Paul R. Pentel

Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans

To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.

A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats.

Vaccination of animals to elicit drug-specific antibodies, or the passive transfer of such antibodies from other animals, can reduce the behavioral effects of drugs such as cocaine and heroin. To study the potential application of this approach to treating nicotine dependence, IgG was isolated from rabbits immunized with a nicotine-protein conjugate vaccine. Anesthetized rats received immune IgG containing nicotine-specific antibodies (Nic-IgG) or control-IgG i.v.. Thirty minutes later, rats received nicotine at 0.03 mg/kg i.v., equivalent on an mg/kg basis to the nicotine intake from two cigarettes by a smoker. Compared to control-IgG, Nic-IgG reduced the brain nicotine concentration in a dose-related manner (65% reduction at the highest IgG dose). Pretreatment with Nic-IgG also reduced the distribution to brain of five repeated doses of nicotine (equivalent to the nicotine intake from 10 cigarettes) administered over 80 min. To study blood pressure effects, rats received control-IgG or Nic-IgG 1 day prior to administering nicotine. Nicotine-induced systolic blood pressure increases were attenuated by Nic-IgG in a dose-related manner, and were almost completely blocked by the highest Nic-IgG dose. Pretreatment with Nic-IgG also completely prevented the nicotine-induced stimulation of locomotor activity observed in rats receiving control-IgG. Nic-IgG did not prevent locomotor activation from cocaine, demonstrating its specificity for nicotine. These data demonstrate that the administration of nicotine-specific antibodies can reduce or prevent some of the pharmacokinetic, cardiovascular, and behavioral consequences of nicotine in rats. Effects were observed at nicotine doses and nicotine serum concentrations equal to or exceeding those typically associated with nicotine exposure in cigarette smokers. A potential role for immunization in the treatment of nicotine dependence is suggested.

Safety and immunogenicity of a nicotine conjugate vaccine in current smokers

Immunotherapy is a novel potential treatment for nicotine addiction. The aim of this study was to assess the safety and immunogenicity of a nicotine conjugate vaccine, NicVAX, and its effects on smoking behavior. Smokers (N = 68) were recruited for a noncessation treatment study and assigned to 1 of 3 doses of the nicotine vaccine (50, 100, or 200 μg) or placebo. They were injected on days 0, 28, 56, and 182 and monitored for a period of 38 weeks. Results showed that the nicotine vaccine was safe and well tolerated. Vaccine immunogenicity was dose‐related (P<.001), with the highest dose eliciting antibody concentrations within the anticipated range of efficacy. There was no evidence of compensatory smoking or precipitation of nicotine withdrawal with the nicotine vaccine. The 30‐day abstinence rate was significantly different across the 4 doses (P = .02), with the highest rate of abstinence occurring with 200 μg. The nicotine vaccine appears to be a promising medication for tobacco dependence.

Asystole complicating physostigmine treatment of tricyclic antidepressant overdose

Physostigmine is a commonly used therapy for the anticholinergic manifestations of tricyclic antidepressant (TCA) overdose. We describe two patients with TCA toxicity who developed asystole following the administration of physostigmine to treat seizures.

Tricyclic antidepressant poisoning. Management of arrhythmias.

SummaryDeaths from tricyclic antidepressant (TCA) overdose are usually due to arrhythmias and/or hypotension. Tricyclic antidepressant toxicity is due mainly to the quinidine-like actions of these drugs on cardiac tissues. Slowing of phase 0 depolarisation of the action potential results in slowing of conduction through the His-Purkinje system and myocardium. Slowed impulse conduction is responsible for QRS prolongation and atrioventricular block, and contributes to ventricular arrhythmias and hypotension. Therapies that improve conduction, e.g. hypertonic sodium bicarbonate, are useful in treating these toxic effects. Other mechanisms contributing to arrhythmias include abnormal repolarisation, impaired automaticity, cholinergic blockade and inhibition of neuronal catecholamine uptake. Toxicity may be worsened by acidaemia, hypotension or hyperthermia.Sinus tachycardia is due to the anticholinergic effects of the tricyclic antidepressants as well as blockade of neuronal catecholamine reuptake. Sinus tachycardia is generally well-tolerated and requires no therapy. Sinus tachycardia with QRS prolongation may be difficult to distinguish from ventricular tachycardia. Electrocardiograms obtained using oesophageal or atrial electrodes may be useful in determining the relationship of atrial and ventricular activity. Although QRS prolongation alone is not compromising, it is a marker for patients at highest risk of developing seizures, arrhythmias or hypotension. Ventricular tachycardia (monomorphic) is a consequence of impaired myocardial depolarisation and impulse conduction. Hypertonic sodium bicarbonate may partially correct impaired conduction and be of benefit in treating ventricular tachycardia. Since hypertonic sodium bicarbonate appears to act by increasing the extracellular sodium concentration as well as by increasing extracellular pH, hyperventilation may be less effective. Hypertonic sodium bicarbonate is of particular benefit in patients who are acidotic, since acidosis aggravates cardiac toxicity. However, administration of hypertonic sodium bicarbonate is beneficial even when blood pH is normal Lignocaine (lidocaine) may be useful in treating ventricular tachycardia but should be administered cautiously to avoid precipitating seizures. Ventricular bradyarrhythmias are due to impaired automaticity or depressed atrioventricular conduction and can be treated by placement of a temporary pacemaker, or with a chronotropic agent, e.g. isoprenaline (isoproterenol), with or without concomitant vasoconstrictors. Ventricular fibrillation is unusual with tricyclic antidepressant toxicity and often represents an agonal rhythm. Treatment is empirical; antiarrhythmic agents that impair conduction (type Ia or Ic) or repolarisation [type Ia or III (bretylium, amiodarone)] should be avoided.Hypotension may aggravate tricyclic antidepressant-induced arrhythmias by impairing myocardial perfusion or causing systemic acidosis. Hypotension should be treated with hypertonic sodium bicarbonate if cardiac contractility is impaired, and with fluids if cardiac filling pressure is low. Inotropic agents may worsen or precipitate tachyarrhythmias and should be reserved for refractory hypotension. Other factors that may aggravate arrhythmias, e.g. hyperthermia, hypoxaemia and electrolyte imbalance, should be corrected. Seizures, and the resulting acidaemia, should be treated promptly. The role of phenytoin (diphenylhydantoin) and haemoperfusion in treating arrhythmias due to tricyclic antidepressant overdose are unclear, and their routine clinical use is not supported.

Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming

The objective of the present study was to determine the relative efficacy of nicotine priming and nicotine-paired stimuli in reinstating extinguished NSA in rats. The relative efficacy of different stimulus conditions in reinstating NSA was also determined. Rats were trained to self-administer nicotine (0.03 mg/kg/inf) under an FR 5 schedule. Onset of a light above the active lever was correlated with nicotine availability, while offset of the light was paired with each nicotine infusion. In Experiment 1, saline extinction was arranged in the presence of these light stimuli. After extinction criteria were met, the effects of priming doses of nicotine (0.01, 0.03. and 0.06 mg/kg/inf, i.v.) on active lever pressing were determined. In Experiment 2, extinction of NSA was arranged in the absence of the light stimuli. After extinction criteria were met, reinstatement sessions were arranged involving either (1) a priming infusion of nicotine (0.03 mg/kg), (2) presentation of the same light stimuli as during NSA training, (3) constant illumination of the cue light, or (4) a combination of a nicotine priming infusion with one of the stimulus-light conditions. In Experiment 1, nicotine generally failed to reinstate NSA at any priming dose. In Experiment 2, both stimulus conditions reinstated NSA, with the stimulus condition identical to training producing a greater effect. Nicotine priming alone failed to significantly reinstate NSA. Nicotine priming combined with either stimulus condition was no more effective than each stimulus condition alone in reinstating NSA. These findings suggest that nicotine-paired cues are more effective than nicotine alone in reinstating extinguished NSA and are consistent with other studies showing that nicotine-paired stimuli play an important role in the reacquisition of NSA.

Effects of portion size on chronic energy intake

BackgroundThis study experimentally examined the effects of repeated exposure to different meal portion sizes on energy intake.MethodsNineteen employees of a county medical center were given free box lunches for two months, one month each of 1528 and 767 average kcal. Foods were identical in the two conditions, but differed in portion size. Meals averaged 44% calories from fat. Participants self-reported how much of each lunch was eaten. Unannounced 24-hour dietary recalls were also conducted by phone twice per week during each exposure period.ResultsMean energy intake at the lunch meal was 332 kcal/day higher in large lunch than in small lunch periods (p < .001). Mean 24-hour energy intake was 278 kcal/day higher in large versus small lunch periods (p < .001). There was no evidence of compensation over time. Average weight change over the month of large and small lunches was 0.64 ± 1.16 kg and 0.06 ± 1.03 kg, respectively, about what would be expected with the observed differences in energy intake.ConclusionThis study suggests that chronic exposure to large portion size meals can result in sustained increases in energy intake and may contribute to body weight increases over time.

High-level secretion of two antibody single chain Fv fragments by Pichia pastoris

The diagnostic and therapeutic applications of antibody single-chain Fv (sFv) fragments often require large amounts of protein that can be problematic and expensive to obtain. Here we report the secretion of two sFv fragments by the yeast Pichia pastoris at levels up to 250 mg/l. Soluble sFv fragments were purified from culture supernatants in one step by affinity or metal-chelating chromatography, and were indistinguishable from their bacterially expressed counterparts in terms of affinity. Secretion of functional sFv fragments by Pichia pastoris provides a low cost, high yield alternative to current sFv expression systems.

Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain

Vaccination against nicotine has been proposed as a potential treatment for nicotine dependence. Because vaccination may take months to elicit satisfactory antibody levels, the clinical usefulness of this approach will be enhanced if vaccination can be accomplished during continued nicotine intake (e.g., before a smoker quits). The current study examined the immunogenicity of a nicotine conjugate vaccine during continued nicotine dosing in rats, and its effects on nicotine distribution to brain. In the first experiment, nicotine was administered over 11 weeks as 20 intra venous (i.v.) bolus injections per day during the rats active cycle to simulate the usual pattern of nicotine intake from cigarette smoking. In the second experiment, rats received a continuous s.c. infusion of nicotine by osmotic pump for 11 weeks to provide serum nicotine concentrations equivalent to those of a heavy smoker and 24 h/day nicotine exposure. Nicotine-specific antibody titers after the third booster dose were not compromised by either regimen of concurrent nicotine administration compared to those of rats receiving saline. A single additional i.v. nicotine dose was administered at the end of each experiment. The distribution of this single nicotine dose to brain was reduced by 40-60% in vaccinated rats compared to controls. Vaccine efficacy in reducing nicotine distribution to brain was not compromised by concurrent nicotine administration. These data suggest that vaccination during concurrent nicotine administration is feasible, and that the ability of vaccination to reduce nicotine distribution to brain is preserved even after months of nicotine dosing at rates approximating cigarette smoking.

Immunization of rats reduces nicotine distribution to brain.

Abstract The effect of active immunization against nicotine on the initial distribution of nicotine to brain was studied in anesthetized rats. Animals received nicotine 0.03 mg/kg nicotine (equivalent to the nicotine dose absorbed by a human smoking two cigarettes) as a rapid injection in the jugular vein. In control animals, the arterial serum nicotine concentration initially exceeded the venous concentration 4.6-fold, similar to the initial arteriovenous difference produced by cigarette smoking in humans. Animals immunized with the nicotine analog CMUNic maintained this arteriovenous gradient, but with both arterial and venous nicotine concentrations several times higher than in controls. The arterial nicotine concentration was higher in immunized animals even at the first (7.5 s) sampling time. The brain nicotine concentration at 3 min was 36% lower in the immunized animals. The time course of nicotine distribution to brain was studied in a second group of animals. Brain nicotine concentration was reduced in rats immunized with CMUNic over the entire 6-min sampling period immediately following nicotine dosing (mean reduction 38%). A reduction was found at the earliest sampling time (30 s) and was maximal at 1 min (48%). Nicotine protein binding in serum was markedly increased in animals immunized with CMUNic compared to controls (91.2 versus 10.9%), and the unbound nicotine concentration in serum was lower (10.0 versus 13.4 ng/ml). The reduction in brain nicotine concentration correlated with antibody affinity for nicotine, and the percentage of nicotine bound in serum. These data demonstrate that nicotine-specific antibodies produced by active immunization rapidly bind nicotine in arterial blood, reduce the unbound nicotine concentration, and reduce the early distribution of nicotine to brain. Effects were observed using a clinically relevant nicotine dose and route of administration. These data suggest that the use of immunization to modify the behavioral effects of nicotine may be possible.