Pseudoepidemic of nontuberculous mycobacteria in a community hospital.
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Diagnostic Errors↗
Biomedical subjects
P Schoch
Publications and source records attributed to P Schoch.
Do neuroactive steroids cause fatigue in pregnancy?
To elucidate factors causing widespread fatigue in pregnancy we studied plasma samples from 23 healthy pregnant volunteers, measuring endogenous neuroactive steroids, endozepines and benzodiazepines by receptor binding assays. The samples were taken at different gestational ages and the women were asked about their feeling of fatigue at the time of sample collection. We found a significant correlation between fatigue in pregnancy and presence of neuroactive steroid-like activity, but could not detect endogenous benzodiazepine-like factors. These results suggest that neuroactive steroids may be involved in fatigue during pregnancy. Their site of synthesis and their biological role remain unclear.
Adult↗
Plasma endogenous benzodiazepine-like activity in sleep disorders with excessive daytime sleepiness.
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Adult↗
Idiopathic recurring stupor.
Idiopathic recurring stupor (IRS) is a disease of unknown pathogenesis presenting with recurrent stuporous states. We describe three IRS patients in whom there were no metabolic, toxic, or structural brain dysfunctions. Ictal EEGs were characterized by fast (14- to 16-Hz), unreactive background activity. Flumazenil, a benzodiazepine receptor antagonist, promptly resolved the clinical and EEG picture. In all patients, ictal plasma determination showed a marked increase in benzodiazepine-like activity identified as endozepine-4. IRS may be due to an unexplained excess of endozepine-4.
Adult↗
Pharmacological characterization of benzodiazepine receptor ligands with intrinsic efficacies ranging from high to zero.
Several benzodiazepine receptor ligands were pharmacologically characterized in a battery of functional tests after oral administration in mice, rats, and monkeys. Previous experiments have consistently demonstrated that diazepam exhibits high intrinsic efficacy, bretazenil exhibits intermediate intrinsic efficacy, Ro 42-8773 and Ro 41-7812 both show low intrinsic efficacy, and flumazenil exhibits virtually zero intrinsic efficacy. In the test battery used here it appears that nearly full intrinsic efficacy is required for clear anterograde amnesia or rotarod impairment. In contrast, full protection in the pentetetrazol test was achieved with intermediate-to-high intrinsic efficacy and nearly full protection with lower intrinsic efficacy. In the audiogenic seizure test full anticonvulsant effects were produced with intrinsic efficacy ranging from low to high. Clear inhibition of punished operant responding was observed for all test compounds except for Ro 41-7812 and flumazenil, which exhibit the lowest intrinsic efficacies. All of the test compounds enhanced palatable food consumption, with even those having low intrinsic efficacy producing maximum effects approximating that of diazepam. By additionally taking into consideration the degree of receptor occupancy required to obtain pharmacological activity in each of the tests in this battery it is possible to order the compounds with respect to intrinsic efficacy: diazepam > bretazenil > Ro 42-8773 > Ro 41-7812 > flumazenil. The latter four compounds all exhibited a maximum antagonistic activity in tests involving reversal of meclonazepam- or flunitrazepam-induced central nervous system depression. Thus, using these tests appears to permit the accurate ordinal classification of benzodiazepine receptor ligands for intrinsic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)
Acoustic Stimulation↗
Environmental stimulation promotes changes in the distribution of phorbol ester receptors.
The translocation of protein kinase C (PKC) from the cytosol to the membrane might be functionally involved in learning and memory. Using [3H]-phorbol 12,13-dibutyrate (3H-PDBu) binding three pools of binding sites could be distinguished in tissue preparations: Pool a comprised the soluble receptors which bound phorbol ester with low affinity in the absence of calcium. Pool b was composed of high-affinity phorbol ester binding sites identified in the soluble fraction upon addition of calcium. Pool c represented stably membrane-bound receptors binding phorbol ester independently of calcium. 3H-PDBu binding was then measured in the cortices and hippocampi of rats trained in an eight-arm radial maze. A progressive training-dependent increase of membrane-bound binding activity with a concomitant decrease in the soluble fraction was detected independent of learning the maze task. These results suggest that it is the experience of an enriched environment by the repeated behavioral stimulation in a maze rather than the acquisition of a memory task that leads to enhanced incorporation of phorbol ester receptors (PKC) into the cell membrane.
Animals↗
Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence.
Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia. Current developments in benzodiazepine receptor pharmacology, i.e. the advent of partial agonists and receptor subtype specific agonists (Fig. 1), however, might eventually overcome these limitations, thus greatly improving therapeutic prospects. The present study demonstrates that subchronic administration of alprazolam (a high-efficacy agonist) results in strong withdrawal reactions upon injection of a benzodiazepine receptor antagonist in mice and monkeys. The partial agonist bretazenil, as well as the benzodiazepine receptor type 1-preferring agonist zolpidem, however, are much less prone to producing such reactions. Neurochemical studies showed that subchronic infusion of lorazepam (a high-efficacy agonist), in contrast to betrazenil, led to benzodiazepine receptor downregulation in vivo and reduced potentiation of gamma-aminobutyric acid (GABA)-stimulated chloride flux by diazepam ex vivo. These findings indicate that partial and receptor subtype 1-selective agonists differ from full, non-selective agonists in their liability to induce drug dependence and tolerance upon chronic administration. It is hypothesized that the neurochemical basis of these adaptive phenomena may be receptor downregulation and/or reduced coupling between GABAA receptor/chloride channel gating and benzodiazepine receptor binding.
Animals↗
Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat.
Increased levels of natural benzodiazepine receptor agonists, produced in the body (endogenous) or ingested with food (exogenous) have been proposed as one of the factors causing hepatic encephalopathy in both experimental animals and human subjects. However, the divergent response of hepatic encephalopathy to benzodiazepine antagonists sheds doubt on this attractive hypothesis. Acute liver failure was induced in male Sprague-Dawley rats (n = 17) with intraperitoneal thioacetamide (600 mg/kg/day for 3 days) while 14 control rats received vehicle only. Acute liver failure developed in all treated rats (AST: 1,898 +/- 1,359 IU/L vs. controls, 45 +/- 5 IU/L, p < 0.005; bilirubin: 36 +/- 27 mumol/L vs. controls, 1.5 +/- 0.5 mumol/L, p < 0.005; centrizonal necrosis) and grade 3 or 4 hepatic encephalopathy (neurologic assessment and activity monitoring). However, benzodiazepine receptor ligand activity, measured in the supernatant of whole-brain homogenates with a [3H]flumazenil binding competition assay, was clearly increased in only 1 of 17 rats with acute liver failure compared with controls (52.7 +/- 34.1 vs. 44.3 +/- 18.9 ng diazepam equivalents/gm; NS). To evaluate whether the reported increase in benzodiazepine receptor ligand activity could be due to prolonged residence of exogenous benzodiazepine-like substances, additional rats with acute liver failure and controls were treated with diazepam (five doses of 0.5 mg/kg at 12-hr intervals by gavage). Benzodiazepine receptor ligand activity was greater in animals with acute liver failure than in controls (223 +/- 65 vs. 103 +/- 23 ng diazepam equivalents/gm; p < 0.002) 1 to 3 hr after the last diazepam dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The multiplicity of actions of benzodiazepine receptor ligands.
The benzodiazepine receptor is an allosteric modulatory site present on most, if not all, gamma-aminobutyric acid A (GABAA) receptor channels (GABAA-R). The benzodiazepine receptor recognizes a large spectrum of compounds from different chemical classes that are grouped together as benzodiazepine receptor ligands--of benzodiazepine and non benzodiazepine structure. The GABAA-R is thought to be a heteropentameric protein complex composed of at least three different classes of subunits, with each subunit comprised of up to six structural variants. Binding of GABA to the extracellular domain of the receptor causes a conformational change that opens the channel pore to anions. A classical benzodiazepine achieves a positive allosteric modulation of the GABA channel gating function by increasing the affinity of the receptor for GABA and, possibly, by facilitating the conformational transition from the closed to the open form (benzodiazepine receptor agonists). Inverse agonists of benzodiazepine receptors cause negative allosteric modulation (a decrease in the GABA activity). Benzodiazepine receptor antagonists bind to the benzodiazepine receptor with little effect on GABAA-R functioning. The intrinsic efficacy of benzodiazepine receptor ligands determines the direction and magnitude of allosteric modulation. Benzodiazepine receptor agonists affect neuronal activity in all major neuronal networks. The classical pharmacological profile of benzodiazepine receptor agonists consists of anxiolytic, anticonvulsant, sedative, and myorelaxant activities. Partial agonists of benzodiazepine receptors conserve anxiolytic and anticonvulsant activity, with greatly reduced sedation and muscle relaxation. They promise to present therapeutic advantages, in particular for long term use. In initial studies. they have produced fewer side-effects and showed reduced tolerance development and physical dependence liability.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Endogenous benzodiazepine receptor ligands in idiopathic recurring stupor.
"Endozepines" are endogenous ligands for the benzodiazepine recognition sites on gamma-aminobutyric acid A receptors in the nervous system. Idiopathic recurring stupor (IRS) is a syndrome of spontaneous stupor or coma that is not associated with known metabolic, toxic, or structural abnormalities but can be reversed by flumazenil, a pure benzodiazepine antagonist. We measured endozepine-2 and endozepine-4 by high-performance liquid chromatography and radioreceptor assay in serum and cerebrospinal fluid from three patients with IRS. During episodes of stupor there was a large (up to 300-fold compared with control patients) increase of endozepine-4 content in cerebrospinal fluid and serum, but a return to normal concentrations between attacks. Endozepine-4 may contribute to, or be the cause of, IRS. The reasons for abnormal concentrations of endozepine in blood and brain are unknown.
Adult↗
Idiopathic recurring stupor: a case with possible involvement of the gamma-aminobutyric acid (GABA)ergic system.
A patient had recurrent spontaneous episodes of stupor or coma in the absence of toxic, metabolic, or structural brain damage. Ictal electroencephalography showed fast 14 Hz background activity; sleep studies excluded narcolepsy. Flumazenil (Anexate), a benzodiazepine antagonist, promptly resolved the episodes and normalized the electroencephalogram. Radioreceptor binding studies showed the presence of a ligand to the central benzodiazepine receptor in plasma and cerebrospinal fluid during the episodes, suggesting a gamma-aminobutyric acid (GABA)ergic system involvement in the origin of the attacks.
Benzodiazepines↗
Relationship between benzodiazepine receptor occupancy and potentiation of gamma-aminobutyric acid-stimulated chloride flux in vitro of four ligands of differing intrinsic efficacies.
Intrinsic efficacy is the inherent ability of a ligand to induce the conformational change of its receptor that is required to transduce the event of signal recognition into a physiologically relevant response. Relating fractional receptor occupancy to fractional effect is an indirect but reliable way to assess relative intrinsic efficacy. The receptor studied was the benzodiazepine receptor (BZR), a modulatory site on the gamma-aminobutyric acidA (GABAA) receptor-chloride channel. The relationship between fractional BZR occupancy, as assessed by inhibition of [3H]flumazenil binding, and potentiation of GABA-stimulated 36Cl- influx into membrane vesicles of rat cerebral cortex was evaluated for four ligands under identical experimental conditions. Triazolam and the quinolizinone Ro 19-8022 potentiated the effect of GABA maximally by nearly 50%, diazepam by about 40% and bretazenil by approximately 20%. Potentiation of GABA-stimulated 36Cl- flux by 25% was observed at about 35% BZR occupancy for diazepam, about 45% for triazolam and about 95% for Ro 19-8022. Bretazenil did not produce 25% potentiation even at receptor saturation. Although the curves relating fractional BZR occupancy to GABA potentiation were hyperbolic and nearly superimposable for triazolam and diazepam, those for Ro 19-8022 and bretazenil displayed parabolic characteristics by inducing an effect only at very high BZR occupancy, reflecting the partial agonistic profile of the latter two compounds. The rank order of relative intrinsic efficacy determined in this study was: triazolam congruent to diazepam much greater than Ro 19-8022 greater than bretazenil.
Animals↗
Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies.
Agonists at the benzodiazepine receptor (BZR) produce their effects through potentiation of the inhibitory alpha-aminobutyric acid-mediated neurotransmission in the central nervous system via positive allosteric modulation of the gamma-aminobutyric acidA receptor. Agonists with high intrinsic efficacy are anticonvulsant, anxiolytic, muscle relaxant and sedative, whereas agonists with low intrinsic efficacy (partial agonists) are predominantly anticonvulsant and anxiolytic, but antagonize muscle relaxant and sedative effects of full agonists. The four BZR ligands triazolam, diazepam, Ro 19-8022 (a benzoquinolizinone) and bretazenil (Ro 16-6028, an imidazobenzodiazepinone) were pharmacologically characterized in various neurological and behavioral paradigms in mice: two anticonvulsant tests (prevention of audiogenic and pentylenetetrazol-induced seizures), a conflict test which reveals both anxiolytic and sedative properties and two tests which mainly measure motor impairment (rotarod and horizontal wire test). Although triazolam and diazepam elicited an effect in all tests, Ro 19-8022 and bretazenil exhibited anticonvulsant and anxiolytic properties, but virtually failed to induce motor impairment and severe sedation. In separate experiments, fractional BZR occupancy in vivo was assessed by inhibition of [3H]flumazenil binding and correlated with the pharmacological effects. Although diazepam and triazolam produced effects beginning at low to intermediate fractional BZR occupancy, Ro 19-8022 and bretazenil required a higher BZR occupancy to do so, in accordance with their partial agonistic character. With the two full agonists, anticonvulsant and anticonflict activities were elicited at a lower fractional BZR occupancy than muscle relaxant and sedative effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders.
The classic benzodiazepines produce anxiolytic, anticonvulsant, sedative and myorelaxant effects at overlapping dose ranges. Efforts to reduce the sedative/myorelaxant component of this profile has a long history. Two rational approaches might theoretically lead to the desired drugs. One is based on the combination of partial (low efficacy) agonists of the benzodiazepine receptor with different receptor reserves in neurons subversing various functions. The other approach is based on the existence of GABAA-benzodiazepine receptor polymorphism and assumes that distinct receptor variants may be more prevalent on neurons involved in various CNS functions. Results are presented that were obtained with the partial agonist bretazenil and three other ligands in vitro as well as in vivo. Curves relating fractional receptor occupancy and various effects (potentiation of GABA-induced chloride flux, anticonvulsant, anticonflict and sedative effects) are fully consistent with the view that the particular profile of activity of bretazenil is the result of partial agonism. Comparison of fractional receptor occupancy required for the various effects of both full and partial agonists confirm earlier suggestions that receptor reserves for the individual effects differ with the same order. Clinical aspects of partial benzodiazepine receptor agonists are discussed on the basis of the preliminary information available to date.
Animals↗
Pseudomeningitis caused by Pseudomonas paucimobilis.
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Aged↗
Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028.
Continuous administration of triazolam, alprazolam or diazepam for a 7-day period by means of minipumps or chronic (17 days) p.o. treatment with alprazolam induced clear physical dependence in DBA/2J mice as assessed by precipitation of a withdrawal syndrome with an i.v. injection of the benzodiazepine receptor partial inverse agonist Ro 15-3505. In contrast, no precipitated withdrawal signs were observed following chronic exposure to high doses of the benzodiazepine receptor partial agonist Ro 16-6028. The use of minipumps and precipitation with a benzodiazepine receptor antagonist permits a simple and rapid evaluation of the physical dependence liability of potent compounds acting at the benzodiazepine receptor. Furthermore, these results support the hypothesis that benzodiazepine receptor partial agonists are less likely to induce physical dependence than full agonists.
Administration, Oral↗
Novel anxiolytics that act as partial agonists at benzodiazepine receptors.
Benzodiazepines in clinical use have a range of pharmacological activities. Some, e.g. sedation, tolerance and addiction, are not welcome. Undesirable side-effects of drugs are often controlled by developing compounds that bind more selectively to one particular receptor subtype. An alternative approach, discussed here by Willy Haefely and colleagues, is the development of partial agonists which exploit regional differences in receptor reserve to tease apart biological responses. Partial agonists for the benzodiazepine modulatory site on the GABAA complex have been developed and their pharmacological profiles can be interpreted to suggest that neurons mediating anticonvulsant and anti-anxiety effects do indeed have a higher receptor reserve than neurons mediating other unwanted effects. This suggests that benzodiazepine receptor partial agonists may have important therapeutic potential.
Animals↗
Patterns and routes of tracheobronchial colonization in mechanically ventilated patients. The role of nutritional status in colonization of the lower airway by Pseudomonas species.
Tracheobronchial colonization by Gram-negative bacteria is common in mechanically ventilated patients. Pseudomonas sp are commonly isolated from the lower airways. We hypothesized that Pseudomonas sp would preferentially colonize the lower airway and would be more common in patients with poor nutritional status. We serially collected 75 pairs of upper and lower respiratory tract cultures from 14 patients treated with mechanical ventilation for at least one week, examined patterns of airway colonization and routes of bacterial entry for Pseudomonas sp and other enteric Gram-negative bacteria (EGNB), and related these findings to host-associated factors, including nutritional status. Pseudomonas sp were the most common species isolates taken from the lower airway, found in nine of 14 patients and in 41.3 percent of all cultures. In contrast to other EGNB, Pseudomonas sp were found significantly (p less than or equal to 0.05) more often in the tracheobronchial tree (31 of 75 cultures) than in the oropharynx (18 of 75 cultures). Primary colonization of the lower airway by Pseudomonas sp was found in four patients, while other EGNB never followed this pattern when subjects were studied with cultures taken every third day. A host-related factor related to lower airway colonization by Pseudomonas species was poor nutritional status, assessed by a multifactorial index (p less than or equal to 0.01). We conclude that in mechanically ventilated patients, Pseudomonas sp colonize the lower airway in a different pattern and by a different route from those of other EGNB. The findings that Pseudomonas sp preferentially colonize the tracheobronchial tree may be important for the design of strategies to prevent airway colonization. The recognition that poor nutritional status, a potentially modifiable host-related factor, favors lower airway growth of Pseudomonas sp suggests one direction for future infection-control efforts.
Adult↗