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Biomedical subjects

M N Brunden

Publications and source records attributed to M N Brunden.

At least 19 recordsLinked to original sources
PubMed1996

Antiarrhythmic and electrophysiologic effects of intravenous ibutilide and sotalol in the canine sterile pericarditis model.

INTRODUCTION: Atrial arrhythmias are a frequent clinical complication following open heart surgery. We compared the Class III agents d,l-so-talol and ibutilide fumarate in an intravenous cross-over study using the canine atrial sterile pericarditis model. METHODS AND RESULTS: We studied pacing-induced sustained atrial flutter over a 7-day post-surgical period in conscious dogs, alternating analysis of ibutilide (1.0 to 30.0 micrograms/kg) and d,l-sotalol (0.1 to 3.0 mg/kg). Ibutilide significantly increased atrial flutter cycle length (AFL CL) 11 +/- 2 msec and atrial effective refractory period (AERP) 13 +/- 2 msec, and terminated atrial flutter in all cases (n = 12) following a mean dose of 6 +/- 2 micrograms/kg. Plasma concentrations of ibutilide were 53 +/- 13 ng/mL. Ventricular effective refractory period (VERP) was not significantly affected (4 +/- 2 msec). Following termination with ibutilide, atrial flutter could be reinitiated in 1 of 12 trials, and was nonsustained (40-sec duration). Sotalol significantly increased AFL CL 23 +/- 3 msec and terminated atrial flutter in 8 of 12 trials following a mean dose of 1.5 +/- 0.4 mg/kg. AERP and VERP were significantly increased 20 +/- 6 and 12 +/- 2 msec, respectively. The incidence of reinduced atrial flutter was 9 of 12 trials (P < or = 0.05 vs ibutilide) (7 nonsustained 57 +/- 7 sec duration, and 2 sustained). Sotalol failed to terminate atrial flutter in two dogs on days 1 and 5, despite increases in AFL CL (21 +/- 8 msec) and AERP (16 +/- 9 msec), whereas on day 3, ibutilide (20 +/- 7 micrograms/kg) terminated atrial flutter in those two dogs while increasing AFL CL and AERP 18 +/- 6 and 15 +/- 0 msec, respectively. CONCLUSION: Both sotalol and ibutilide terminate atrial flutter in this model. Ibutilide converted atrial flutter in dogs in which sotalol was not successful. Following atrial flutter termination, ibutilide had a lower incidence of reinduced arrhythmias compared to sotalol. Ibutilide produced atrial antiarrhythmic effects while having no significant electrophysiologic effects on the ventricle.

Animals↗
PubMed1995

The penetration enhancer SEPA augments stimulation of scalp hair growth by topical minoxidil in the balding stumptail macaque.

The purpose of this study was to determine if the penetration enhancer SEPA (2-n-nonyl-1,3-dioxolane) would augment the scalp hair growth effects of topical minoxidil in the balding stumptail macaque. A 1-in2 area on the balding scalp of 40 adult female monkeys (four drug-treated and four vehicle-treated groups of 5 monkeys each) was topically treated 5 days/week, q.d. or b.i.d., with approximately 250 microliters of minoxidil-SEPA (2.5% minoxidil, weight/volume in 10% SEPA, 25% propylene glycol and 65% isopropyl alcohol), Rogaine topical solution (TS, 2% minoxidil, weight/volume in 20% propylene glycol, 60% ethanol and 20% water) or respective vehicles (without drug) for 16 weeks via paintbrush application. Scalp hair was collected by shaving and vacuuming the dosed area at baseline and at 4-week intervals. The shaved hair was filtered, weighed and recorded as the change from baseline. The q.d. and b.i.d. minoxidil-SEPA groups displayed a significant increase in hair weight compared to their respective vehicles at week 4 whereas q.d. and b.i.d. Rogaine TS groups were not active until week 8 and 12, respectively. Both minoxidil-SEPA treatments produced significantly greater cumulative hair weight over the entire 16-week study compared to either of the Rogaine TS treatments. Comparable increases in cumulative hair weight were evident between q.d. and b.i.d. minoxidil-SEPA groups and between q.d. and b.i.d. Rogaine TS groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1994

In vivo validation of a transit-time ultrasonic volume flow meter.

The objective of this investigation was to validate a transit-time ultrasound blood flow metering system in vivo. Implanted chronically and acutely on the ascending aorta of the dog, the transit-time flow probe determined varying flow rates simultaneously with measurements made by the electromagnetic flow metering method. The transit-time technique was also compared to two methods in which blood was collected volumetrically by either graduated cylinder (ascending aorta/dog) or pump withdrawal (abdominal aorta/cat). Statistical analysis of the results provided evidence that the transit-time ultrasound method measured in vivo blood flow rate no differently than the electromagnetic or pump withdrawal techniques, however, transit-time determinations of blood volume were 10% below that indicated by graduated cylinder collection. With transit time represented on the y-axis, three linear regressions of all paired blood flow measurements were calculated yielding the following slopes (delta y/delta x) and regression coefficients (r), respectively: electromagnetic (1.00, 0.98), graduated cylinder (0.85, 0.93), and pump withdrawal (0.93, 1.00). The results validate the transit-time ultrasound system used in the present investigation as an accurate method capable of measuring blood flow in both acutely and chronically instrumented animal preparations.

Animals↗
PubMed1993

Potassium channel conductance as a control mechanism in hair follicles.

The opening of intracellular potassium channels is a common mechanism of action for a set of anti-hypertensive drugs that includes the hair-growth-inducing agent minoxidil. Recent work suggests potassium channel openers (PCOs) also influence hair growth. Correlative studies demonstrate that a series of PCOs including minoxidil, pinacidil, P-1075, an active pinacidil analog, RP-49,356, cromakalim, and nicorandil maintain hair growth in cultured vibrissa follicles. Studies using balding stumptail macaques verify that minoxidil, P-1075, and cromakalim but not RP-49,356 stimulate hair growth. The definition of potassium channels and documentation of drug effects on these channels is classically done using electrophysiologic techniques. Such studies require the identification and isolation of target cells. Both these are among the unsolved problems in the area of hair biology. Estimating K+ flux using 86Rb+ as a K+ tracer is an accepted method of assessing potassium channel conductance in other organ systems. Both pinacidil and RP-49,356 induce measurable Rb+ flux in isolated vibrissa follicles and a hair epithelial cell line whereas neither minoxidil nor minoxidil sulfate had measurable effects. Potassium channels have been studied successfully in other organ systems using specific pharmacologic blockers for the various channel subtypes. Blockers including glyburide, tetraethylammonium, and procaine failed to inhibit minoxidil stimulation of cultured follicles. The current explosion of knowledge on potassium channel biology, cloning of channels, and continued progress in hair biology promise to clarify the role of K+ ions in the control of hair follicles.

Hair↗
PubMed1993

Comparative assessment of ibutilide, D-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia.

Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarization through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during alpha 1 stimulation with methoxamine produces early after depolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class III agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class III agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class III effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.

Animals↗
PubMed1992

Effects of ibutilide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium.

Ibutilide fumarate is currently in Phase II clinical trials for the treatment of life-threatening cardiac arrhythmias. The cardiovascular effects of ibutilide and its d- and l-stereoisomers, U82208E and U82209E were tested in an isolated rabbit myocardium system. In a series of repeated measures experiments, threshold, effective refractory period, force of contraction, conduction time and rate were measured at various pacing frequencies in isolated papillary muscles, ventricular muscle strips and right atria exposed to 10(-7), 10(-6) and 10(-5) M drug. Although there were occasional instances where one form had a greater or lesser effect on a given parameter, overall there was little pharmacological difference between the racemic mixture and its constituent forms. At the highest dose, effective refractory periods at 1 and 3 Hz increased by 18-32 ms, conduction times measured at 3 Hz increased by 27-30% and atrial rate decreased by 19-32%, while threshold and force of contraction were generally unaffected. In this study there were no clear cut pharmacologic differences between the three forms of this class III antiarrhythmic agent. Parallel studies to determine pA2 values of ibutilide and sotalol demonstrated that ibutilide possesses weak beta-adrenoceptor blocking properties.

Adrenergic beta-Antagonists↗
PubMed1992

Modification of the error-rate bounded classification scheme for use with two MIC break points.

In antimicrobic susceptibility testing, minimum inhibitory concentration (MIC) susceptibility break points are defined by correlation of bacteriologic-clinical outcome data with MIC data for the infecting organisms. Disk diffusion [that is, zone-diameter (Z)] correlates are then established that provide for the prediction of organism susceptibility, while misclassification errors are kept to a minimum. The determination of Z break points through an error-rate-bounded classification scheme was first proposed by Metzler and DeHaan (1972). This method involves one MIC break point that separates susceptible and resistant strains. More recently, researchers have preferred to use two MIC break points (susceptible and resistant) that separate susceptible, moderately susceptible, and resistant strains. There is no known methodology for determining the Z break points for this latter situation, other than enumerating solutions for all feasible Z break-point pairs and choosing among the results. Our interest lay in presenting a methodology for determining the Z break points once the MIC break points are established. By deriving an index as a function of Z break points, a search method for finding the optimal Z break points is given. For the data set examined, our index interval solution required only a small percentage of solutions to be examined.

Bacteria↗
PubMed1992

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Potassium channel conductance: a mechanism affecting hair growth both in vitro and in vivo.

The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.

Animals↗
PubMed1992

Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque.

A 5 alpha-reductase inhibitor, finasteride, was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stumptail macaque monkeys. A 7-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum dihydrotestosterone (DHT) in male stumptails. Hair growth was evaluated by shaving and weighing scalp hair at baseline and at 4-week intervals during treatment to obtain cumulative delta hair weight (sum of the 4-week changes in hair weight from baseline) for the 20-week study. The activity of the 5 alpha-reductase enzyme was assessed by RIA of serum testosterone (T) and DHT at 4-week intervals. The combination of finasteride and minoxidil generated significant augmentation of hair weight (additive effect) compared to either drug alone. Finasteride increased hair weight in four of five monkeys. When the data of the one nonresponsive monkey were excluded, finasteride elicited a significant elevation in hair weight compared to topical vehicle alone. Minoxidil also evoked a significant increase in hair weight compared to vehicle alone. Serum T was unchanged, whereas serum DHT was significantly depressed in monkeys that received either finasteride or the combination of finasteride and minoxidil. These data suggest that inhibition of the conversion of T to DHT by this 5 alpha-reductase inhibitor reverses the balding process and enhances hair regrowth by topical minoxidil in the male balding stumptail macaque.

5-alpha Reductase Inhibitors↗
PubMed1991

Platelet-derived growth factor potentiates cellular responses of articular chondrocytes to interleukin-1.

Recombinant human interleukin-1 alpha (IL-1 alpha) induced a time-dependent (0-72 hours) and concentration-dependent (0.01-10 ng/ml) production of metalloproteinases (collagenase, gelatinase, stromelysin) and prostaglandin E2 (PGE2) in rabbit articular chondrocytes (RAC). Exposure of RAC to recombinant human platelet-derived growth factor homodimer BB (PDGF-BB; 2-200 ng/ml) in the presence of stimulatory and substimulatory concentrations of IL-1 alpha resulted in a marked augmentation of metalloproteinase and PGE2 production. PDGF-BB exerted no agonist effects on RAC responsiveness. PDGF-BB up-regulated the number of IL-1 receptors per chondrocyte but had no effect on receptor affinity. Cycloheximide and actinomycin D caused a concentration-dependent suppression of the PDGF-BB-mediated potentiation of radiolabeled IL-1 alpha binding to RAC and cell responsiveness to IL-1 alpha. Similarly, IL-1 increased the number of PDGF receptors on RAC without changing receptor affinity. These data are discussed within the context of cytokine-growth factor interactions as components of the pathogenesis of arthritic diseases.

Animals↗
PubMed1991

Estimating the postantibiotic effect: a two-phase mathematical model.

The postantibiotic effect (PAE) is a suppression of bacterial growth that persists after a short exposure to antimicrobials. The active antibiotic delays the resumption of normal growth. This suppression of bacterial growth following antibiotic removal is described by a two-phase model. The quantification of PAE is a function of the model parameters, for which consistent and asymptotically normal estimators are available.

Anti-Bacterial Agents↗
PubMed1991

Additive combination studies of captopril and ditekiren, a renin inhibitor, in nonhuman primates.

Additive combination studies of an angiotensin converting enzyme (ACE) inhibitor, captopril, and a renin inhibitor, ditekiren (U-71038), were carried out in conscious sodium-depleted and sodium replete cynomolgus monkeys. The agents elicited dose-additive hypotensive responses regardless of the order of drug administration in sodium-depleted monkeys. A dose-additive blood pressure response was also observed when the administration of captopril was preceded by ditekiren in conscious sodium replete monkeys. None of the animals in these groups exhibited significant alterations of heart rate. An apparent over-additive hypotensive response, accompanied by tachycardia, occurred in sodium replete monkeys when ditekiren was administered after captopril. It was proposed that the captopril-induced hyperreninemia may have allowed the blood pressure to become partially renin-dependent and therefore susceptible to the inhibitory action of ditekiren. The results of these studies suggested that both ditekiren and captopril elicited cardiovascular effects in conscious cynomolgus monkeys via a decreased formation of angiotensin II.

Angiotensin II↗
PubMed1990

Planning the purification process of active cDNA in expression cloning strategies.

In principle, it is possible to clone the gene for any receptor that can be expressed in the Xenopus laevis frog oocyte and assayed electrophysiologically (E. S. Levitan, 1988, TINS 11, 41-43). Repeated fractionation of a lambda vector cDNA library made from mRNA which encodes the receptor protein will eventually lead to a single cDNA clone. This strategy poses the question as to how large should a lambda vector cDNA aliquot be at any fractionation stage in order that one may be relatively certain that the aliquot contains the clone of interest, and how many times should the fractionation be repeated in order that one isolate the single clone of interest? The purification of active cDNA is an iterative process. At each fractionation stage we specify the probability of at least one active cDNA in the total aliquot to be high. The required size of the aliquot taken depends upon this specified probability and the additional probability of selecting at random an individual cDNA which is active. We require an estimate of the latter probability for the initial stage. For subsequent stages Baye's estimators of these probabilities are used in the formula for calculating the aliquot size at each stage. We show how to perform this calculation when there is equal amplification of the active and remaining sequences and when the active sequence has a non-representative (unequal) amplification. When equal amplification holds a relatively simple formula is provided for calculating the expected number of stages needed in the process. When unequal amplification holds there is no simple calculation for this quantity and the entire sequence of calculations leading to termination of the process must be performed. In either case the minimum lambda vector amplification (growth) factor required at each stage to yield an adequate amount of cDNA for analysis is calculable.

Animals↗
PubMed1990

Differences in activity of minoxidil and cyclosporin A on hair growth in nude and normal mice. Comparisons of in vivo and in vitro studies.

Hair growth effects of minoxidil and cyclosporin A were assessed in a series of experiments using nude mice. Systematic monitoring of coat hair showed that untreated nude mice grow extremely sparse and transient hair in cycles. This monitoring was done by photographing each animal through at least one full growth cycle and rating peak growth on a 1 to 4 scale. Topical administration of minoxidil or minoxidil sulfate did not influence this cyclic hair growth. Orally administered minoxidil also had no effect but oral cyclosporin A increased peak hair growth. None of the treatments altered the length of the hair cycle. Direct drug effects on follicles were tested in vitro using organ cultured vibrissae from both nude and normal mice. Minoxidil stimulated hair growth in follicles from normal but not nude mice. In contrast, cyclosporin A stimulated growth only in vibrissae follicles from nude but not normal animals. These studies show that minoxidil and cyclosporin A influence hair growth differentially. Cyclosporin A directly affects nude hair follicles by apparently compensating for a genetic defect inherent in nude follicles. Minoxidil does not have a similar effect. Apparently, the biochemical pathway activated by minoxidil is not a critical defect of hair growth in nude mice. We conclude that nude mice are not useful for studying minoxidil effects but they may be useful in studying pleiotropic effects of the nude gene on hair growth.

Administration, Cutaneous↗
PubMed1989

Hepatic protection by 16, 16-dimethyl prostaglandin E2 (DMPG) against acute aflatoxin B1-induced injury in the rat.

Studies were conducted to assess the possible protective action of 16,16-dimethyl prostaglandin E2 (DMPG) against acute aflatoxin B1 (AFB1) induced hepatic injury in the rat. Evaluation of liver damage by histopathologic techniques and clinical chemistry indicated that hepatic necrosis was ameliorated by treatment with DMPG even though binding of radiolabeled (3H)-AFB1 to hepatic DNA was unaffected by this prostaglandin. However, DMPG did not protect rats against AFB1-induced mortality. These data suggest that hepatic protection by DMPG was due to mechanisms other than an interference with the activation or hepatic binding of AFB1.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Studies on the mechanism of the protective action of 16,16-dimethylPGE2 in carbon tetrachloride induced acute hepatic injury in the rat.

We have previously demonstrated the partial protection of the rat liver by 16,16-dmPGE2 (DMPG) against a number of hepatotoxins including carbon tetrachloride (CCl4). However, it has not been determined whether hepatoprotection by DMPG represents a true "cytoprotective" action or if merely accomplished through inhibition of CCl4 metabolism to reactive, toxic trichoromethyl (CCl3.) free radicals. This report details a series of experiments in which the effects of DMPG on CCl4 metabolism was evaluated in the rat. These data indicate that pretreatment with DMPG may reduce the hepatic concentration of the toxic CCl3. free radicals in CCl4 poisoned rats. Evidence is presented which suggests that this reduction in binding may have been due to a decrease in the rate of CCl4 metabolism. However, DMPG did not affect the hepatic concentration of total microsomal cytochrome P450, the necessary enzyme in this metabolic process. On the other hand, free radical spin trapping experiments indicate that the rate of free radical formation from CCl4 was slowed by treatment. Also, indirect evidence suggests that the metabolism of another cytochrome P450 substrate, phenobarbital, was slowed in DMPG treated rats. We conclude that the rate of CCl4 metabolism may be reduced by pretreatment with DMPG. Furthermore, some measure of hepatic protection might be expected to occur as a result of the reduction in the rate of CCl4 metabolism. However, we are unable to determine if this action was solely responsible for the observed hepatic protection.

16,16-Dimethylprostaglandin E2↗