The effect of combinations of ampligen and zidovudine or dideoxyinosine against human immunodeficiency viruses in vitro.

The combinations of ampligen and zidovudine at ratios of 100:1, 25:1, 10:1, and 1:50 acted synergistically to reduce cytopathology caused by HIV in MT-2 cell cultures. Combination indices were less than 1 at all of these ratios representing different combinations of concentrations and at 3 effective doses (ED30, ED50, ED70). Combination of drugs which show synergism at a wide range of ratios of combinations suggest that they may be useful clinically, and that the antiviral efficacy of ZDV may be increased in combination with ampligen. Synergism was also found between ampligen and zidovudine by reduction of HIV-produced plaques in a HeLa cell line expressing CD-4 receptors. However the combination of ampligen and dideoxyinosine against HIV in MT-2 cells was only additive and not synergistic.     

A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study.

AIMS: Uncertainty exists as to which reperfusion strategy for ST-elevation myocardial infarction (MI) is optimal. We evaluated whether optimal pharmacologic therapy at the earliest point of care, emphasizing pre-hospital randomization and treatment was non-inferior to expeditious primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Which Early ST-elevation myocardial infarction Therapy (WEST) was a four-city Canadian, open-label, randomized, feasibility study of 304 STEMI patients (> 4 mm ST-elevation/deviation) within 6 h of symptom onset, emphasizing pre-hospital ambulance treatment and participation of community and tertiary care centres. All received aspirin, subcutaneous enoxaparin (1 mg/kg), and were randomized to one of three groups: (A) tenecteplase (TNK) and usual care, (B) TNK and mandatory invasive study < or = 24 h, including rescue PCI for reperfusion failure, and (C) primary PCI with 300 mg loading dose of clopidogrel. Time from symptom onset to treatment was rapid (to TNK for A = 113 and B = 130 min and for PCI in C = 176 min). The primary outcome, a composite of 30-day death, re-infarction, refractory ischaemia, congestive heart failure, cardiogenic shock, and major ventricular arrhythmia, was 25% (Group A), 24% (Group B), and 23% (Group C), respectively. However, there was a higher frequency of the combination of death and recurrent MI in Group A vs. Group C (13.0 vs. 4.0%, respectively, P-logrank = 0.021), yet no difference between Group B (6.7%, P-logrank = 0.378) and C. CONCLUSION: These data suggest that a contemporary pharmacologic regimen rapidly delivered, coupled with a strategy of regimented rescue and routine coronary intervention within 24 h of initial treatment, may not be different from timely expert PCI.     

Serum lipids and blood pressure in relation to age and sexual maturity.

This study was designed to examine serum lipid profile and blood pressure in relation to age and sexual maturity. Written informed consent to participate was obtained from 42% of the eligible population of two Devon communities. The blood pressure of 343 boys and 336 girls, aged 11-16 years, was recorded and sufficient blood for analysis was obtained from 320 boys and 301 girls. Of these, sexual maturity of 221 boys and 209 girls was visually assessed using the indices developed by Tanner. In girls there was a significant (p less than 0.05) correlation between age and serum triglyceride level (r = 0.16) and in boys both serum cholesterol and HDL-cholesterol were significantly (p less than 0.01) and negatively correlated with age (r = -0.25 and -0.18 respectively). Girls had significantly higher (p less than 0.05) levels of HDL-cholesterol than boys but neither sex demonstrated significant changes (p greater than 0.05) in serum lipids or lipoproteins with sexual maturity. No significant differences (p greater than 0.05) were detected between the mean diastolic blood pressures of boys and girls but older boys had significantly higher (p less than 0.05) systolic blood pressures than similarly aged girls. Age was positively and significantly correlated (p less than 0.01) with blood pressure in both boys (systolic, r = 0.49; diastolic, r = 0.30) and girls (systolic, r = 0.28; diastolic, r = 0.29). More mature children were demonstrated to have both higher systolic and diastolic blood pressures than less mature children (p less than 0.05) but when allowance was made for school year group through analysis of co-variance the relationship for diastolic blood pressure in boys no longer remained significant. Blood pressures observed in this study do not raise general cause for concern but the data indicate that unfavourable serum lipid and lipoprotein profiles are common.     

Plasma Concentrations of Mycophenolic Acid Acyl Glucuronide Are Not Associated with Diarrhea in Renal Transplant Recipients

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.     

Surgical treatment of paravalvular abscess: long-term results.

OBJECTIVE: To examine the outcomes of surgery for active infective endocarditis with paravalvular abscess. METHODS: Paravalvular abscess was defined as infective necrosis of the valve annulus that required patch reconstruction before implanting a new valve. Of 383 patients with active infective endocarditis who underwent surgical treatment, 135 (35%) had paravalvular abscess. Patients' mean age was 51+/-16 years and 68% were men. The infected valve was native in 69 patients and prosthetic in 66. The abscess involved the aortic annulus in 73 patients, the mitral annulus in 27, the aortic and mitral annuluses in 33, and the aortic and tricuspid and/or pulmonary annuluses in 2. Surgery consisted of radical resection of the abscess, reconstruction of the annulus with patches and valve replacement. Mean follow-up was 6.2+/-5.2 years and complete. RESULTS: There were 21 (15.5%) operative deaths. Preoperative shock and abscess in the aortic and mitral annuluses were independent predictors of operative death. There were 34 (25%) late deaths. Survival at 15 years was 43+/-6% for all patients, 50+/-8% for native valve endocarditis and 35+/-9% for prosthetic (p=0.41). Age by increments of 5 years and recurrent endocarditis were independent predictors of late death. There were 16 episodes of recurrent endocarditis in 15 patients, and the freedom from recurrent endocarditis was 82+/-4% at 15 years. Fifteen reoperations were performed in 14 patients. Freedom from reoperation was 72+/-9% at 15 years. CONCLUSIONS: Surgery for active endocarditis with paravalvular abscess was associated with high operative mortality, particularly in patients in shock and abscess of both mitral and aortic annuluses. Long-term survival was adversely affected by age and recurrent bouts of endocarditis.     

Dose dependent effects of S-20098, a melatonin agonist,on direction of re-entrainment of rat circadian activity rhythms

The chronobiotic properties of melatonin are well documented. For example, following an 8-h phase advance of the light-dark cycle daily injections of melatonin administered at the pre-shift dark onset alter the direction of re-entrainment of rat activity rhythms. Using this 8-h phase advance paradigm, the effects of the melatonin agonist S-20098 (1 mg/kg and 3 mg/kg) on the rat circadian system were compared with those of melatonin. S-20098 altered the direction of reentrainment in the same manner as melatonin. A study using lower doses of S-20098 showed that the effect on direction of re-entrainment was dose-dependent, with 100% of rats responding at a dose of 100 µg/kg. S-20098 may, therefore, have therapeutic potential as a chronobiotic in the treatment of circadian disorders in humans.