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.

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.

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.

Reciprocal effects of chronic diazepam and melatonin on brain melatonin and benzodiazepine binding sites.

Recent reports indicate that benzodiazepines can suppress melatonin levels and that melatonin can increase brain benzodiazepine binding. We have studied the possibility of reciprocal effects of chronic diazepam and melatonin on brain melatonin and benzodiazepine binding sites. Daily injections (3 weeks) of diazepam markedly reduced 125I-melatonin binding site density in the medulla-pons but not cortex of male rats, whereas benzodiazepine binding was not significantly affected. Melatonin, administered via the drinking water, significantly enhanced benzodiazepine (3H-RO 15-1788) binding in the medulla-pons and slightly reduced it in the cortex, but did not affect 125I-melatonin binding. Diazepam and melatonin combination reversed the suppression by diazepam of 125I-melatonin binding in the medulla-pons and the suppression by melatonin of benzodiazepine (3H-RO 15-1788 and 3H-flunitrazepam) binding in the cerebral cortex. These results indicate benzodiazepine-mediated suppression of brain melatonin binding sites that can be abrogated by melatonin administration.

Reactogenicity and immunogenicity of a new recombinant hepatitis B vaccine containing Pre S antigens: a preliminary report.

A new vaccine against hepatitis B virus (HBV) infection, produced in mammalian Chinese hamster ovary (CHO) cells, contains the small(s), middle (Pre S2) and large (Pre S1) surface proteins of HBV. Three injections of a 5-micrograms or 10-micrograms dose were administered intramuscularly (i.m.) at 0, 1 and 6 months to a group of 105 young adults, who were monitored for a period of 6 months after the third injection. Seroconversion rates were 100% after the second injection of the 5-micrograms or 10-micrograms dose. Geometric mean titres of HBsAb at 1 month after the third injection were 12,156 mIU ml-1 and 13,482 mIU ml-1 in those receiving the 5-micrograms and 10-micrograms dose respectively. The vaccine was well tolerated with no significant adverse events. These preliminary results suggest that the Pre S-s recombinant vaccine, produced in mammalian cells, is highly immunogenic, leading to 100% seroconversion in the population tested after injection of only two doses of 5 micrograms.

[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.

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.

Postexercise syncope: evidence for increased activity of the sympathetic nervous system.

This report describes an association of postexertional syncope with increased levels of circulating catecholamines. A 36-year-old male who experienced postexercise bradycardia and asystole had higher basal plasma norepinephrine (120 versus 68 +/- 6 pg/ml) and epinephrine (18 versus less than 10 pg/ml) but a similar vagal tone (vagal tone index of 5.44 versus 5.81 +/- 1.00 U) when compared with 6 closely matched subjects who underwent an uneventful stress test.

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.

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.

Functional adaptation of rat remnant colon after proximal hemicolectomy.

Functional adaptation of the remnant intestine after extensive resection of small bowel is well documented. The effects of partial resection of large bowel on the remaining colon have not been characterized. Transepithelial potential (VT), tissue resistance (RT), and short-circuit current (Isc) were measured in vitro across distal colonic tissue of rats three weeks after proximal hemicolectomy with ileotransversotomy and compared to the same parameters measured in the distal colon of control animals. In a second series of experiments, an in vivo perfusion technique was used to measure changes in sodium, potassium, and water transport in distal colon following proximal hemicolectomy. A 2.5-fold increase in VT (P less than 0.01), a 62% increase in RT (P less than 0.001), and a 35% increase in Isc (P less than 0.05) were observed three weeks following hemicolectomy when compared to control animals. A 64% increase in net sodium absorption (P less than 0.025), no significant change in net potassium transport, and a 115% increase in net water absorption (P less than 0.01) were demonstrated in hemicolectomized animals when compared to control. It is concluded that in the rat the distal colon is capable of functional adaptation to increase net sodium and water absorption within three weeks after proximal hemicolectomy. The mechanism responsible for this adaptive process has yet to be defined. Our findings may explain the lack of chronic diarrhea in patients undergoing right hemicolectomy.

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.

Outline of hospital organization for a chemical warfare attack.

A plan for hospital organization in the event of chemical warfare is described. The basic principles are: a) isolation of the hospital receiving the casualties, b) several levels of triage, and c) treatment according to simple therapeutic protocols using appropriate treatment sites. Triage is based upon walking feasibility, respiratory status, age, and additional conventional injuries. The nurse's diagnostic and treatment authority is extended. Auxiliary staff (numbering hundreds of people) are needed for decontamination, stretcher bearing, artificial ventilation, etc. A nation-wide educational program on the prevention, decontamination and treatment of chemical warfare casualties is conducted in Israeli hospitals and drills are exercised frequently. This scheme is suitable for nerve gas poisoning, but can be easily modified for other chemical agents.