A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials.

During 15 years, 23 clinical reports and 6 studies have demonstrated associations between sub-sedative doses of zolpidem and recoveries from brain damage due to strokes, trauma and hypoxia. Clinical findings include unexpected awakenings from vegetative states and regressions of stroke symptoms after dosing that disappear during elimination and reappear on repeat dosing. Initially single-photon emission computed tomography scans showed improved perfusion within, around and distant from infarctions. Then positron emission tomography scans and electroencephalography detected renewed metabolic and neuronal activity. Placebo or a similar, gamma-aminobutyric acid (GABA)-ergic, sedative zopiclone has no such effect. The effect appears only several months after the injury, reflecting recent evidence in mice of substantial differences between the states of GABA receptors in acute and chronic repair phases of recovery. Zolpidem's good safety record and rapid absorption further indicate a need for more clinical trials. List of acronyms: BOLD, Blood-Oxygen-Level Dependent contrast imaging in MRI; CRS, Coma Recovery Scale; CRS-R, Coma Recovery Scale Revised; CSI, Cerebral State Index; CSM, Cerebral State Monitor; DOC, Disorder of Consciousness; EEG, Electro Encephalography; FDG-PET, FluoroDeoxyGlucose-Positron Emission Tomography; FTD, Frontotemporal dementia; GABA, Gamma-Aminobutyric Acid; MCS, Minimally Conscious State; M-EEG, Magneto-Encephalography; MRI, Magnetic Resonance Image; MSN, Median Spiny Neurones; PET, Positron Emission Tomography; PVS, Persistent Vegetative Sate; RLAC, Rancho Los Amigos Cognitive scores; SPECT, Single-photon emission computed tomography; TFES, Tinetti Falls Efficacy Scale; 99mTc HMPAO, Technetium hexamethylpropyleneamine oxime.

Physiological interpretation of electrical impedance epigastrography measurements.

Measurement of the electrical impedance of the gastric region is carried out with the epigastrograph. This generates and applies alternating current around the abdominal area and measures the potential difference in order to determine the impedance externally, via electrodes. The change of epigastric impedance for a subject, given a meal after fasting, depends on the conductivity of the meal compared to the stomach and surrounding tissues. Typically a conductive meal has conductivity >7 mS cm(-1), non-conductive <2 mS cm(-1) and neutral about 4.5 mS cm(-1). Half-emptying times (T50s) from gastric emptying studies in volunteers using three test meals of 450 ml volume were obtained and found to be shorter than expected from the literature. The meals were a 10% glucose solution and two milk shakes of energy 1,300 kJ and 2,850 kJ, respectively. These electrical impedance epigastrography (EIE) measurements were carried out with scintigraphy. The T50 values of the latter were significantly longer. The direct comparison of the normalized experimental data obtained by both methods led to the concept that EIE measurements are mainly influenced by gastric secretion. Thus the EIE trace of a 'neutral' meal suggests the hypothesis that the volume of the meal is not the significant factor but is influenced by gastric acid secretions. Physiology of the gastric mucosa during the digestion of a meal and intragastric pH values also suggests this. Gastric function studies using EIE measurements may therefore reflect gastric ionic concentration rather than the volume of the contents of the stomach. In turn this could lead to the development of a non-invasive method for the continuous recording of gastric acid secretions.

Solvent/detergent treatment does not alter the tolerance or uptake of human normal immunoglobulin for intramuscular injection.

BACKGROUND AND OBJECTIVES: The tolerability and pharmacokinetics of a solvent/detergent-treated intramuscular immunoglobulin were compared with those of the standard product. MATERIALS AND METHODS: Single, 750-mg intramuscular (i.m.) injections were administered to a total of 36 healthy individuals: 23 in a double-blind trial and 13 in an open trial. Changes in specific serum hepatitis A and hepatitis B antibodies were monitored for a period of up to 3 months postinjection. RESULTS: No serious adverse reactions were reported, and the bioavailability of the solvent/detergent-treated preparation was equivalent to that of the standard i.m. immunoglobulin. CONCLUSION: There is no evidence that solvent/detergent treatment alters the pharmacokinetics or tolerance of human normal immunoglobulin, but it offers additional assurance against potential virus transmission.

Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina.

OBJECTIVE: We sought to study the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure (BP) in men taking the nitric oxide (NO) donor drugs isosorbide mononitrate (ISMN) or glyceryl trinitrate (GTN) for stable angina. BACKGROUND: Sildenafil, a selective phosphodiesterase type 5 inhibitor, is an orally effective treatment for erectile dysfunction. The presence of phosphodiesterases in the vasculature suggests the possibility of an interaction between sildenafil and NO donor drugs. METHODS: Two double-blind, placebo-controlled, randomized, two-way crossover trials were undertaken. Sixteen male patients received oral ISMN (20 mg twice a day) for five to seven days before their dose of sildenafil or placebo and continued receiving ISMN daily until administration of the alternate drug seven days later. For the second study, 15 male patients received sublingual GTN (500 microg) 1 h after sildenafil or placebo on each of two study days, which were seven days apart. Sitting or standing BP was measured before and for 6 h after the administration of the study drug. RESULTS: The effects of sildenafil plus ISMN on BP (standing mean maximum reductions from baseline in systolic/diastolic BP, -52/-29 mm Hg) were greater than the effects of placebo plus ISMN on BP (-25/-15 mm Hg; p < 0.001). Sildenafil plus GTN also resulted in greater sitting mean maximum reductions from baseline in systolic/diastolic BP (-36/-21 mm Hg) compared with placebo plus GTN (-26/-12 mm Hg; p < 0.01). CONCLUSIONS: Coadministration of sildenafil with ISMN or GTN produced significantly greater reductions in BP than ISMN or GTN alone. Based on these data, sildenafil should not be administered to patients taking nitrates.

No effect of glucagon-like peptide-1 on short-term satiety and energy intake in man.

Centrally administered glucagon-like peptide-1 (GLP-1) inhibits feeding in fasted rats, but its role in human satiety has been largely unexplored. The present study investigated the effect of peripheral GLP-1 infusion on gastric emptying and satiety in man. Ten non-obese male subjects were infused in a randomized single-blind within-subject crossover study using saline infusion as control. They received either a GLP-1 infusion (1.2 pmol/kg per min) or a saline infusion for 1 h, at 18.00 hours. At 20 min after starting the infusion the gastric emptying of a 400 ml water load was measured. Subjects completed behavioural self-rating scales to assess hunger and satiety. After 40 min subjects were given a buffet meal ad libitum and their food intake was recorded. GLP-1 infusion raised circulating GLP-1 concentrations to approximately twice those seen following a meal. It did not affect circulating insulin levels but caused a small fall in glucose levels. Gastric emptying of the water load was significantly delayed by the GLP-1 infusion. Energy intake from the buffet was unaffected by GLP-1 infusion. Self-assessment of hunger and satiety was similarly unaffected by the infusion before the buffet meal, although subjects tended to be less hungry after the buffet meal following GLP-1 infusion (P < 0.09). GLP-1 infusion delayed gastric emptying but had a minimal effect on food intake and satiety. This study casts doubts on whether GLP-1 is a major satiety factor in man, although a raised circulating plasma glucose level, as would normally occur postprandially, might be necessary for GLP-1 to increase satiety.

Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.

BACKGROUND: Opioids delay gastric emptying, which in turn may increase the risk of vomiting and pulmonary aspiration. Naloxone reverses this opiate action on gastric emptying, but it is not known whether this effect in humans is mediated by central or peripheral opiate antagonism. The importance of peripheral opioid receptor antagonism in modulating opioid-induced delay in gastric emptying was evaluated using methylnaltrexone, a quaternary derivative of the opiate antagonist naltrexone, which does not cross the blood-brain barrier. METHODS: In a randomized, double-blind, crossover placebo-controlled study, 11 healthy volunteers were given either placebo (saline), 0.09 mg/kg morphine, or 0.09 mg/kg morphine plus 0.3 mg/kg methylnaltrexone on three separate occasions before ingesting 500 ml deionized water. The rate of gastric emptying was measured by two methods: a noninvasive epigastric bioimpedance technique and the acetaminophen absorption test. RESULTS: The epigastric bioimpedance technique was sufficiently sensitive to detect opioid-induced changes in the rate of gastric emptying. The mean +/- SD time taken for the gastric volume to decrease to 50% (t0.5) after placebo was 5.5 +/- 2.1 min. Morphine prolonged gastric emptying to (t0.5) of 21 +/- 9.0 min (P < 0.03). Methylnaltrexone given concomitantly with morphine reversed the morphine-induced delay in gastric emptying to a t0.5 of 7.4 +/- 3.0 (P < 0.04). Maximum concentrations and area under the concentration curve from 0 to 90 min of serum acetaminophen concentrations after morphine were significantly different from placebo and morphine administered concomitantly with methylnaltrexone (P < 0.05). No difference in maximum concentration or area under the concentration curve from 0 to 90 min was noted between placebo and methylnaltrexone coadministered with morphine. CONCLUSIONS: The attenuation of morphine-induced delay in gastric emptying by methylnaltrexone suggests that the opioid effect is mediated outside the central nervous system. Methylnaltrexone may have the potential to decrease the side effects of opioid medications, which are mediated peripherally, while maintaining the central analgesia effect of the opioid.

Comparative central nervous system effects and pharmacokinetics of neu-metoclopramide and metoclopramide in healthy volunteers.

Metoclopramide, a drug used for the relief of nausea and emesis, is currently under development as a radio- and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous system side effects. Neu-metoclopramide (Neu-Sensamide), a novel, concentrated, phosphate-buffered, pH-adjusted (pH = 6.5-7.0) formulation of metoclopramide, has been shown to have an improved side-effect profile in animal studies. The present double-blind, four-way crossover study compared the central nervous system effects and pharmacokinetics of neu-metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) with intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one because of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclopramide administration, whereas 16, 15, and 6 such events were attributed to intravenous neu-metoclopramide, intramuscular neu-metoclopramide, and placebo, respectively. Extra-pyramidal effects occurred on 10 occasions: 7 after intravenous metoclopramide, 2 after intravenous neu-metoclopramide, and 1 after intramuscular neu-metoclopramide. No significant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore, that the molecular conformational changes inherent to neu-metoclopramide result in a reduced side-effect profile compared with conventional metoclopramide formulations.

The clinical pharmacology of single doses of otilonium bromide in healthy volunteers.

OBJECTIVE: Otilonium is a smooth muscle spasmolytic with greater affinity for receptors in the smooth muscle of distal than proximal gut in rats. This study was the first to compare distal and proximal GI transit effects in human subjects. METHODS: Using an increasing dose design for the safe exploration of clinical and supraclinical single dose levels, two groups of eight volunteers received either 40, 120 and 200 mg or 80, 160 and 240 mg otilonium. Gastric emptying of 400 ml 10% glucose solution was assessed by epigastric impedance (EI), orocaecal transit time (OCTT) by the lactulose breath-hydrogen method and whole gut transit time (WGTT) by the method of Hinton et al. [1]. Potential anticholinergic effects were assessed via visual accommodation using the RAF rule and saliva flow in response to sucking a sweet. RESULTS: Median WGTT after 120 mg significantly increased by 4.1 h relative to placebo, but at higher doses median changes relative to placebo were not significant due to wide increases in group variance. The EI t50% was delayed by 1.4 min when results from the two highest doses were combined and compared with placebo; this small difference was statistically significant but seems unlikely to achieve physiological or clinical significance. OCTT, visual accommodation and saliva flow were unaltered. Otilonium bromide was well tolerated at all doses, due mainly to low systemic absorption.

Faeces feeding by adult Phormia regina (Diptera: Calliphoridae): impact on reproduction.

Fresh beef liver, sugar, and five different types of faeces were evaluated as supportive diets for egg development in the blowfly Phormia regina. Females on a sugar diet were unable to develop follicles beyond stage 3, whereas liver proved to be the best diet for complete egg maturation. Some faecal diets were unable to support egg maturation when fed upon for a short period of time; however, longer periods of feeding produced complete egg maturation. The necessity to feed for longer periods of time in order to produce eggs on most of these diets was attributed to their low protein content. Males, in a shorter period of time than females, obtained enough protein from faeces to activate the neuroendocrine system involved in mating.

Requirement for HIV-1 TAR sequences for Tat activation in rodent cells.

HIV-1 gene expression is activated via an interaction between the virally encoded Tat protein and a target RNA, TAR. TAR is located at the immediate 5' end of all viral mRNAs and comprises a partially base-paired stem with a tripyrimidine bulge in the upper stem and a hexanucleotide loop. In vitro, Tat binds specifically to the bulge and upper stem region with no requirement for the loop. In contrast, when Tat activation is analyzed in primate cells, mutations in the loop abolish activation, suggesting a critical role for loop binding cellular factors. However, in rodent cells the reverse is true. Messages with a mutation in the TAR loop are activated whereas messages harboring a wild-type TAR sequence are not activated. By testing the effect of mutations in the bulge and stem in the context of mutation in the loop we now show that this loop-independent activation by Tat in rodent cells requires the critical bulge-stem sequences needed for Tat binding in vitro. These data suggest that in rodent cells, as in vitro, Tat does not require a loop binding cofactor. In rodent cells containing human chromosome 12 (CHO12), however, Tat activation is both bulge and loop dependent. It appears that rodent cells, but not CHO12 cells, are refractory to the normal Tat/TAR activation pathway not by virtue of lacking a loop binding cofactor, but rather by the presence of a loop binding inhibitor of either Tat binding or the activation process.

The acute and chronic toxicity of ten chlorinated organic compounds to the American flagfish (Jordanella floridae).

The acute toxicity (96-hr median lethal concentrations (LC50s) of ten chlorinated isomers of benzene, phenol, ethane, and ethylene to the American flagfish (Jordanella floridae) were determined in both static and flow-through systems. Chronic toxicity to embryo-larval fish was also estimated from hatching success and post-hatch survival as well as fry growth rates and survival. Maximum acceptable toxicant concentrations (MATC) were estimated where possible. In general, for both acute and chronic toxicity tests, the order of increasing relative toxicity based on the water-borne exposure concentrations was: chloroethanes, chloroethylenes, chlorobenzenes, and chlorophenols. Within groups, more highly chlorinated isomers were usually more toxic. The presence of suspended or colloidal 1,2,4,5-tetrachlorobenzene was observed in acute toxicity testing and affected toxicity estimates.

A correlation between severity of migraine and delayed gastric emptying measured by an epigastric impedance method.

1. This study examined the ability of a bioimpedance method to detect the delay in gastric emptying which occurs during attacks of migraine. 2. In 64 non-migraineur control patients and 46 migraine patients outside an attack, gastric emptying rates were within the predicted normal range. 3. In contrast, rates in 14 migraineurs during 20 attacks were delayed during severe or moderate attacks and were significantly correlated with the intensity of headache, nausea and photophobia. 4. The epigastric impedance method was generally well tolerated by patients and appears to merit further investigation as a clinical method of monitoring gastric emptying of liquids.

A comparison of the gastric and central nervous system effects of two substituted benzamides in normal volunteers.

Eight healthy male volunteers participated in a single-blind, random allocation, crossover, comparison of intravenous metoclopramide (10 mg), the peripherally acting, gastrointestinal stimulant BRL 20627 (10 mg) and saline. The central nervous system effects were assessed by quantitative electroencephalography (EEG) and by visual analogue scales. Gastric motility and emptying were assessed by epigastric impedance. Metoclopramide increased the EEG amplitude by 10.4% (a statistically significant, P less than 0.05, effect) and increased frequencies above 22 Hz, whereas both BRL 20627 and placebo had only minor effect on the EEG frequencies and slightly decreased the EEG amplitude. Ratings on visual analogue scales showed that metoclopramide caused statistically significant (P less than 0.01 difference from placebo) restlessness and slight but significantly less (P less than 0.05 difference from placebo) feeling of happiness. Epigastic impedance changes indicated that both metoclopramide and BRL 20627 increased gastric contractile activity, but the rate of gastric emptying was not significantly altered by either drug although it tended to be shortened following metoclopramide but not BRL 20627 treatment. It is concluded that since the published animal data show that BRL 20627 has only weak dopamine antagonistic properties this study further implicates dopamine receptor blockade in the akathisia but not in the gastric effect of metoclopramide.

Epigastric impedance: a non-invasive method for the assessment of gastric emptying and motility.

The impedance of the epigastrium to a 4 mA, 100 KHz AC current increases while liquids of low electrical conductivity are being drunk. Logically, the decline which follows occurs as the liquid leaves the stomach. This impedance measurement of gastric emptying proved comparable with the dye dilution method. In a placebo controlled trial the impedance method recorded significantly faster gastric emptying rates after metoclopramide. The impedance trace contains regular activity in the 2-4 cycle/min range consistent with gastric contractions. This non-invasive and technically simple method may thus provide a measure of simultaneous gastric emptying rates and motility.

Measurement of gastric emptying rates by radioactive isotope scanning and epigastric impedance.

When liquids of low electrical conductivity enter the stomach the impedance of the epigastric region to a 4 mA, 100 kHz current increases. There follows a decline, which logically represents gastric emptying. This method of measuring gastric emptying was compared against scintigraphy in six volunteers, and similar results were obtained. Impedance monitoring is entirely noninvasive, inexpensive, simple, and quick. The method merits further exploration.

Bioavailability and pharmacokinetics of clavulanic acid in healthy subjects.

The bioavailability and pharmacokinetics of clavulanic acid were studied following oral solution and rapid intravenous administration to healthy volunteers. Plasma and urine samples were collected at frequent intervals following dose administration and were assayed for clavulanic acid by an enzyme inhibition method. Plasma data after intravenous administration were subjected to pharmacokinetic analysis using a two-compartment open model. The mean absolute bioavailability of clavulanic acid from oral solution was 0.75, derived from both urine and plasma data. No changes in the disposition pharmacokinetics of clavulanic acid with route were found, with a mean renal clearance of 0.1051 X min-1 and mean terminal elimination rate constant of 0.0134 min-1.

Pilot investigation of the quantitative EEG and clinical effects of ketazolam and the novel antiemetic nonabine in normal subjects.

Nonabine is a chromenol structurally related to the cannabinoids which has shown antiemetic efficacy in clinical trials. Oral doses of 5, 10, and 15 mg were given to healthy volunteers in a crossover study with the benzodiazepine ketazolam, 30 and 45 mg. Ketazolam produced sedative effects, with decreased quantitative EEG alpha activity and increased beta activity. Nonabine also produced sedative clinical effects, but with an EEG profile which resembled that reportedly caused by cannabinoids. In contrast to cannabinoids, nonabine did not cause changes of mood or perception, suggesting that nonabine lacks the potential for social abuse at antiemetic doses.

Adverse reactions to intravenous anaesthetics.

One hundred consecutive reports of reactions to intravenous anaesthetics Althesin, thiopentone and Epontol are reviewed and analysed. Ten reactions are attributed to causes other than the anaesthetic drug, and four are believed to have been caused by the muscle relaxant employed. The remaining 86 reactions were grouped according to their clinical presentation: histaminoid reactions ( 19), histaminoid with bronchospasm (33), bronchospasm (12), cardiovascular collapse (uu), delayed histaminoid reactions (6), and clonic contractions (5). None of the first four reaction types was associated with only one anaesthetic. A knowledge of the sales of Althesin has allowed the incidence of reactions to be estimated as between one in 11,000 and one in 19,000.