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Biomedical subjects

J L Falk

Publications and source records attributed to J L Falk.

At least 73 records · Page 4Linked to original sources
PubMed1991

Midazolam withdrawal and discriminative motor control: effects of FG 7142 and Ro 15-1788.

Rats chronically drank either water or midazolam solution (0.1 mg/ml) in daily, 3-h schedule-induced polydipsia sessions and were evaluated in daily motor control sessions after polydipsia when midazolam metabolite levels had fallen to zero (withdrawal). Under midazolam polydipsia, animals orally self-administered between 21 and 38 mg/kg daily. The effect of acute drug administration [midazolam (0.75-3 mg/kg, SC), FG 7142 (1-8 mg/kg, IP), Ro 15-1788 (10-20 mg/kg, IP)] on motor control performance was similar after either chronic water or midazolam polydipsia. Thus chronic, oral midazolam self-administration did not lead to tolerance to the motor impairment produced by SC midazolam, nor did the daily discontinuation lead to impaired motor performance, nor had these performances, which occurred after daily elevated midazolam metabolite levels had reached zero (withdrawal), become sensitized to the effects of either the benzodiazepine inverse agonist FG 7142 or the agonist Ro 15-1788.

Animals↗
PubMed1991

Synergism by caffeine and by cocaine of the motor control deficit produced by midazolam.

To evaluate the effects of caffeine and cocaine on the impairment of discriminative motor control produced by midazolam, rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-s period to deliver each food pellet. Acute doses of 3 mg/kg midazolam SC impaired motor performance. Except for one animal, caffeine (10-40 mg/kg IP) had little or no effect on performance, while cocaine (3.75-22.5 mg/kg IP) produced dose-related impairment. When each dose of caffeine was combined with 3 mg/kg midazolam, a marked synergism in motor performance impairment occurred. Cocaine plus midazolam produced mainly an additive synergism. The conspicuous synergistic action of caffeine on the motor control deficit produced by midazolam contrasts with the typical antagonism found between the benzodiazepines and methylxanthines when performance is evaluated by psychomotor tests not requiring fine motor control.

Animals↗
PubMed1991

Behavioral tolerance to flurazepam.

Rats were trained to earn 180 food pellets in daily, fixed-interval 1-min sessions. When performance had stabilized, a Before group was given a weekly 16 mg/kg flurazepam injection IP for 3 weeks immediately before the sessions, while an After group received their weekly injections immediately after the sessions. Then, the After group received 3 such weekly injections before the sessions. Behavioral tolerance developed by the 2nd flurazepam injection for the Before group, but for the After group, the 3 postsession flurazepam injections resulted in subsequent tolerance to presession flurazepam injection for session lever presses, but not for the time taken to earn 180 pellets. Dispositional tolerance to the serum elimination rate of flurazepam did not develop over the course of 3 injections. Behavioral suppression still evident in the initial portion of sessions with the 2nd and 3rd presession injection coincided with the duration of rising and high levels of serum flurazepam.

Animals↗
PubMed1991

Untoward reaction to adenosine therapy for supraventricular tachycardia.

Adenosine, a naturally occurring nucleoside that slows conduction through the atrioventricular node, has recently been approved for the treatment of supraventricular tachycardia. It has been shown to convert patients with supraventricular tachycardia to sinus rhythm in up to 92% of cases. Its intravascular half-life of only 10 seconds and absence of reported serious side effects have made adenosine an attractive antiarrhythmic agent. This report describes two cases in which significant side effects from the administration of adenosine were encountered including: (1) prolonged sinus arrest with syncope, and (2) syncope with prolonged bradycardia and hypotension. Emergency physicians should be cognizant of the potential complications resulting from adenosine administration, and should be prepared to deal with them when using this newly available agent.

Adenosine↗
PubMed1991

Rectal thiopental compared with intramuscular meperidine, promethazine, and chlorpromazine for pediatric sedation.

STUDY OBJECTIVES: We studied the hypothesis that rectal thiopental is an effective agent for emergency department pediatric sedation and may have advantages over a more traditional regimen. DESIGN: Rectal thiopental 25 mg/kg was compared with the combination of meperidine 2 mg/kg, promethazine 1 mg/kg, and chlorpromazine 1 mg/kg in a prospective, randomized, double-blinded study. TYPE OF PARTICIPANTS: Children between 18 months and 6 years of age presenting to our teaching hospital ED for laceration repair were entered after the clinical decision was made to sedate. Patients with altered sensorium, medical contraindications to sedation, or medication allergy were excluded. INTERVENTIONS: After informed consent, each patient received IM injection (drug combination or placebo) and rectal suspension (rectal thiopental or placebo) simultaneously. MEASUREMENTS AND MAIN RESULTS: Vital signs, pulse oximetry, and pediatric Glasgow Coma Scores were recorded before and every 15 minutes after sedation until discharge. Intradermal lidocaine and suturing began when the patient appeared adequately sedated, and response was numerically scored. Patients were discharged when able to stand. Twenty-nine patients 34 +/- 13 months old were studied. Fifteen patients received rectal thiopental, and 14 received the drug combination. Analysis using the Wilcoxon two-sample test revealed no differences in age, sex, weight, or wound location between groups. The time course of sedation was different for the two treatment regimens. At 15 and 30 minutes after administration, patients who received rectal thiopental were more deeply sedated than those who received the drug combination, as evidenced by significantly lower Glasgow Coma Scores (P less than .05). Accordingly, time from medication administration to suturing was 29 +/- 12 minutes in the thiopental group and 54 +/- 33 minutes (P less than .01) in the drug combination group. Patients in the thiopental group also recovered more quickly and were discharged approximately one-half hour earlier than those in the drug combination group (89 +/- 25 vs 120 +/- 44 minutes, P less than .05). No difference in response to lidocaine injection or suturing was demonstrated between the groups. Laceration repair time was comparable between the groups. There were eight sedation failures (three of 15 in thiopental group and five of 14 in drug combination group, P = NS). Vital signs remained stable, no adverse reactions occurred, and no patient had decreased oxygen saturation to less than 95%. CONCLUSION: Rectal thiopental is superior to this drug combination for pediatric sedation because it can be administered painlessly, has a more rapid onset and offset of action, and is of equal safety and efficacy at the dosage studied.

Administration, Rectal↗
PubMed1991

Acute effects of cocaine on spontaneous and discriminative motor functions: relation to route of administration and pharmacokinetics.

Rats administered cocaine i.p. and p.o. (7.5-30 mg/kg) showed dose-related increases in locomotor (LM) and small-movement activities, with LM rates decreasing over the 2-hr session, except at the largest i.p. dose, for which rates were greater in the 2nd hr. Lidocaine p.o. (15-30 mg/kg) did not increase activity. Relating the area under the curve measures for serum cocaine (concentration-time) and LM activity (LM activity-time) for 2 hr postadministration indicated that cocaine was about twice as potent i.p., compared to p.o., in increasing LM activity. Cocaine (i.p. and p.o.) produced dose-related decrements in both discriminative motor control performance and in task work rate, whereas lidocaine p.o. did not. The motor control decrements produced by cocaine were approximately comparable by i.p. and p.o. routes, whereas effects on LM rates were much greater by i.p. than by p.o. administration. The effects of cocaine by both routes on LM rates were proportionally much greater than its effect on motor control performance. Changes in LM rates and motor control performance over the postadministration period were related to the pharmacokinetic features (maximum serum concentration, time to maximum serum concentration and elimination half-life) of cocaine observed for the routes explored (i.p., p.o. and s.c.). Tail-tip serum samples, although yielding conservative estimates of cocaine concentration, correlated well with trunk serum and brain cocaine levels.

Administration, Oral↗
PubMed1991

Chronic oral cocaine self-administration: pharmacokinetics and effects on spontaneous and discriminative motor functions.

Rats receiving repeated doses of oral cocaine (15 mg/kg) showed replicable increases in large-movement and small-movement activity rates, but sensitization to the repeated doses did not develop. With a schedule-induction procedure, as the daily, 3-hr, oral dose of self-administered cocaine increased, marked dose-related increases occurred in both large-movement locomotor activity rate and the time for which these elevations were sustained during the following daily 2-hr activity session. Sensitization developed. At the highest levels of self-administered oral cocaine (about 80 mg/kg), post-administration serum cocaine levels remained undiminished for the activity-session period, as did the large-movement activities of most animals, indicating no development of acute tolerance. Rats receiving repeated doses of oral cocaine (15 mg/kg) showed discriminative motor control deficits as well as increases in work rate. These changes were dose-related in animals self-administering oral cocaine under the schedule-induction procedure. Upon withdrawal of cocaine from the schedule-induction animals, motor behavior returned to precocaine base-line performance for most animals. The behavior of the animal with the largest cocaine intake did not return. After a schedule-induced oral cocaine intake session, the tail-tip and trunk serum measures for cocaine and its metabolites were approximately equivalent, while brain cocaine and norcocaine levels remained markedly elevated over serum values.

Animals↗
PubMed1990

Simultaneous determination of cocaine and its metabolites with caffeine in rat serum microsamples by high-performance liquid chromatography.

A single, isocratic high-performance liquid chromatographic method is described for the determination of cocaine and three of its metabolites along with caffeine in serum microsamples (50 microliters). The small sample size permits the tracking of pharmacokinetic data over time in individual, small animals. The method also was used to demonstrate that cocaine, benzoylecgonine and norcocaine in rat serum samples were stable for at least a month without the presence of sodium fluoride.

Animals↗
PubMed1990

Motor performance decrement by midazolam: antagonism by Ro 15-1788 and CGS 8216.

Rats were trained in a fine motor control performance that required operation by a paw of a force transducer so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of midazolam (0.75-3.0 mg/kg, SC) impaired indices of motor performance in a graded, dose-related fashion. When administered alone, Ro 15-1788 (0.1-5.0 mg/kg, SC) had no effect on motor behavior while CGS 8216 (0.5 and 1.0 mg/kg, IP) alone had small effects. In general, the motor performance decrements produced by midazolam were antagonized in a dose-related fashion by both Ro 15-1788 and CGS 8216.

Animals↗
PubMed1990

Diazepam and discriminative motor control: acute, chronic and withdrawal effects.

Rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of diazepam impaired measures of this performance. Separate groups received chronic diazepam injections (6 mg/kg, IP) either presession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups demonstrated that neither chronic postsession diazepam, nor time alone, altered motor performance. The performance of the Before Group was affected by the daily diazepam, and although tolerance to the impairment developed, it was incomplete. Late in the chronic-administration phase (after 75 days) a toxic effect of the suspending agent became evident in all groups as a decrease in work rate, although the other performance indices were not affected. The withdrawal of diazepam from the Before Group led to improved performance which returned to the original baseline level.

Animals↗
PubMed1990

Schedule-induced cocaine drinking: choice between cocaine and vehicle.

Rats were exposed to daily 3-hr schedule-induced polydipsia sessions (fixed-time 1-min food-pellet delivery) with two drinking fluids available: cocaine solution and water. Fluid position was alternated daily. Polydipsia occurred mostly from a preferred-side spout (position preference) until cocaine solution concentration was increased to between 0.52 and 1.04 mg/ml and animals drank mostly water. Within a lower concentration range (0.28-0.6 mg/ml) maximum session cocaine intakes ranged from 54.3 to 120.1 mg/kg. Postsession serum cocaine levels were about 200 ng/ml. At individually chosen cocaine solution concentrations, the addition of saccharin to the solution did not increase cocaine intake, but a compound solution (saccharin plus glucose) did. With progressive dilution of the compound vehicle, an almost complete preference for cocaine solution was maintained. But with a return to water as the vehicle, animals reverted to a position preference after a few sessions, although one maintained a clear cocaine preference. Schedule-induced polydipsia produced chronic, oral self-administration of cocaine resulting in pharmacologically significant intakes and serum levels.

Animals↗
PubMed1990

Schedule-induced oral self-administration of cocaine and ethanol solutions: lack of effect of chronic desipramine.

Groups of rats drinking either solutions of cocaine HCl (0.16 mg/ml), ethanol (2.5% v/v), or water, drank excessive, equivalent volumes in daily, 3-h sessions of food-pellet delivery under a fixed-time 1-min (FT 1-min) schedule. During single-session exposures to pellet-delivery schedules using longer inter-pellet values (FT 3- or 5-min probe sessions), the cocaine and ethanol groups, but not the water group, drank greater ml/pellet amounts, confirming previous research. Inasmuch as enhanced ml/pellet intake during the greater FT probes correlated with the abuse potential of the drinking solution in previous research, the effect of chronic desipramine HCl (2 mg/kg, i.p. daily) on this enhanced intake response was determined. For all groups, chronic desipramine treatment (2 mg/kg was judged to be the maximum dose free of non-specific, suppressive effects) affected neither FT 1-min schedule-induced polydipsia nor did it affect the enhanced ingestional response to the greater FT probes for the cocaine and ethanol groups. Chronic administration of desipramine may have therapeutic efficacy in treating cocaine abuse only in subjects attempting to refrain from cocaine who are aided in their passage through a withdrawal phase by desipramine.

Alcohol Drinking↗
PubMed1989

Anxiolytic effect of caffeine and caffeine-clonazepam interaction: evaluation by NaCl solution intake.

The administration of drugs with anxiolytic action to rehydrating rats augments the intake of 1.5% NaCl solution. In order to clarify the status of caffeine as an anxiolytic agent and its possible interaction with a benzodiazepine having high potency and efficacy in this regard, caffeine (0.78-100 mg/kg) alone and caffeine (0.78-50 mg/kg) plus clonazepam (0.05 or 0.50 mg/kg) injections (IP) were administered to rehydrating rats prior to 1-hr sessions during which they drank 1.5% NaCl solution. When given alone, caffeine, within a particular dose range, and clonazepam at both doses, augmented NaCl solution intake, but when administered in combination, caffeine antagonized the effects of clonazepam.

Animals↗
PubMed1989

Schedule-induced chlordiazepoxide intake: differential effect of cocaine and ethanol histories.

Groups of rats were given differential histories of drinking either water, cocaine (0.15 mg/ml), or ethanol (2.5%) solutions under fixed-time (FT) 1-min schedule-induced polydipsia conditions in daily, 3-hr sessions. The session solution for all groups was then changed to chlordiazepoxide (0.25 mg/ml), and after daily session intakes had stabilized, FT values of 3 and 5 min were probed for single sessions. Probe-session chlordiazepoxide intakes were greater for the Ethanol History Group than for Cocaine History and Water History Groups. Previous research showed that probe conditions elevated intakes for agents with abuse potential (cocaine, ethanol, midazolam), but not for those lacking such potential (water, chlordiazepoxide, flurazepam). The present study demonstrated that a history of ethanol overindulgence yielded elevated probe intakes for chlordiazepoxide, while a history of cocaine or water overindulgence did not. This is consistent with animal and human evidence indicating that a history of either alcohol or sedative abuse increases the probability that benzodiazepines will function as reinforcers and/or be abused.

Chlordiazepoxide↗
PubMed1989

Effects of pentastarch and albumin infusion on cardiorespiratory function and coagulation in patients with severe sepsis and systemic hypoperfusion.

Twenty consecutive patients with severe sepsis were randomized to fluid challenge with 5% albumin or 10% low MW hydroxyethyl starch (pentastarch) solutions. Fluid challenge was administered iv as 250 ml of test colloid every 15 min until the pulmonary artery wedge pressure (WP) was greater than or equal to 15 mm Hg or a maximum dose of 2000 ml was infused. Hemodynamic, respiratory, and coagulation profiles were measured before and after fluid infusion. The amount of colloid required to achieve a WP of 15 mm Hg was comparable between groups. Both colloid infusions resulted in similar increases in cardiac output, stroke output, and stroke work. The effect of fluid infusion with pentastarch on coagulation was not significantly different from albumin, although pentastarch was associated with a 45% decrease in factor VIII:c. We conclude that pentastarch is equivalent to albumin for fluid resuscitation of patients with severe sepsis.

Adult↗