Brian F. Johnson

Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model

We studied the effect of cod-liver oil on the development and progression of coronary artery disease in swine subjected to coronary balloon abrasion and fed an atherogenic diet for eight months. Sections from serial 3-mm segments of the coronary arteries were analyzed morphometrically in 7 pigs given a cod-liver-oil supplement and 11 control animals not given the supplement. Significantly less disease was seen in the sections from the animals fed cod-liver oil. The mean lesion area per vessel, mean luminal encroachment per vessel, and mean maximal luminal encroachment per vessel were reduced in animals fed cod-liver oil, as compared with controls, (P = 0.05, P = 0.016, and P = 0.011, respectively). Both groups of animals had severe hyperlipidemia throughout the study. Differences in the extent of coronary atherosclerosis were not related to differences in plasma lipid levels. Platelet arachidonate was markedly reduced, platelet eicosapentaenoic acid was increased, and serum thromboxane was decreased in the oil-fed group as compared with the control group. We conclude that in our animal mode, dietary cod-liver oil retarded the development of coronary artery disease, possibly through changes in prostaglandin metabolism.

Effect of rotavirus vaccination on death from childhood diarrhea in Mexico.

BACKGROUND A phased introduction of a monovalent rotavirus vaccine occurred in Mexico from February 2006 through May 2007. We assessed the effect of vaccination on deaths from diarrhea in Mexican children in 2008 and 2009. METHODS We obtained data on deaths from diarrhea, regardless of cause, from January 2003 through May 2009 in Mexican children under 5 years of age. We compared diarrhea-related mortality in 2008 and during the 2008 and 2009 rotavirus seasons with the mortality at baseline (2003-2006), before the introduction of the rotavirus vaccine. Vaccine coverage was estimated from administrative data. RESULTS By December 2007, an estimated 74% of children who were 11 months of age or younger had received one dose of rotavirus vaccine. In 2008, there were 1118 diarrhea-related deaths among children younger than 5 years of age, a reduction of 675 from the annual median of 1793 deaths during the 2003-2006 period. Diarrhea-related mortality fell from an annual median of 18.1 deaths per 100,000 children at baseline to 11.8 per 100,000 children in 2008 (rate reduction, 35%; 95% confidence interval [CI], 29 to 39; P<0.001). Among infants who were 11 months of age or younger, diarrhea-related mortality fell from 61.5 deaths per 100,000 children at baseline to 36.0 per 100,000 children in 2008 (rate reduction, 41%; 95% CI, 36 to 47; P<0.001). As compared with baseline, diarrhea-related mortality was 29% lower for children between the ages of 12 and 23 months, few of whom were age-eligible for vaccination. Mortality among unvaccinated children between the ages of 24 and 59 months was not significantly reduced. The reduction in the number of diarrhea-related deaths persisted through two full rotavirus seasons (2008 and 2009). CONCLUSIONS After the introduction of a rotavirus vaccine, a significant decline in diarrhea-related deaths among Mexican children was observed, suggesting a potential benefit from rotavirus vaccination.

Pharmacokinetic interactions with digoxin.

SummaryNumerous pharmacological agents have been shown to produce clinically significant pharmacokinetic interactions with digoxin. Drugs which reduce digoxin absorption include the antacids aluminium hydroxide, magnesium hydroxide and magnesium trisilicate, the antidiarrhoeals kaolin and pectin, the hypocholesterolaemic agent cholestyramine and the chemotoxins cyclophosphamide, vincristine and bleomycin. Certain antibiotics including sulphasalazine, neomycin and aminosalicylic acid reduce digoxin absorption while others, including erythromycin and tetracycline, increase the bioavailability of digoxin in some patients. Capsule preparations of digoxin in solution are less subject to several of the interactions which affect the absorption and bioavailability of digoxin tablets.Various drugs induce alterations in the volume of distribution and clearance of digoxin. Cardiac patients receiving digoxin therapy are particularly prone to interactions with commonly co-administered medications such as the antiarrhythmics quinidine and amiodarone, the calcium channel blockers verapamil and nifedipine, and possibly some vasodilating agents. Studies of digoxin interactions have yielded discrepant results, indicating the need for careful analysis of investigational design before arriving at clinical conclusions.

Comparative effects of verapamil and isradipine on steady‐state digoxin kinetics

The effects on the steady‐state digoxin pharmacokinetics of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), were compared. Nineteen healthy white men, aged 23 to 40 years, ingested 0.25 mg digoxin tablets every 12 hours for two consecutive periods of 2 weeks. Each subject also received one of the calcium channel blockers during one of these periods, with agent and sequence randomized. Analyst‐blind RIA serum digoxin determinations demonstrated that the nine subjects who received isradipine, 5 mg t.i.d., had a small increment in peak digoxin level from 2.3 ± 0.6 to 2.9 ± 0.7 ng/ml (p < 0.05) but no significant change in steady‐state level or AUC over 12 hours. By contrast, the 10 subjects who received verapamil, 80 mg t.i.d., showed significant increases in steady‐state (0.9 ± 0.1 to 1.3 ± 0.2 ng/ml; p < 0.001) and peak serum digoxin concentrations (2.5 ± 0.7 to 3.6 ± 0.8ng/ml; p < 0.001) and in AUC (15.7 ± 1.7 to 23.6 ± 2.9 ng · hr/ml; p < 0.001). Neither calcium channel blocker reduced renal digoxin clearance. Verapamil increases digoxin levels without affecting renal clearance. Isradipine has no clinically important interaction with digoxin.

A Study Design for Comparing the Effects of Missing Daily Doses of Antihypertensive Drugs.

In this double-blind, 6-week study comparing once-daily oral betaxolol and atenolol, the study design allowed the effects of simulated drug noncompliance to be examined. Overall similar blood pressure and heart rate responses were seen in 114 patients with mild-to-moderate hypertension. Similarly, there was no statistically significant difference in percentage of patients achieving goal diastolic blood pressure reductions at the end of 6 weeks of active therapy (betaxolol, 87%, 46/53; atenolol, 82%, 44/54), and safety results overall were similar. However, when patients randomly received placebo for two consecutive treatment days in either the fifth or sixth week of the study to simulate the effect of missing doses, magnitude and duration of effect on systolic blood pressure (p = 0.006), diastolic blood pressure (p = 0.02) and heart rate (p = 0.001) were significantly greater for betaxolol than atenolol as calculated from 28-h ambulatory blood pressure monitoring data. Although betaxolol and atenolol monotherapy are equally effective in controlling blood pressure when taken consistently, the blood pressure and heart rate response with betaxolol is significantly superior for at least 24 h after missing a dose, an important consideration related to patient noncompliance. These results are compatible with the different elimination half-lives of each drug.

A comparison of minoxidil and hydralazine in non-azotemic hypertensives.

In 36 patients with normal renal function receiving hydrochlorothiazide and propranolol, lying diastolic blood pressure remained above 95 mmHg. In a double-blind trial, Step 3 therapy with 5–40 mg/day of minoxidil reduced blood pressure somewhat more effectively than 25–200 mg/day of hydralazine. The percentage of patients with lying diastolic blood pressure below 90 mmHg was 69 versus 35% at four weeks, and 55 versus 40% at 28 weeks. Transient falls in blood pressure within 4 h of any dose were greater with hydralazine which usually needed to be given in divided daily doses. Minoxidil caused tachycardia, and more adverse effects. Minoxidil is more effective, produces more consistent blood pressure control throughout the day, and may often be administered once daily.

Amiodarone for tachyarrhythmias: pharmacology, kinetics, and efficacy.

Amiodarone, although widely studied in Europe, is a recent addition to the investigational antiarrhythmics being used in the U.S. Pharmacologically, its primary cardiac effects are to increase coronary artery blood flow, increase the effective refractory period, and produce an atropine-resistant bradycardia. Amiodarone is incompletely (~ 50 percent) and slowly (peak serum concentration ~ 6 h) absorbed. With chronic administration, it deposits both in adipose tissue and in organs with high blood perfusion. It has an apparent elimination half-life of 15–45 days, which presents unique dosing problems. The apparent therapeutic range is 0.6-3 μg/ml. Amiodarone is 85–95 percent effective in the treatment of atrial tachyarrhythmias and 70–80 percent effective in ventricular tachyarrhythmias. It appears to be of particular value in chronic atrial fibrillation/flutter because it may be able to maintain sinus rhythm after cardioversion. Side effects, although uncommon, may prevent the drug from becoming a standard of therapy. Drug interactions, particularly with warfarin and digoxin, as well as pulmonary fibrosis are of concern.

Comparative effects of propranolol and prazosin upon serum lipids in thiazide-treated hypertensive patients

Earlier reported thiazide-induced changes in serum lipid concentrations were confirmed with increased triglyceride and total cholesterol levels. However, lipoprotein cholesterol ratios were unchanged. Propranolol caused further increases in triglyceride and very low-density lipoprotein cholesterol, and lowered high-density lipoprotein cholesterol and the high-density lipoprotein:total cholesterol ratio. With the addition of prazosin to the polythiazide regimen, there was a significant increase in serum high-density lipoprotein cholesterol when compared with the placebo.

Multicenter clinical evaluation of long-term efficacy and safety of labetalol in treatment of hypertension

The long-term efficacy and safety of labetalol, an antihypertensive agent with combined beta- and alpha-blocking activity, were evaluated alone (number = 193) and in combination with a diuretic (number = 144) in an open-label multicenter trial of 337 hypertensive patients aged 21 to 75 years, including initially 205 (61 percent) men and 219 (65 percent) Caucasians. There were 219 (65 percent) mild, 85 (25 percent) moderate, and 33 (10 percent) severe hypertensive patients. Labetalol (100 to 1,200 mg twice a day) alone or in combination with a diuretic reduced the mean standing blood pressure by 13/11 and 25/16 mm Hg to 135/88 and 130/91 mm Hg, respectively (p less than 0.01), and supine blood pressure by 6/7 and 18/13 mm Hg to 141/86 and 138/90 mm Hg (p less than 0.01), respectively. Blood pressure reductions observed at one month were maintained after one year; 206 (62 percent) patients had 10 mm Hg or greater reductions and 184 (56 percent) patients were maintained at diastolic blood pressures less than 90 mm Hg. Most frequently reported drug-related side effects included fatigue (14 percent), dizziness (12 percent), nausea (11 percent), nasal stuffiness (8 percent), headache (4 percent), and male sexual dysfunction (14 percent). Side effects were generally of mild to moderate intensity and often transient. In addition, in 27 (8 percent) patients reversible asymptomatic transaminase elevations to greater than twice normal developed at some time during the study. In 13 (4 percent) patients these alterations resolved during continued labetalol therapy, but in five (2 percent) patients these marked elevations led to discontinuation of the drug. A total of 32 (9.5 percent) patients were terminated prematurely due to side effects (most commonly genitourinary or gastrointestinal) possibly attributable to the drug. These findings indicate that labetalol with or without a diuretic is a potentially effective, safe, and relatively well-tolerated long-term antihypertensive therapy.

Theophylline serum protein binding in obstructive airways disease

The percentage of theophylline bound to protein in sera obtained from patients with obstructive airways disease was determined by ultrafiltration. The bound theophylline fraction in 71 serum specimens collected from 51 patients was 60.7 ± 10.0% (x ± SD) and ranged from 30.8% to 83.2%. The correlation between unbound serum theophylline concentration and total concentration (range 0.8 to 90 mg/l) was linear (r = 0.97, p < 0.001). Theophylline binding correlated poorly with serum albumin (r = 0.39) and total serum protein (r = 0.35), although the correlations were statistically significant (p < 0.05). Theophylline binding in women did not differ from that in men. The extent of theophylline binding in younger patients was greater than in patients over 55 yr (64.3 ± 8.5% and 57.0 ± 10.4%, p < 0.005). Variation in theophylline binding in 12 patients from whom two or more serum samples were collected was relatively small. Analysis of variance showed interpatient variation in theophylline binding (p < 0.01) but not between sampling occasions in the same patient. The demonstrated variability in serum protein binding of theophylline should influence theophylline distribution and elimination kinetics and may be another determinant of clinical response. Patients with lower binding levels should have higher plasma levels of unbound drug after a loading dose and will need more frequent dosing.