Conjugation of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 with intracellular glutathione and enhancement of its antiproliferative activity by glutathione depletion.

The major dehydration product of prostaglandin D2, 9-deoxy-delta 9,delta 12(E)-prostaglandin D2, is a potent cytotoxic compound. Like other cytotoxic prostaglandins, this compound possesses an alpha, beta-unsaturated ketone group to which cytotoxic activity has been attributed. This prostaglandin was found to readily conjugate with glutathione (GSH) in vitro. When 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 was incubated with Chinese hamster ovary or hepatoma tissue culture cells, it was rapidly taken up and was recovered in the cell lysate primarily as a GSH conjugate in which the keto group at C-11 and the delta 12 double bond had been reduced. Identification of the GSH conjugate was accomplished by analysis by fast atom bombardment mass spectrometry following purification by high performance liquid chromatography. This GSH conjugate and its cysteinylglycinyl and cysteinyl metabolites were also identified in the cell culture medium. 9-Deoxy-delta 9,delta 12(E)-prostaglandin D2 inhibited cell proliferation of these two cell lines in a concentration dependent manner. Depletion of intracellular glutathione by treatment with diethyl maleate and buthionine sulfoximine decreased the amount of intracellular conjugated prostaglandin recovered, and significantly enhanced the antiproliferative effect of 9-deoxy-delta 9-delta 12(E)-prostaglandin D2 on the growth of these cell lines in a concentration dependent fashion. We conclude that intracellular GSH may modulate the antiproliferative activity of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 and, possibly, of other cytotoxic prostaglandins.

Safety of pyridostigmine in hypertensive patients receiving beta blockers.

In the last decade, pyridostigmine, a quaternary carbamate that reversibly inhibits the enzyme acetylcholinesterase, was proposed for pretreatment of nerve gas (organophosphate) poisoning. The objective of this study was to assess the cardiovascular effects of pyridostigmine in patients treated with beta blockers. Eight hypertensive patients receiving regular treatment with beta blockers were randomized in a double-blind crossover study to receive pyridostigmine (30 mg 3 times daily) or placebo for 2 days. Heart rate and blood pressure in the supine and standing positions were recorded every 2 hours during the day, and 24-hour Holter monitoring was performed. In addition, a symptom-limited exercise test was performed, and plasma catecholamine levels were determined at rest and at peak exercise. Pyridostigmine, as compared with placebo, did not induce any significant effect on heart rate, plasma catecholamine levels or resting blood pressure. Both systolic and diastolic blood pressures increased in accordance with exercise intensity (p less than 0.01), although a significantly lower diastolic blood pressure was observed when pyridostigmine was used (average decrease 5 mm Hg compared with placebo; p less than 0.01). No clinical adverse reactions were observed, confirming the relative safety of the combination of low-dose pyridostigmine with beta-adrenergic blocking agents.

The effects of powered air supply to the respiratory protective device on respiration parameters during rest and exercise.

The common chemical warfare protective masks impose an excessive respiratory load on the wearer due to elevated breathing resistance and increased dead space. For patients with severe respiratory disease, the excessive respiratory effort may be intolerable. Besides, the substantial negative pressure created within the mask during inspiration may result in an inward leakage in individuals having difficulties with proper facial fitting of the mask. The purpose of the current investigation was to evaluate the effects of a blower, actively driving air, through the mask's filter, at a flow (mean +/- SD) of 42 +/- 2 L/min, on respiratory parameters during rest and moderate exercise. Ten healthy subjects of either sex participated in two experimental sessions, wearing the mask with and without the blower. Each session included 6 min of sitting at rest and 6 min of walking on a treadmill (3.2 mph, and 10 percent grade). In nine of the subjects, the active air supply produced a positive inspiratory pressure at rest (5 +/- 4 vs -24 +/- 9 mm H2O peak inspiratory pressure with and without the blower, respectively, p < 0.0001). Inspiratory carbon dioxide concentration (FICO2) at rest was diminished (0.4 +/- 0.4 vs 1.3 +/- 0.7 percent with and without the blower, respectively; p < 0.01) while FIO2 increased from 19.5 +/- 0.7 percent to 20.6 +/- 0.4 percent with the device (p < 0.01). These changes were associated with a significant decrease in respiratory rate (15 +/- 2 vs 18 +/- 3 per minute, p < 0.01). During exercise the blower barely decreased the negative inspiratory pressures, had no effect on other respiratory parameters measured, but significantly shortened the inspiratory/cycle-length time ratio (0.46 +/- 0.03 vs 0.53 +/- 0.03, p < 0.005). The effects of active air supply were not different between male and female subjects. We conclude that the blower is expected to be a useful accessory to respiratory protective devices for patients with pulmonary disease.

Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report.

A 43 year old woman had suffered from insomnia for the past 11 years and was being treated with benzodiazepines. All attempts to stop benzodiazepine treatment resulted in withdrawal symptoms and a renewal of the insomnia. Treatment with 1 mg of controlled release melatonin enabled the patient to completely cease any benzodiazepine use within two days, with an improvement in sleep quality and no side effects. Examination of urinary 6-sulphatoxymelatonin levels before the melatonin treatment indicated that the levels were very low and lacked the typical circadian rhythm of excretion. Reexamination of 6-sulphatoxymelatonin levels during melatonin treatment revealed the existence of a normal circadian rhythm of excretion. This case may suggest that some of the people suffering from insomnia and addicted to benzodiazepines may successfully undergo withdrawal from these drugs and improve their sleep by means of treatment with melatonin. The results of this single case study warrant further investigation of a larger population by means of a double-blind placebo-drug study.

Thallium poisoning in Israel.

We report the first case of thallium poisoning in Israel in almost 30 years. A 40-year-old man was apparently poisoned by a business associate when, on several occasions, he unknowingly drank an alcoholic beverage containing the toxic substance. Delayed admission and recurrent thallium ingestion resulted in both acute and chronic symptoms being present concomitantly. Conventional treatment modalities (Prussian blue and forced diuresis) were employed. The patient survived, although neurological sequelae ensued. The problems encountered in diagnosis and treatment of this relatively uncommon entity are discussed.

The effect of a chemical protective ensemble on intravenous line insertion by emergency medical technicians.

Protective gear is mandatory for medical personnel treating casualties in a contaminated environment. In the present study, we assessed the ability of emergency medical technicians to insert an intravenous line in this situation. Sixty emergency medical technicians were randomized to a control group, wearing fatigues, and a study group, wearing full protective gear. The ability to insert an intravenous line in healthy volunteers was assessed 1, 2, 4, and 8 hours after randomization. We found no effect of protective gear (p = 0.543) or time in protective gear (p = 0.8869) on success rate or on time needed for successful task completion (p = 0.4005 and p = 0.9021, respectively). The overall success rate was 58.6%, 65% in the unprotected state and 56% in the protected state, and the time was 303 +/- 115 and 351 +/- 113 seconds, respectively. These findings suggest that introduction of an intravenous line is possible but time consuming even after a prolonged stay in full protective gear. Alternative methods for antidotal treatment, such as the use of automatic autoinjectors for intramuscular administration, might be suggested.

Medical limitations of gas masks for civilian populations: the 1991 experience.

Using a gas mask (GM) may involve considerable inconvenience, impairment of respiration and communication, and serious psychological reactions. The medical literature is primarily focused on the occupational aspects of using the GM by young and healthy workers. In contrast, there is hardly any information concerning the use of GMs by large, unselected populations, including children, the elderly, and the sick. Issuing GMs to all residents of Israel prior to Operation Desert Storm created an urgent need to define the populations whose health might be jeopardized by using the standard GM. Adding an active air supply system (AASS) to a standard GM may ease the burden on this high-risk group. We evaluated the physiological aspects of breathing with a GM, with and without AASS, in respect to pathophysiology of diseases, and reached a set of criteria for identifying those who may be endangered by a GM and are expected to benefit from the AASS. The method used to sort and identify those entitled to the AASS is described.

[Is routine monitoring of theophylline blood levels really effective?].

Theophylline is widely used by patients with asthma and chronic obstructive pulmonary disease as a bronchodilator. The therapeutic range is relatively narrow: 10-20 mcg/ml. In a survey of 344 blood samples from 290 patients over a period of 12 months, 60% had levels lower than 10 mcg/ml, and only 28% were within the therapeutic range. This was especially the case among those using oral preparations. Our data raise several questions concerning the individualization of theophylline dosage, the effectiveness of its routine blood monitoring, and the implications of these results for ambulatory patients who are possibly being under treated.

Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Combined chemical and conventional injuries--pathophysiological, diagnostic and therapeutic aspects.

Chemical warfare (CW) agents may cause both conventional and chemical injuries. The effects of the two types of injuries may be reciprocal, leading to difficulties in assessing and treating such patients. Several aspects of the combined injury are discussed: increased exposure to CW agents following conventional trauma, owing to skin laceration or inability to use a gas mask (head, face or chest trauma); pathophysiological interactions between the two types of injuries; protection of medical personnel against CW intoxication; treatment limitations of personnel caused by their CW protection gear, when treating patients requiring urgent decontamination; and the influence of conventional trauma on the management of CW casualties. The Israel Defense Forces' recommendations for the treatment of combined injuries in a contaminated area include: a) airway maintenance, b) securing breathing and ventilation, c) circulation and hemorrhage control, d) antidote administration, e) decontamination with fuller's earth, f) dressing the wound, and g) evacuation to a noncontaminated area.

The effects of continuous operation in a chemical protective ensemble on the performance of medical tasks in trauma management.

Treating casualties in a chemically hazardous environment constitutes a unique problem. Physical protection of the medical personnel may impair their performance and potentially affect patients' prognoses. The present study examined the effect of prolonged physical protection on the accomplishment of medical tasks related to trauma management. Sixty one emergency medical technicians, acclimatized to operating in protective gear, underwent four rounds of testing during eight hours of continuously wearing either a chemical protective suit or regular fatigues. The quality of the designated medical tasks, including sterility, was maintained throughout the study. A significant reduction in speed of performance was noted (approximately 30% slowing, p < 0.0001 in multivariate analysis) because of protective clothing. There was no additional decrement in performance following a prolonged stay in the protective gear. We conclude that in a chemically contaminated area, fully protected medical personnel are capable of treating trauma patients reasonably well, and for a relatively long period of time. The importance of pretraining and proper instruction is emphasized.