multi-directional protocol with martial arts sticks. Subjects were randomly assigned to ingest either the supplement (SUP) or the placebo (PL) during Visit 2. Subjects were provided with the cross-over treatment on the last testing visit. Testing occurred 20 min following ingestion of both treatments.

Results

Significant (p < 0.05) main effects for the SUP were observed for leg press (SUP: 13 ± 6 reps, PL: 11 ± 3 reps), perceived energy (SUP: 3.4 ± 0.9, PL: 3.1 ± 0.8), alertness (SUP: 4.0 ± 0.7, PL: 3.5 ± 0.8), focus (SUP: 4.1 ± 0.6, PL: 3.5 ± 0.8), choice reaction audio single-step (SUP: 0.92 ± 0.10 s, PL: 0.97 ± 0.11 s), choice reaction multi-direction 15 s (SUP: 1.07 ± 0.12 s, PL: 1.13 ± 0.14 s), and multi-direction for 30 s (SUP: 1.10 ± 0.11 s, PL: 1.14 ± 0.13 s).

Conclusions

Ingesting the SUP before exercise significantly improved agility choice reaction performance and lower body muscular endurance, while increasing perceived energy and reducing subjective fatigue. These findings suggest that the SUP may delay fatigue during strenuous exercise.     

Studies on levamisole--induced agranulocytosis

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet- induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.     

Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction

BACKGROUND: Vascular endothelial growth factor (VEGF)-165 promotes cardiomyogenesis in chronic myocardial ischemia and nonreperfused myocardial infarction (MI). It is unknown whether this effect is present in reperfused MI. We sought to investigate the effect of VEGF-165 gene therapy on cardiomyogenesis after reperfused MI. METHODS AND RESULTS: Twenty-four Yucatan minipigs underwent thoracotomy and a vascular clamp was placed in the left circumflex artery. Reperfusion was reestablished after 90 minutes, and VEGF-165 gene therapy or placebo was administered. A replication-deficient recombinant human adenovirus serotype 5 was used for gene transfer (Ad5-VEGF165). The same viral vector devoid of VEGF gene (Ad5-beta-galactosidase) was used as placebo. Two administration routes were tested, intramyocardial (IM) injection and circumflex intracoronary (IC) infusion. The pigs were assigned to one of the following groups: IM Ad5-VEGF165 (n = 6), IM Ad5-betaGal (n = 6), IC Ad5-VEGF165 (n = 6), and IC Ad5-betaGal (n = 6). All pigs received 5-bromo-2'-deoxyuridine (BrdU) 250 mg IV twice a week to label cells undergoing DNA replication. The hearts were explanted at 4 weeks. BrdU-labeled cardiomyocytes in the peri-infarct area were counted by a pathologist blinded to group assignment. The number of BrdU-labeled cardiomyocytes per million cells was 4-fold higher in the group receiving IM VEGF-165 (64 +/- 11.4) vs. IM placebo (16 +/- 10.6), P = 0.034. No difference in infarct size or ventricular function was observed between the groups. CONCLUSIONS: IM VEGF-165 gene therapy promotes cardiomyogenesis in reperfused MI. However, no benefit in infarct size or cardiac function was observed at 4 weeks. The origin of these cells remains unknown and needs to be determined.