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Biomedical subjects

J H Patterson

Publications and source records attributed to J H Patterson.

At least 19 recordsLinked to original sources
PubMed2001

Angiotensin II-receptor blockers: clinical relevance and therapeutic role.

The limitations of angiotensin-converting-enzyme (ACE) inhibitors and the role of angiotensin II-receptor blockers (ARBs) in the treatment of hypertension, heart failure, and diabetic nephropathy are discussed. Although ACE inhibitors are generally well tolerated, two important class-related adverse effects are cough, which is common, and angioedema, which is rare but serious. Cough and angioedema appear to be less frequent with ARBs than with ACE inhibitors. ARBs seem to be as capable as ACE inhibitors of producing renal dysfunction. ARBs may offer more complete inhibition of angiotensin II than ACE inhibitors. The mechanism of action is based on selective binding to angiotensin type 1 receptors. Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including ACE inhibitors. ARBs do not appear to have a greater clinical effect than ACE inhibitors in patients with heart failure. Some studies of combination ARB and ACE inhibitor therapy for heart failure indicate advantages of the combination over therapy with either class. ARBs may exert renal protective effects in diabetic nephropathy. ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.

Angiotensin II↗
PubMed2001

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double-blind, two-period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12-hour carvedilol dosing interval, and the concentrations of the R(+) and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (+/- SD) R(+) enantiomer AUC0-12 (522 +/- 413 vs. 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enantiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/- 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(-) enantiomer. However, this interaction was of little clinical significance in our sample population.

Adrenergic beta-Antagonists↗
PubMed2000

Identification of a methyltransferase from Mycobacterium smegmatis involved in glycopeptidolipid synthesis.

Glycopeptidolipids (GPLs) are major components of the cell walls of several species of mycobacteria. We have isolated a transposon mutant of Mycobacterium smegmatis that is unable to synthesize mature GPLs and that displays a rough colony morphology. The disrupted gene, mtf1, shares a high degree of homology with several S-adenosylmethionine-dependent methyltransferases. The enzyme encoded by mtf1 is required for the methylation of a single rhamnose residue that forms part of the conserved GPL core structure. This conclusion is supported by the finding that (a) the mutant synthesized only GPLs with undermethylated (either mono- or nonmethylated instead of di- or trimethylated) rhamnose residues; (b) complementation of the mutant with a wild-type copy of mtf1 restored high levels of synthesis of GPLs containing di- and trimethylated rhamnose; and (c) S-adenosylmethionine-dependent methylation of rhamnosylated GPLs could be detected in cell lysates of wild-type cells and mtf1-complemented mutant cells, but not in mutant cells lacking intact mtf1. Structural analysis of wild-type and mutant GPLs suggests that disruption of mtf1 specifically inhibits addition of O-methyl groups to the 3 (or 2)-position of the rhamnose. In the absence of 3-O-methylation, further methylation of GPL rhamnose is apparently inhibited, and overall GPL synthesis is down-regulated by 90%.

Amino Acid Sequence↗
PubMed2000

The major surface antigens of Entamoeba histolytica trophozoites are GPI-anchored proteophosphoglycans.

Trophozoites of the parasitic protozoa, Entamoeba histolytica, synthesize a cell surface lipoglycoconjugate, termed lipophosphoglycan, which is thought to be an important virulence factor and potential vaccine candidate against invasive amebiasis. Here, we show that the E. histolytica lipophosphoglycans are in fact glycosylphosphatidylinositol (GPI)-anchored proteophosphoglycans (PPGs). These PPGs contain a highly acidic polypeptide component which is rich in Asp, Glu and phosphoserine residues. This polypeptide component is extensively modified with linear glycan chains having the general structure, [Glcalpha1-6](n)Glcbeta1-6Gal (where n=2-23). These glycan chains can be released after mild-acid hydrolysis with trifluoroacetic or hydrofluoric acid and are probably attached to phosphoserine residues in the polypeptide backbone. The PPGs are further modified with a GPI anchor which differs from all other eukaryotic GPI anchors so far characterized in containing a glycan core with the structure, Gal(1)Man(2)GlcN-myo-inositol, and in being heterogeneously modified with chains of alpha-galactose. Trophozoites of the pathogenic HM-1:IMSS strain synthesize two distinct classes of PPG which have polydisperse molecular masses of 50-180 kDa (PPG-1) and 35-60 kDa (PPG-2) and are modified with glucan side-chains of different average lengths. In contrast, the non-pathogenic Rahman strain synthesizes one class of PPG which is only elaborated with short disaccharide side-chains (i.e. Glcbeta1-6Gal). However, the PPGs are abundant in all strains (8x10(7) copies per cell) and are likely to form a protective surface coat.

Animals↗
PubMed2000

The role of the renin-angiotensin-aldosterone system in the management of heart failure.

Numerous clinical trials have highlighted the role of the renin-angiotensin-aldosterone (RAA) system in the development and progression of heart failure. Over 30 randomized, controlled trials have evaluated the effects of angiotensin-converting enzyme (ACE) inhibitors on morbidity and mortality in over 7,000 patients with heart failure. Cumulative evidence from these trials shows that these agents significantly reduce mortality and hospitalizations, slow disease progression, and improve exercise tolerance and New York Heart Association class. The Heart Failure Society of America guidelines recommend ACE inhibitors as standard therapy for patients with left ventricular systolic dysfunction. The angiotensin receptor blockers and spironolactone offer alternative and perhaps complimentary mechanisms by which the RAA system may be therapeutically manipulated. The role of these therapies in treating heart failure is discussed.

Aged↗
PubMed1999

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Adolescent↗
PubMed1998

Clinical predictors of worsening heart failure during withdrawal from digoxin therapy.

Previous work provides limited information concerning predictors of clinical deterioration after digoxin withdrawal. We investigated the association between selected baseline clinical characteristics and symptomatic deterioration in two similarly designed trials: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Cox proportional-hazards analysis found the following independent predictors of worsening during follow-up in the combined PROVED and RADIANCE patients: heart failure score, left ventricular ejection fraction, cardiothoracic ratio, use of an angiotensin-converting enzyme inhibitor, use of digoxin, and age. When these factors, except for digoxin use, were tested in the subgroup of patients withdrawn from digoxin, they all were significant independent predictors of worsening heart failure. In contrast, only use of angiotensin-converting enzyme inhibitor predicted deterioration in patients who continued digoxin. Patients with more congestive symptoms, worse ventricular function, greater cardiac enlargement, or who were not taking an angiotensin-converting enzyme inhibitor were significantly more likely to worsen early after digoxin discontinuation than patients without these characteristics.

Aged↗
PubMed1998

Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers.

BACKGROUND: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174. OBJECTIVE AND METHODS: Ten healthy volunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pharmacokinetics were determined. RESULTS: Rifampin decreased the area under the concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the AUC(0-24) of E3174 by 40% (1336 +/- 445 versus 792 +/- 302; p < 0.005). Losartan oral clearance was increased by 44% (p = 0.0001). The half-life values of both compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not significantly affect the AUC(0-24) or half-life of either losartan or E3174. CONCLUSIONS: Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.

Adult↗
PubMed1998

Superiority of "triple" drug therapy in heart failure: insights from the PROVED and RADIANCE trials. Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin. Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme.

OBJECTIVES: We sought to study the efficacy of "triple" therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction. BACKGROUND: Controversy continues concerning the role of combining digoxin with diuretic and ACEI in the initial management of patients with heart failure. METHODS: The study utilized data from two studies of digoxin efficacy: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Worsening heart failure defined as augmentation of heart failure therapy or an emergency room visit or hospitalization for increased heart failure was the main outcome measure. RESULTS: A total of 266 patients comprising the four treatment groups of the combined PROVED (diuretic alone or digoxin and diuretic) and RADIANCE (ACEI and diuretic, or digoxin, diuretic and ACEI) trials were analyzed. Worsening heart failure occurred in only 4 of the 85 patients who continued digoxin, diuretic and ACEI therapy (4.7%) compared to 18 of the 42 patients (19%) on digoxin and diuretic therapy (p=0.009), to 23 of the 93 patients (25%) on ACEI and diuretic therapy (p=0.001) and to 18 of the 46 patients (39%) on diuretic alone (p < 0.001). Life table and multivariate analysis also demonstrated that worsening heart failure was least likely in patients treated with triple therapy (p < 0.01 vs. all other groups). CONCLUSION: Pending definitive, prospective clinical trials, our results argue for triple therapy as the initial management of patients with symptomatic heart failure due to systolic dysfunction.

Adult↗
PubMed1997

Blast overpressure induced structural and functional changes in the auditory system.

Blast overpressure of sufficient intensity can produce injury to various organ systems. Unprotected ears result in the auditory system being the most susceptible. The injuries to the auditory system include: rupture of the tympanic membrane, dislocation or fracture of the ossicular chain, and damage to the sensory structures on the basilar membrane. All these injuries can be characterized as a form of mechanical damage to the affected structure. Injury to the sensory structures on the basilar membrane leads to temporary and permanent loss of hearing sensitivity. The temporary component of the hearing loss shows a time course after removal from the noise which frequently will include an initial increase in hearing loss followed by a recovery period during which threshold may return to preexposure levels or stabilize at a higher level which represents a permanent loss of hearing sensitivity. This type of recovery function suggests that there are damage processes which continue after the traumatic event and that intervention might mitigate some of the damage and hearing loss.

Air Pressure↗
PubMed1997

The AHCPR clinical practice guideline for heart failure revisited.

OBJECTIVE: To review the Agency for Health Care Policy and Research (AHCPR) clinical practice guideline for heart failure and comment on the guideline regarding pharmacotherapy from the perspective of the latest clinical trial data and the authors' clinical experience. DATA SOURCES: A MEDLINE search (1966 to June 1997) of English-language literature pertaining to the pharmacotherapy of heart failure was performed. Special emphasis was placed on literature published in the last 5 years. Additional literature was obtained from reference lists of key articles identified through the search. DATA SYNTHESIS: Pertinent clinical trials were reviewed and considered along with information from the authors' database of over 800 patients with heart failure. Evidence concerning the use of angiotensin-converting enzyme inhibitors at appropriate dosages in all New York Heart Association classes of heart failure and the inclusion of digoxin as part of triple therapy in all symptomatic patients with left ventricular systolic dysfunction are reviewed. Strategies to circumvent clinical problems that may limit the proper application of standard therapeutic agents are considered, and the possible future role of beta-blockers as the therapeutic agents in patients with heart failure is discussed. CONCLUSIONS: The AHCPR guideline provides the clinician with an excellent framework for treating the patient with heart failure. Building on the fundamentals of the guideline, the clinician can carefully apply current therapy at appropriate dosages and in the best combinations to individualize and thereby optimize pharmacologic therapy for this patient population.

Adrenergic beta-Antagonists↗
PubMed1996

Effects of ofloxacin on the pharmacokinetics and pharmacodynamics of procainamide.

Procainamide is a class I antiarrhythmic agent that undergoes active tubular secretion through the organic cation transport system, with approximately 50% of a dose excreted in the urine as unchanged drug. The remainder is metabolized to an active metabolite, n-acetyl procainamide (NAPA). Ofloxacin is a fluoroquinolone antibiotic that is excreted in the urine as unchanged drug via active tubular secretion and glomerular filtration. To test the hypothesis that ofloxacin may interfere with the renal elimination of procainamide, 9 healthy volunteers were randomly assigned to receive 1 g of oral procainamide as a single dose with or without pretreatment with 400 mg of ofloxacin twice a day for 5 doses. Blood and urine samples were obtained and pharmacokinetic parameters for procainamide were determined for each treatment period. Standard 12-lead and signal-averaged electrocardiographic recordings were used for pharmacodynamic analysis. The mean area under the concentration-time curve (AUC) and peak plasma concentration (Cmax; mug/mL) for procainamide increased by 27% and 21%, respectively, and the plasma clearance for procainamide decreased by an average of 22% with coadministration of ofloxacin. Ofloxacin did not significantly influence the pharmacokinetics of NAPA, nor were pharmacodynamics of procainamide significantly affected by coadministration of ofloxacin. These results suggest that procainamide concentrations should be monitored closely when coadministered with ofloxacin.

Administration, Oral↗
PubMed1996

The effects of epoprostenol on drug disposition. I: A pilot study of the pharmacokinetics of digoxin with and without epoprostenol in patients with congestive heart failure.

The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.

Adult↗
PubMed1996

The effects of epoprostenol on drug disposition. II: A pilot study of the pharmacokinetics of furosemide with and without epoprostenol in patients with congestive heart failure.

The effect of epoprostenol on the pharmacokinetics of furosemide was investigated in 23 patients with end-stage congestive heart failure (CHF) receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of the apparent oral clearance, volume of distribution, and absorption rate constant for furosemide were generated from 198 serum furosemide concentrations using nonlinear mixed effects modeling (NONMEM). Univariate analyses were performed to assess the effects of patient factors on the apparent oral clearance of furosemide. The final multivariate model determined by backwards elimination included concomitant digoxin therapy. When concomitant epoprostenol therapy was included in the final model, there was a 13% decrease in the apparent oral clearance of furosemide in response to short-term administration of epoprostenol. However, the effect of concomitant epoprostenol therapy was not statistically significant and was no longer apparent by the end of the 12-week study. These data suggest that epoprostenol may have a slight short-term effect on the pharmacokinetics of furosemide; the interaction between epoprostenol and furosemide is not clinically significant, however.

Diuretics↗
PubMed1996

Relation between gender, etiology and survival in patients with symptomatic heart failure.

OBJECTIVES: This study investigated the relation between gender, etiology and survival in patients with symptomatic heart failure. BACKGROUND: Previous work provides conflicting results concerning the relation between gender, clinical characteristics and survival in patients with heart failure. METHODS: We examined the relation of these factors in 557 patients (380 men, 177 women) who had symptomatic heart failure, predominantly nonischemic in origin (68%) and typically associated with severe left ventricular dysfunction. RESULTS: Follow-up data were available in 99% of patients (mean follow-up period 2.4 years, range 1 day to 10 years) after study entry, and 201 patients reached the primary study end point of all-cause mortality. By life-table analysis, women were significantly less likely to reach this primary end point than men (p < 0.001). A significant association was found between female gender and better survival (p < 0.001), which depended on the primary etiology of heart failure (p = 0.008 for the gender-etiology interaction) but not on baseline ventricular function. Women survived longer than men when heart failure was due to nonischemic causes (men vs. women: relative risk [RR] 2.36, 95% confidence interval [CI] 1.59 to 3.51, p < 0.001). In contrast, outcome appeared similar when heart failure was due to ischemic heart disease (men vs. women: RR 0.85, 95% CI 0.45 to 1.61, p = 0.651). CONCLUSIONS: Women with heart failure due to nonischemic causes had significantly better survival than men with or without coronary disease as their primary cause of heart failure.

Adolescent↗
PubMed1995

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Torsemide: a pyridine-sulfonylurea loop diuretic.

OBJECTIVE: To review the clinical pharmacology of torsemide and to compare it with currently available loop diuretics, particularly furosemide. DATA SOURCES: An English-language MEDLINE search, 1985 to October 1994, was used to identify pertinent literature, including review articles. DATA EXTRACTION: Data from scientific literature were extracted, evaluated, and summarized for presentation. Pivotal and representative studies are discussed relating to the pharmacology, pharmacokinetics, and use of torsemide in patients with congestive heart failure, renal disease, hepatic disease, and hypertension. DATA SYNTHESIS: Torsemide is a loop diuretic of the pyridine-sulfonylurea class. The bioavailability of torsemide is approximately 80%, with little first-pass metabolism, and torsemide can be given without regard to meals. The serum concentration reaches its peak within 1 hour after oral administration and diuresis lasts approximately 6-8 hours. Torsemide is eliminated both hepatically (80%) and renally (20%) as unchanged drug with an elimination half-life of about 3.5 hours. Because of the high bioavailability, oral and intravenous doses are therapeutically equivalent. Torsemide, and other loop diuretics such as furosemide, are indicated for the treatment of edema associated with congestive heart failure, renal disease, and hepatic disease. They also are indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. Depending on the indication, the recommended initial adult dosage of torsemide is between 5 and 20 mg once daily orally or intravenously. Special dosage adjustments in the elderly are not necessary. CONCLUSIONS: Torsemide is a loop diuretic similar to furosemide, with similar indications. Torsemide is characterized by good bioavailability and once-daily dosing and, compared with furosemide, provides generally equivalent therapeutic efficacy.

Clinical Trials as Topic↗