Search PubMed⌕ Search

Biomedical subjects

J L Falk

Publications and source records attributed to J L Falk.

At least 91 records · Page 5Linked to original sources
PubMed1989

Schedule induction of drug intake: differential responsiveness to agents with abuse potential.

In previous research, two groups of rats exposed to a fixed time (FT) 1-min schedule of food-pellet delivery exhibited equal schedule-induced polydipsia for water vehicle and a 0.05 mg/ml solution of midazolam, respectively. Exposure to FT schedule values greater than 1 min (3 and 5 min) resulted in greater milliliter per pellet intakes of midazolam than of water, perhaps reflecting the reinforcing efficacy of the drug. To determine if drugs with unequivocal reinforcing efficacy display similar elevations at the larger FT values, solutions of cocaine and ethanol, but also of the equivocally reinforcing agents chlordiazepoxide and flurazepam, as well as water, were offered to groups of rats at concentrations isoacceptable under FT 1-min schedule-induction conditions. Under the FT 1-min schedule, separate groups of rats drank equal and excessive amounts of water, cocaine (0.15 mg/ml), ethanol (2.5% v/v), chlordiazepoxide (0.25 mg/ml) and flurazepam (0.175 mg/ml). Differential group milliliter per pellet intakes occurred under larger FT values: ethanol, cocaine and midazolam yielded greater values than water, chlordiazepoxide or flurazepam. Schedule-induced drug intake perhaps offers a method for evaluating the oral abuse potential of a drug under conditions which generate a variety of behavioral excesses and may potentiate intrinsic reinforcing efficacy.

Animals↗
PubMed1988

End-tidal carbon dioxide concentration during cardiopulmonary resuscitation.

We prospectively measured the end-tidal carbon dioxide concentration during 13 episodes of cardiac arrest in 10 critically ill patients receiving mechanical ventilation, to evaluate its usefulness as an indicator of circulatory status during cardiac arrest and resuscitation. The end-tidal carbon dioxide concentration decreased from a mean (+/- SD) of 1.4 +/- 0.9 to 0.4 +/- 0.4 percent after the onset of cardiac arrest. During precordial compression, it increased to 1.0 +/- 0.5 percent. The decreases in the end-tidal carbon dioxide concentration were associated with increases in systemic oxygen extraction (r = 0.79). Spontaneous circulation was restored on seven occasions. This was heralded by a rapid increase in the end-tidal carbon dioxide concentration, from 1.3 +/- 0.5 percent to an overshoot value of 3.7 +/- 2.1 percent, within approximately 30 seconds. The concentration then declined to a stable value of 2.4 +/- 1.8 percent four minutes after resuscitation. However, it remained 0.7 +/- 0.4 percent in six patients in whom resuscitative efforts failed to restore spontaneous circulation. These observations are consistent with experimental studies of cardiopulmonary resuscitation in pigs, in which the end-tidal carbon dioxide concentration varied directly with the cardiac output produced by precordial compression. We therefore propose that measurement of the end-tidal carbon dioxide concentration may be a practical, non-invasive method for monitoring blood flow generated by precordial compression during cardiopulmonary resuscitation and an almost immediate indicator of successful resuscitation.

Aged↗
PubMed1988

Effects of hetastarch and albumin on coagulation in patients with septic shock.

The effect of 6% hydroxyethyl starch (hetastarch) and 5% human serum albumin (albumin) infusion on coagulation in 12 patients with septic shock was evaluated. Patients were randomly assigned to receive either albumin (N = 6) or hetastarch (N = 6) infusion over a 24-hour study interval. The prothrombin time (PT), partial thromboplastin time (PTT), and quantitative platelet count (PC) were obtained prior to and following 24 hours of fluid infusion. Hetastarch patients received 4934 +/- 1354 mL and albumin patients received 3067 +/- 256 mL over the study interval. After hetastarch infusion, the PT increased 2.2 +/- 0.7 seconds, PTT increased 20.0 +/- 4.1 seconds (P less than .01), and PC decreased 158 +/- 36 X 10(3)/mm3 (P less than .02). After albumin administration, the PT decreased 1.2 +/- 1.7 seconds, PTT increased 20.5 +/- 10.6 seconds and PC decreased 100 +/- 34 X 10(3)/mm3. There were no significant differences in the changes in PT, PTT, or PC between the groups. The authors conclude that hetastarch infusion does not result in increased bleeding in patients with septic shock compared with albumin infusion, despite moderate effects on the hemostatic coagulation profile.

Aged↗
PubMed1988

Prior schedule exposure reduces the acquisition of schedule-induced polydipsia.

Two groups of rats were given different initial histories before exposing them to daily, 2-hr fixed-interval 1-min (FI 1-min) food-pellet sessions with water freely available. For the initial-history phase (approximately 17 weeks), a Schedule-History Group had no water available during FI 1-min sessions, while a Home-Cage-History Group was maintained at the same body weight (80% of free feeding) in home cages. When water then became available for both groups during FI 1-min sessions, the Schedule-History Group was retarded in their rate of acquisition and final level of schedule-induced polydipsia relative to the Home-Cage-History Group. Substitution of 5% ethanol solution for session water in the final phase produced a like intake level for both groups typical for these inducing conditions. It was concluded that the probability of drinking water in a session situation is reduced by a lengthy history of water unavailability, thereby attenuating the acquisition rate and final level of schedule-induced water overdrinking.

Alcohol Drinking↗
PubMed1988

The role of central- and peripheral-type benzodiazepine receptors in anxiolytic-agent augmentation of NaCl solution intake: effects of clonazepam and Ro 5-4864.

Two 1,4 benzodiazepines bind preferentially to the central- and peripheral-type benzodiazepine receptor in the brain, clonazepam and Ro 5-4864, respectively. They were administered to rats to determine if the relation between known anxiolytic action and efficacy in augmenting NaCl solution ingestion in rehydrating rats would remain the case for these prototypic agents. Clonazepam (0.062-32.0 mg/kg, PO) was highly potent and efficacious and increased 1.5% NaCl solution intake in a dose-related fashion. Water intake could also be increased, but to a relatively minor degree. Ro 5-4864 (4-8 mg/kg, IP) did not affect 1.5% NaCl solution ingestion, nor did this dose range suppress the augmenting effect of clonazepam (0.5-2.0 mg/kg, PO) on the solution intake. Since clonazepam does, and Ro 5-4864 does not, possess punishment-attenuation properties in other tests, drug augmentation of NaCl solution ingestion by rehydrating rats continues to correlate well with known anxiolytic action.

Animals↗
PubMed1988

Relationship of oxygen delivery and mixed venous oxygenation to lactic acidosis in patients with sepsis and acute myocardial infarction.

Critical decreases in oxygen delivery (DO2) and mixed venous oxygen saturation (SvO2) are associated with anaerobic metabolism and, therefore, lactic acidosis. We studied 50 consecutive patients with sepsis and 50 consecutive patients with acute myocardial infarction (AMI) in whom the arterial blood lactate was greater than 1 mmol/L in order to determine critical thresholds of DO2 and SvO2. In both groups, critical values of DO2 or SvO2 associated with lactic acidosis could not be identified. The DO2 ranged from 136 to 811 ml/min.m2 and SvO2 ranged from 28% to 73% in the patients with sepsis. The DO2 ranged from 115 to 434 ml/min.m2 and SvO2 from 17% to 72% in patients with AMI. The absence of threshold values for DO2 and SvO2 probably reflects the influence of distributive flow abnormalities as well as differences in metabolic requirements in these critically ill patients.

Acidosis, Lactic↗
PubMed1988

What schedule-induced polydipsia can tell us about alcoholism.

An animal model of chronic and excessive voluntary (unforced) alcohol ingestion is presented in which, by drinking, animals produce repeated, substantial elevations in blood ethanol concentration and develop physical dependence. The overindulgence is elective in that ethanol is chosen in preference to certain other fluid-ingestive alternatives. Beside the usual demonstrations of acutely compromised motor performance, tolerance development, cross-tolerance, etc., the model demonstrates that the consequences of even short, but continued, daily drinking episodes results in the disruption of reinforced behavior that occurs later in the day when blood ethanol is absent (impaired general functioning). The conditions which induce the ethanol overindulgence can generate a variety of behavioral excesses which places alcoholism in a context of environmentally determined malfunctions that are subject to therapeutic change by altering situational parameters. Efficacious experiments utilizing therapeutic and preventive strategies are described that may serve as suggestions for corresponding human alcoholism intervention strategies.

Alcohol Drinking↗
PubMed1988

Midazolam and discriminative motor control: chronic administration, withdrawal and modulation by the antagonist Ro 15-1788.

To evaluate the effects of chronic midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H- imidazo[1,5-a][1,4]benzodiazepine) administration on discriminative motor control, 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 midazolam (0.75-3.0 mg/kg s.c.) impaired indices of motor performance as well as session work rate, a measure of sedation. Separate groups received chronic midazolam injections either pressession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups indicated that neither chronic postsession midazolam, its withdrawal, nor time alone, changed motor performance. The Before Group was affected, and although complete tolerance to work-rate decrements developed rapidly to chronic dosing (3.0 mg/kg), tolerance to motor impairment was incomplete even after 4 months. Presession drug probes with midazolam to the After Group revealed that, although tolerance to work-rate decrement had developed, no tolerance had developed with respect to the capacity for midazolam to impair motor performance. During the chronic phase of midazolam injection to the Before Group, sessions that omitted midazolam, or antagonized it with Ro 15-1788, led to improved motor performance (a drug-purge effect). Precipitated withdrawal was not produced by Ro 15-1788, although simple drug withdrawal did disrupt Before Group motor performance after 4 months of chronic dosing. Ensuing sessions showed a marked improvement in motor performance which returned to the original, prechronic, base-line level.

Animals↗
PubMed1987

Simultaneous determination of flurazepam and five metabolites in serum by high-performance liquid chromatography and its application to pharmacokinetic studies in rats.

A reversed-phase high-performance liquid chromatographic method is described which allows the quantification of flurazepam and five of its metabolites with a single, isocratic determination. In addition, it has the advantage of possessing a low detection limit and high precision. A 2 mm I.D. column was used to minimize sample size (50 microliter), increase sensitivity and reduce solvent consumption. The method was used to demonstrate that N-1-desalkylflurazepam, the major metabolite, has a short half-life in the rat in contrast to its prolonged life in humans.

Animals↗
PubMed1987

Characteristics of reserpine-induced suppression of NaCl solution intake in rats.

Effects of single and repeated administration of reserpine on time-limited drinking of a hypertonic (1.5% w/w) NaCl solution were investigated in rats to assess whether this drug possesses anxiolytic action. Rats adapted to a 23-hr water-deprivation schedule with a free-feeding regimen were allowed a daily 1-hr water rehydration session. In the single-administration experiment, reserpine (0.1, 0.2 and 0.4 mg/kg, IP) was administered to rats at 15 min or 23 hr before a drinking session, where the fluid available was 1.5% NaCl solution. Drug was administered every 7th day. In the repeated-administration experiment, reserpine (0.1 mg/kg/day) was injected daily for 10 days 15 min before each drinking session. The fluid available was water on the first 9 days and NaCl solution on the 10th day. Reserpine suppressed NaCl solution intake when it was singly administered at 15 min before the rehydration, whereas no significant change in the fluid intake occurred when it was administered 23 hr before drinking, even though rats showed ptosis in response to 0.2 and 0.4 mg/kg doses. Tolerance developed to the suppressing effect of repeated administration of reserpine on fluid intake, although ptosis and sedation continued and body weights decreased. Tolerance was almost complete after 11 days. The results suggest that reserpine does not have an anxiolytic effect.

Animals↗
PubMed1987

Oral self-administration of cocaine: chronic excessive intake by schedule induction.

Rats were exposed to daily 3-hr schedule-induced polydipsia sessions (fixed-time 1 min food-pellet delivery) with a cocaine hydrochloride solution as the available session fluid. Cocaine intake level (mg/kg) was a direct function of solution concentration (0.02-0.2 mg/ml). In a second experiment with 0.15 mg/ml cocaine solution available, mean daily session cocaine intake remained constant at about 40 mg/kg over the 5-week period of the experiment. Post-session serum samples of animals drinking either 0.15 or 0.2 mg/ml cocaine solution yielded serum cocaine values that were similar to those producing subjective "highs" in coca-leaf chewers and experienced users of cocaine. The schedule-induction technique can be used to induce the intake of drug solutions, including those which perhaps taste bitter, so that chronic and pharmacologically significant consequences ensue.

Animals↗
PubMed1987

Development of physical dependence on midazolam by oral self-administration.

Groups of rats drank either a solution of the ultrashort-acting benzodiazepine midazolam or water under schedule-induced polydipsia conditions in chronic, daily, 3-hr sessions. In Experiment 1, the physical dependence status of animals was tested after 9 months by the precipitated withdrawal method using the benzodiazepine-blocking agent Ro 15-1788 and by exposure to a brief audio stimulus at 1.5, 12 and 24 hr following drug withdrawal. Ro 15-1788 failed to produce withdrawal signs, while the audio stimulus plus withdrawal did. In Experiment 2, similar groups were periodically tested for susceptibility to audiogenically-induced seizures at 3, 6, 12, 15, 18, 21, 24 and 26 weeks 90 minutes after their drug or vehicle intake sessions. In the midazolam-drinking group, physical dependence developed at about 12 weeks and increased in severity over the course of the study. Serum measures confirmed that continuous elevation of drug and active metabolite levels are not necessary for the development of physical dependence. A chronic, daily, single elevation of a few hr was sufficient.

Administration, Oral↗
PubMed1987

Oxygen delivery and consumption in patients with hyperdynamic septic shock.

We analyzed the relationship of increases in oxygen delivery to changes in oxygen consumption in ten patients with hyperdynamic septic shock. Increases in oxygen delivery from 413 +/- 14 (SEM) to 535 +/- 19 ml/min X m2 (p less than .01) were associated with increases in oxygen consumption from 136 +/- 10 to 161 +/- 5 ml/min X m2 (p less than .05). Arterial lactate decreased from 4.6 +/- 1.6 to 2.1 +/- 0.3 mmol/L (p less than .05). These observations suggest that oxygen utilization is perfusion-limited in hyperdynamic septic shock.

Aged↗
PubMed1987

Hemodynamic response to fluid repletion in patients with septic shock: evidence for early depression of cardiac performance.

We prospectively studied 18 patients with septic shock prior to and during volume infusion in order to evaluate their hemodynamic response to fluid repletion. Fluid challenge increased left heart filling pressure from 7.7 +/- 0.5 to 15.4 +/- 0.6 mm Hg (P less than .01). The increases in left ventricular filling were associated with significant increases in stroke volume index from 25.4 +/- 2.5 to 35.7 +/- 2.5 ml/min/M2 and cardiac index from 2.49 +/- 0.19 to 3.32 +/- 0.16 L/min/M2. However, at the end of fluid challenge, the patients exhibited depressed left ventricular performance as evidenced by a left ventricular stroke work index of 29.5 +/- 2.6 g X m/M2. Over the next 24 hours of maintenance fluid infusion, the left ventricular stroke work index increased to 36.8 +/- 4.2 g X m/M2 (not significant). These data suggest that volume infusion restores ventricular filling in patients with sepsis. Although fluid repletion increases stroke and cardiac output, depressed left ventricular performance appears to be an early finding in septic shock.

Aged↗
PubMed1986

Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation.

We investigated the acid-base condition of arterial and mixed venous blood during cardiopulmonary resuscitation in 16 critically ill patients who had arterial and pulmonary arterial catheters in place at the time of cardiac arrest. During cardiopulmonary resuscitation, the arterial blood pH averaged 7.41, whereas the average mixed venous blood pH was 7.15 (P less than 0.001). The mean arterial partial pressure of carbon dioxide (PCO2) was 32 mm Hg, whereas the mixed venous PCO2 was 74 mm Hg (P less than 0.001). In a subgroup of 13 patients in whom blood gases were measured before, as well as during, cardiac arrest, arterial pH, PCO2, and bicarbonate were not significantly changed during arrest. However, mixed venous blood demonstrated striking decreases in pH (P less than 0.001) and increases in PCO2 (P less than 0.004). We conclude that mixed venous blood most accurately reflects the acid-base state during cardiopulmonary resuscitation, especially the rapid increase in PCO2. Arterial blood does not reflect the marked reduction in mixed venous (and therefore tissue) pH, and thus arterial blood gases may fail as appropriate guides for acid-base management in this emergency.

Acid-Base Equilibrium↗
PubMed1985

Midazolam oral self-administration.

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).

Administration, Oral↗