Hemodynamic and cardiovascular effects of nitric oxide modulation in the therapy of septic shock.

Nitric oxide synthase (NOS) of the inducible subtype (iNOS) plays a pivotal role in vasodilation associated with sepsis. Various biochemical pathways are involved, revealing targets for inhibiting the consequence of iNOS activation. Interactions of transcription factors, inducers, cofactors, and regulators of iNOS are important in understanding the development of iNOS inhibitors. Inhibition through L-arginine analogs, depletion of arginine, inhibition of cofactors, modulating gene transcription, and scavenging nitric oxide have been studied. Human studies were conducted only with nonselective L-arginine analogs. Reduction of mortality from sepsis was not reported. It is anticipated that iNOS-specific compounds will be clinically useful. The focus of future human trials will be on these agents. Although ideal therapy for treating vasodilation from sepsis is not available, research into the pathophysiology of NOS in sepsis clarified the complexities surrounding this therapeutic dilemma.

A pilot study of estrogen's effects on bronchial myocyte adhesion molecule expression.

We examined the effects of estrogen on tumor necrosis factor alpha (TNF-alpha)-induced expression of intracellular adhesion molecule (ICAM-1) and vascular adhesion molecule (VCAM-1) in cultured human bronchial smooth muscle cells (BSMC). Experiments were performed in triplicate in T-75 tissue culture flasks containing normal human BSMC. Four experiments were carried out: untreated BSMC cells (control); TNF-alpha 1000 U/ml stimulation of BSMC; forskolin 5 microM before TNF-alpha stimulation of BSMC; and estradiol 30 microM before TNF-alpha stimulation of BSMC. Cyclic adenosine monophosphate was measured by a commercially available radioimmunoassay kit. Cell expression of ICAM-1 and VCAM-1 was quantified by flow cytometry Incubation of cells with TNF-alpha 1000 U/ml for 24 hours elicited a 27-fold increase in basal expression of ICAM-1 and a 2-fold increase in VCAM-1 (p>0.05). Incubation of BSMC with forskolin 5 microM, for 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 62% and VCAM-1 slightly by 17%. The BSMC incubated with estradiol 30 microM, 1 hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 21%; VCAM-1 remained unchanged (p>0.05). We found a trend toward inhibition of TNF-alpha-stimulated ICAM-1 expression in cultured BSMC with pretreatment with estradiol. However, due to large variability within the cell culture model, statistical significance was not reached.

Alpha1-acid glycoprotein concentrations and cerebrospinal fluid drug distribution after subarachnoid hemorrhage.

STUDY OBJECTIVE: To test the hypothesis that changes in alpha1-acid glycoprotein (AAG) concentration alter central nervous system (CNS) drug distribution after subarachnoid hemorrhage. DESIGN: Two-phase, prospective study. SETTING: University-associated medical center. PATIENTS: Twenty-one patients with subarachnoid hemorrhage. INTERVENTION: In phase I, serum AAG concentrations of patients with subarachnoid hemorrhage were measured serially and compared with those in 21 controls undergoing elective neurosurgical procedures. In phase II, nimodipine was the pharmacologic probe to determine the relationship between drug distribution into the CNS and changes in AAG concentration. MEASUREMENTS AND MAIN RESULTS: Serum and cerebrospinal fluid (CSF) samples were collected from patients with subarachnoid hemorrhage treated with nimodipine and used to measure total and unbound drug concentrations. Concentrations of AAG were 39% higher in patients than in controls preoperatively. They decreased significantly by 24 hours after surgery in patients and increased in controls. In both groups the concentrations were higher than reported normal values. During the period of reduced AAG concentration, calculated unbound nimodipine concentrations were 3-fold higher (p<0.05) than at later periods, with a trend toward higher total concentrations. Overall, mean CSF nimodipine concentration was 6.4% of mean serum total concentration. The CSF concentrations decreased as AAG concentrations increased, independent of serum concentrations (r = -0.52, p<0.02). CONCLUSION: Concentrations of AAG change after subarachnoid hemorrhage and are transiently influenced by surgery. Unbound drug concentration increases when AAG concentrations decrease, whereas CSF concentrations decrease when AAG concentrations increase. These preliminary findings suggest that changes in AAG concentrations can alter unbound serum nimodipine concentrations and may affect CSF drug distribution.

Influence of myocardial ischemia and reperfusion on beta-adrenoceptor subtype expression.

The effects of ischemic injury and reperfusion on myocardial beta-adrenoceptor expression were examined in dogs after 30 min of left anterior descending coronary artery (LAD) ligation. Three sets of six dogs were allocated to either sham ligation (group I), 30 min ischemia without reperfusion (group II), or ischemia with 1 h of reperfusion (group III). The density of total beta-adrenoceptors along with beta1- and beta2-adrenoceptor subtypes were compared in tissue from the ischemic LAD and nonischemic left lateral zones by using radioligand binding with 125-labeled iodocyanopindolol (ICYP). In the control animals, there was no difference between total beta-adrenoceptors (43.8 +/- 7.2 vs. 40.7 +/- 8.0 fmol/mg protein +/- SEM) or percentage beta-adrenoceptor subtypes between the two zones. In group II, total beta-adrenoceptors increased 19.9% (p = 0.03) in the LAD compared with the lateral zone after 30 min of ischemia. Both beta-adrenoceptor subtypes increased, but only the increase in beta2-adrenoceptor was significant (39.8%; p = 0.02). Animals in group III revealed no difference in total beta-adrenoceptors density between LAD and lateral zones (48.3 +/- 13.4 vs. 55.2 +/- 8.5 fmol/mg protein). Brief myocardial ischemia is associated with an increase in total beta-adrenoceptors, attributed predominantly to increased beta2-adrenoceptors density. The increase in beta-adrenoceptor density is reversible after 1 h of reperfusion.

T lymphocyte beta 2-adrenergic receptor function and density after acute myocardial infarction.

The T lymphocyte beta 2-adrenergic receptor (beta 2AR) density and function were compared in 15 patients suffering acute myocardial infarction and 10 patients with stable coronary artery disease (CAD). Density was determined using radioligand binding with 125IPIN, and function by in vitro cyclic adenosine 3',5'-monophosphate (cAMP) production. In patients suffering acute myocardial infarction, T lymphocyte beta 2AR density (823.8 +/- 480 sites/cell) was slightly but not significantly different from that in patients with stable CAD (629 +/- 301 sites/cell). There was no difference in T lymphocyte cAMP production at baseline (1.11 +/- 0.70 vs 1.04 +/- 0.49 pM/10(6) cells) or after isoproterenol stimulation (2.53 +/- 1.63 vs 2.62 +/- 2.05 pM/10(6) cells), respectively. Further study is necessary to determine if beta 2AR numbers on T lymphocytes are significantly increased after acute myocardial infarction.

Heparin as adjunctive therapy to coronary thrombolysis in acute myocardial infarction.

For many years anticoagulation has played a role in the prevention and management of thromboembolic complications associated with acute myocardial infarction. However, the role of heparin therapy after pharmacologic thrombolysis in myocardial infarction remains controversial. Debate continues regarding the necessity of heparin treatment after thrombolytic therapy as well as the mode by which it is administered. The purpose of this review is to summarize the findings of clinical trials designed to evaluate the effectiveness and safety of heparin as an adjuvant agent to thrombolytic therapy in acute myocardial infarction. Data regarding the clinical effectiveness of heparin are presented. Information and recommendations regarding the optimal dose, route of administration, timing of initiation, and duration of heparin treatment are provided.

Toxicology and management of acute drug ingestions in adults.

We reviewed the current literature on the toxicology and management of acute drug ingestions in adults after a MEDLINE search of English-language journal articles. Information on toxicology was also acquired from relevant textbooks. Present statistics were gathered through information from the U.S. Department of Health and Human Services and the American Association of Poison Control Centers. All patients with acute drug ingestions should be treated with supportive care initially, and when stabilized, undergo active removal of the ingested substance, based on the diagnostic and prognostic assessment. Identification of the ingested substance may prove useful in some instances when specific therapy or antidotes are indicated.

Reliability of blood pressure, heart rate, and Doppler-derived hemodynamic measurements during exercise.

Doppler echocardiography of aortic blood flow, heart rate, and blood pressure represent noninvasive methods for evaluation of the hemodynamic effects of pharmacologic agents or other stimuli during rest and exercise. In this study the reliability of continuous-wave Doppler echocardiography for detecting the effects of various interventions on left ventricular systolic function during exercise was assessed. The reliability of Doppler measurements was compared with that found for measurements of simultaneously obtained heart rate and blood pressure. Exercise treadmill testing was performed at 0, 2, 4, 6, and 8 hours in 18 healthy male subjects. All measurements were performed at rest and during the last half of each exercise stage. Reliability of peak modal velocity, peak aortic blood flow acceleration, heart rate, and blood pressure was measured by the intraclass correlation coefficient (ICC) at each stage. ICC reliability of greater than 0.75 is considered excellent, 0.4 to 0.75 fair to good, and less than 0.4 poor. The reliability of all Doppler-derived parameters, heart rate, and blood pressure improved with increasing stage of exercise. Peak modal velocity, peak acceleration, heart rate, and manually obtained systolic blood pressure had ICCs of 0.75 or greater by stage 3. The reliability of Doppler-derived aortic blood flow parameters was good or excellent at rest and advanced stages of exercise. Continuous-wave Doppler echocardiography is a reliable method for performing studies to assess the effects of interventions on cardiovascular function during exercise.

Effect of nebulized albuterol on serum potassium and cardiac rhythm in patients with asthma or chronic obstructive pulmonary disease.

STUDY OBJECTIVE: To evaluate the metabolic and cardiopulmonary effects of nebulized albuterol in patients suffering moderate to severe exacerbations of asthma or chronic obstructive pulmonary disease. DESIGN: Open-label, prospective study. SETTING: The emergency department of a university medical center. PATIENTS: Ten patients with moderate to severe exacerbation of asthma. INTERVENTIONS: Each patient received nebulized albuterol 2.5 mg for approximately 10 minutes. MEASUREMENTS AND MAIN RESULTS: Serum potassium, heart rate and rhythm, blood pressure, and pulmonary function were measured before treatment and every 15 minutes for 2 hours after treatment. Serum potassium concentrations decreased significantly (p < 0.05) within 75 minutes after initiation of treatment, from a baseline value of 4.5 +/- 0.6 mEq/L (range 3.5-5.5 mEq/L) to 3.7 +/- 0.5 mEq/L (range 2.8-4.4 mEq/L) at the end of the collection period (120 minutes). Forced expiratory volume in 1 second significantly increased over time in patients with asthma (p < 0.05). No statistically significant changes in blood pressure, heart rate, or corrected QT intervals occurred. Pre-emergency department use of a beta 2-agonist by metered-dose inhaler was not associated with a decreased serum potassium on admission. CONCLUSIONS: Nebulized beta 2-agonists are generally efficacious and safe in patients with acute bronchospasms. However, close monitoring of serum electrolytes, heart rate, and rhythm in patients at risk (elderly, those with pre-existing cardiac disease) is advised before these individuals receive repeat doses by continuous aerosol administration.

Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension.

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (Cmax), mean time to maximum concentration (Tmax), concentration at 24 hours after the dose (C24), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and Cmax for digoxin increased by 14% and 32%, respectively (p < 0.05), with no change in Tmax. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p < 0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.

Pharmacodynamics of racemic and S(-)-atenolol in humans.

The cardiovascular actions of racemic atenolol (RSATN) have been well characterized in humans, but the actions of S(-)-atenolol (SATN) when administered alone are unknown. In this study, responses of heart rate (HR) and Doppler-derived aortic blood flow profiles to upright treadmill exercise were compared after oral administration of 50 mg SATN and 100 mg RSATN in eight healthy, adult, male volunteers. After a single-blind, placebo run-in period, subjects were randomly allocated in a double-blind, crossover fashion to receive SATN and RSATN. Each study period was separated by a 7-day washout period. Multiple submaximal exercise tests were performed and data were collected over the 24 hours after each treatment. Both SATN and RSATN significantly (P < .05) blunted peak exercise HR by 38 +/- 3 and 37 +/- 3 beats/min, respectively. Aortic blood flow acceleration measured during peak exercise decreased after SATN and RSATN, by 13 +/- 4 and 13 +/- 3 m/sec2, respectively (P < .05). No difference in hemodynamic effect was observed between treatments. Pharmacodynamic parameters derived from plasma S(-)-atenolol concentration-effect (HR) curves after SATN, RSATN, and total atenolol plasma concentrations after RSATN did not differ significantly. Predicted maximum reductions in heart rate (Emax) and EC50 for S(-)-atenolol after SATN were 39.6 +/- 5.8 beats/min and 38.4 +/- 40.9 ng/ml versus 34.5 +/- 8 beats/min and 25.9 +/- 29.9 ng/ml for RSATN, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a successful research grant application.

The process of identifying appropriate funding agencies for research projects is described, and grant application and review procedures are explained. Although the federal government is the largest single source of research funding, financial support is also offered by associations, foundations, and corporations. Research funding may be divided into two major types: grants, which are awarded in response to investigator-initiated projects, and contracts, under which the research topic is proposed by the funding agency. Competing successfully for grants and contracts requires a sound research plan whose objectives are consistent with those of the funder. Identification of an appropriate potential funding agency requires familiarity with its areas of interest, the size of grants offered, and other criteria. The development of the grant application has several steps, including determining specific aims and long-term project goals, reviewing the literature, obtaining letters of consent from collaborators and consultants, securing colleagues' assistance in reviewing the drafts, preparing a budget, and drafting and revising the proposal. Most grant applications have a number of common elements; each funder also may have unique requirements. Authors should familiarize themselves with the application criteria of the agency or institution from which they are seeking support and follow them scrupulously. Competition for grant funds is high, and many worthwhile proposals are rejected. After studying the reviewers' comments, the author may wish to revise the application for resubmission or submission to a different funding agency. Sound planning, selection of an appropriate funding agency, and preparation of a well-written proposal play key roles in successful grantsmanship.

Single dose pharmacokinetics of (S)-atenolol administered orally as a single enantiomer formulation and as a racemic mixture (Tenormin).

The purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)-atenolol (SATN) and (R)-atenolol (RATN) after oral administration of (S)-atenolol and (R,S)-atenolol (Tenormin) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin (TMN) using a randomized, double-blind, 2-period, complete crossover study design. Subjects performed exercise tolerance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin attenuate exercise-induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were -38 +/- 3 bpm and -37 +/- 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were -42 +/- 12 mm Hg and -55 +/- 14 mm Hg for SEF and TMN, respectively, P = 0.484. Mean area under the plasma level time curve (AUC0-24) and mean Cmax for SATN for SEF were significantly lower than for SATN after TMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Febrile reaction associated with urokinase.

Urokinase is an endogenously produced human proteolytic enzyme used to treat many thrombotic disorders. A 54-year-old man with recurrent myocardial infarction experienced fever during intracoronary urokinase infusion into a saphenous vein graft; the fever resolved after discontinuation of the infusion. After excluding all other possible etiologies of fever, urokinase was determined to be the cause. Several studies indicated that this reaction may be associated with urokinase infusion, but it is actually recognized by few individuals. This is the first published case report of the adverse event to our knowledge.

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.