Barbiturates

It has been claimed that the effects of amphetamines on schedule-controlled behavior depend to a large extent on the rate of responding in control conditions. A review of the literature shows that there is considerable support for this hypothesis if the behavior is not suppressed by aversive procedures, is not under the control of powerful external stimuli or is not occurring very infrequently. The extension of a rate-dependency hypothesis to the effects of other drugs has less empirical support, however. It is argued that many of the procedures used for studying rate-dependent drug effects do not provide critical tests of the hypothesis. If it is to be shown unequivocally that it is rate of operant responding which determines the behavioral effects of drugs, procedures are needed in which other varibles such as reinforcement frequency are more adequately controlled.

Standard cardiopulmonary-cerebral resuscitation fails to achieve restoration of spontaneous circulation in approximately 50% of normovolemic sudden cardiac arrests outside hospitals and in essentially all victims of penetrating truncal trauma who exsanguinate rapidly to cardiac arrest. Among cardiopulmonary-cerebral resuscitation innovations since the 1960s, automatic external defibrillation, mild hypothermia, emergency (portable) cardiopulmonary bypass, and suspended animation have potentials for clinical breakthrough effects. Suspended animation has been suggested for presently unresuscitable conditions and consists of the rapid induction of preservation (using hypothermia with or without drugs) of viability of the brain, heart, and organism (within 5 mins of normothermic cardiac arrest no-flow), which increases the time available for transport and resuscitative surgery, followed by delayed resuscitation. Since 1988, we have developed and used novel dog models of exsanguination cardiac arrest to explore suspended animation potentials with hypothermic and pharmacologic strategies using aortic cold flush and emergency portable cardiopulmonary bypass. Outcome evaluation was at 72 or 96 hrs after cardiac arrest. Cardiopulmonary bypass cannot be initiated rapidly. A single aortic flush of cold saline (4 degrees C) at the start of cardiac arrest rapidly induced (depending on flush volume) mild-to-deep cerebral hypothermia (35 degrees to 10 degrees C), without cardiopulmonary bypass, and preserved viability during a cardiac arrest no-flow period of up to 120 mins. In contrast, except for one antioxidant (Tempol), explorations of 14 different drugs added to the aortic flush at room temperature (24 degrees C) have thus far had disappointing outcome results. Profound hypothermia (10 degrees C) during 60-min cardiac arrest induced and reversed with cardiopulmonary bypass achieved survival without functional or histologic brain damage. Further plans for the systematic development of suspended animation include the following: a) aortic flush, combining hypothermia with mechanism-specific drugs and novel fluids; b) extension of suspended animation by ultraprofound hypothermic preservation (0 degrees to 5 degrees C) with cardiopulmonary bypass; c) development of the most effective suspended animation protocol for clinical trials in trauma patients with cardiac arrest; and d) modification of suspended animation protocols for possible use in normovolemic ventricular fibrillation cardiac arrest, in which attempts to achieve restoration of spontaneous circulation by standard external cardiopulmonary resuscitation-advanced life support have failed.

Large numbers of specimens (5000-18,000) were screened for amphetamines, barbiturates, cocaine, marijuana, opiates, and phencyclidine by RIA (Roche), Emit II (Syva), and a new immunoassay, CEDIA (cloned enzyme donor immunoassay, Microgenics). All immunoassays performed equivalently for cocaine, opiates, and phencyclidine. All immunoassays detected the same amphetamine/methamphetamine-positive specimens, but all also detected numerous specimens containing cross-reacting sympathomimetic amines. CEDIA detected 100%, Emit II 93%, and RIA 82% of the barbiturate-positive specimens. Emit II and CEDIA detected 86-88% of the specimens found by RIA to be marijuana positive. A subset of specimens was additionally screened by OnLine (Roche) and TDx (Abbott) for amphetamines, cocaine, and marijuana. OnLine and TDx also detected all of the amphetamine-positive specimens and numerous specimens containing cross-reacting sympathomimetic amines. All immunoassays performed equivalently for cocaine, an...

The aim of the current study was to compare the predictive performance of a mechanistically based model and an empirical artificial neural network (ANN) model to describe the relationship between the tissue-to-unbound plasma concentration ratios (Kpu's) of 14 rat tissues and the lipophilicity (LogP) of a series of nine 5-n-alkyl-5-ethyl barbituric acids. The mechanistic model comprised the water content, binding capacity, number of the binding sites, and binding association constant of each tissue. A backpropagation ANN with 2 hidden layers (33 neurons in the first layer, 9 neurons in the second) was used for the comparison. The network was trained by an algorithm with adaptive momentum and learning rate, programmed using the ANN Toolbox of MATLAB. The predictive performance of both models was evaluated using a leave-one-out procedure and computation of both the mean prediction error (ME, showing the prediction bias) and the mean squared prediction error (MSE, showing the predic...

A study has been made to determine the validities of certain theoretical relationships, based on the law of mass action, which predict the influence of pH, electrolyte concentration, and additives such as alcohol on solubilities of weakly acidic pharmaceuticals. Experimental data obtained from sulfathiazole, barbiturates, and terramycin indicate that deviations from the expected relationships are usually small unless complex formation takes place.

Raised intracranial pressure (ICP) is a life threatening condition that is common to many neurological and non-neurological illnesses. Unless recognized and treated early it may cause secondary brain injury due to reduced cerebral perfusion pressure (CPP), and progress to brain herniation and death. Management of raised ICP includes care of airway, ventilation and oxygenation, adequate sedation and analgesia, neutral neck position, head end elevation by 20°–30°, and short-term hyperventilation (to achieve PCO2 32–35 mm Hg) and hyperosmolar therapy (mannitol or hypertonic saline) in critically raised ICP. Barbiturate coma, moderate hypothermia and surgical decompression may be helpful in refractory cases. Therapies aimed directly at keeping ICP <20 mmHg have resulted in improved survival and neurological outcome. Emerging evidence suggests that cerebral perfusion pressure targeted therapy may offer better outcome than ICP targeted therapies.

Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates. OX A and B significantly decreased pentobar...

Suspended animation is defined as the therapeutic induction of a state of tolerance to temporary complete systemic ischemia, i.w., protection-preservation of the whole organism during prolonged circulatory arrest ( &amp;gt; or = 1 hr), followed by resuscitation to survival without brain damage. The objectives of suspended animation include: a) helping to save victims of temporarily uncontrollable (internal) traumatic (e.g., combat casualties) or nontraumatic (e.g., ruptured aortic aneurysm) exsanguination, without severe brain trauma, by enabling evacuation and resuscitative surgery during circulatory arrest, followed by delayed resuscitation; b) helping to save some nontraumatic cases of sudden death, seemingly unresuscitable before definite repair; and c) enabling selected (elective) surgical procedures to be performed which are only feasible during a state of no blood flow. In the discussion session, investigators with suspended animation-relevant research interests brainstorm on present knowledge, future research potentials, and the advisability of a major research effort concerning this subject. The following topics are addressed: the epidemiologic facts of sudden death in combat casualties, which require a totally new resuscitative approach; the limits and potentials of reanimation research; complete reversibility of circulatory arrest of 1 hr in dogs under profound hypothermia ( &amp;lt; 10 degrees C), induced and reversed by portable cardiopulmonary bypass; the need for a still elusive pharmacologic or chemical induction of suspended animation in the field; asanguinous profound hypothermic low-flow with cardiopulmonary bypass; electric anesthesia; opiate therapy; lessons learned by hypoxia tolerant vertebrate animals, hibernators, and freeze-tolerant animals (cryobiology); myocardial preservation during open-heart surgery; organ preservation for transplantation; and reperfusion-reoxygenation injury in vital organs, including the roles of nitric oxide and free radicals; and how cells (particularly cerebral neurons) die after transient prolonged ischemia and reperfusion. The majority of authors believe that seeking a breakthrough in suspended animation is not utopian, that ongoing communication between relevant research groups is indicated, and that a coordinated multicenter research effort, basic and applied, on suspended animation is justified.

Catatonia is the psychiatric syndrome of disturbed motor functions amid disturbances in mood and thought first described in 1874. It was quickly found in 10% to 38% of psychiatric populations. After it was tied to schizophrenia as a type in the psychiatric classification, its recognition became increasingly limited and by the 1980s questions were asked as to where the catatonics had gone. The decline is largely owing to the change in venue for psychiatric practice from asylum to office, the rejection of physical examination, and the dependence on item rating scales for diagnosis. In the 1970s, broad surveys again showed that catatonia was as common as before among patients with mania and depression, and as a toxic response to neuroleptic drugs. The latter recognition, that the neuroleptic malignant syndrome is the same syndrome as malignant catatonia, and is effectively treated as such, sparked a renewed interest. Clinicians developed rating scales to identify the catatonia syndrome...