Direct measurement of human plasma corticotropin-releasing hormone by "two-site" immunoradiometric assay

A "two-site" immunoradiometric assay (IRMA) which allows the direct estimation of human CRH (hCRH) in plasma is described. Using this IRMA, basal levels of CRH in normal subjects ranged from 2-28 pg/mL [mean, 15 +/- 7 (+/- SD) pg/mL; n = 58]. Values in men and women were similar. Plasma CRH values within this range were also found in patients with Cushing's syndrome, Addison's disease, and Nelson's syndrome, with no correlation between plasma CRH and ACTH levels in these patients. Elevated plasma CRH levels were found in pregnant women near term [1462 +/- 752 (+/- SD) pg/mL; n = 55], and the dilution curve of this CRH-like immunoreactivity paralleled the IRMA standard curve. After its immunoadsorption from maternal plasma, this CRH-like material eluted on reverse phase high performance liquid chromatography with a retention time identical to that of synthetic CRH and had equipotent bioactivity with the synthetic peptide in the perfused anterior pituitary cell bioassay. Circulating CRH was not detected in Wistar rats, even after adrenalectomy and subsequent ether stress. Synthetic hCRH was degraded by fresh human plasma relatively slowly; 65% of added CRH remained after 1 h of incubation at 37 C. Degradation was inhibited by heat treatment (54 C; 1 h), cold treatment (4 C; 4 h), or freezing and thawing. Loss of synthetic rat CRH occurred more rapidly when fresh rat plasma was used; only 20% of added CRH remained under the same conditions. The inability to measure CRH in peripheral rat plasma may be due to the presence of active CRH-degrading enzymes which fragment the CRH molecule into forms not recognized by the CRH IRMA.     

Cardiac dysrhythmias in the acute setting: pathophysiology or anyone can understand cardiac dysrhythmias

Cardiac dysrhythmias are easy. Unlike the lung (which has formidable neuroendocrine, metabolic, and respiratory responsibilities), the heart is simple. It is an innervated muscular pump. A resting Purkinje or ventricular muscle cell membrane maintains a charge of about 90 millivolts. The five phases of a cardiac action potential are similar to the action potential in skeletal muscle, however, the cardiac action potential lasts a hundred times longer. When sodium specific "fast" channels and calcium specific "slow" channels open, positive ions rush into the myocardial cell, thus causing rapid membrane depolarization. In order to produce an action potential, some stimulus must decrease the membrane potential from -90 millivolts to "threshold" or -60 millivolts. Purkinje fibers do not have a stable phase for diastolic potential. These fibers continuously depolarize during diastole. Hypoxemia or hypokalemia may exacerbate this diastolic depolarization, thus promoting "hyperexcitability" or "automatic" ectopy. When myocardium is damaged, characteristically with myocardial ischemia, rapid conduction of cardiac impulses may be slowed dramatically. Very slow impulses may course through muscle such that by the time the activation wave front returns to the initiating site, this origin has had a chance to repolarize. This is the basis for re-entrant dysrhythmias. All cardiac dysrhythmias are automatic, re-entrant or both.     

Phytotoxins from the pathogenic fungi Drechslera maydis and Drechslera sorghicola

Drechslera maydis, the causal agent of Southern corn leaf blight, and Drechslera sorghicola, the causal agent of leaf spot on Johnson grass, produce a series of phytotoxic sesterterpenoids. These sesterterpenoids belong to the ophiobolin family. One of them, ophiobolin I, was characterized by x-ray diffraction and served as a crucial reference compound for characterizing four other ophiobolins. All of the ophiobolins studied produce characteristic lesions on host plants at concentrations of 1 mM to 1 μM. The ophiobolin characterized as 6-epiophiobolin A is selectively toxic to corn bearing Texas-male-sterile (Tms) cytoplasm when assayed in a dark CO₂ fixation assay. It is plausible that these ophiobolins had a role in the 1970 corn-blight epidemic in North America.     

A double-blind study on the effect of discontinuation of gold therapy in patients with rheumatoid arthritis

Summary To assess the benefit of further gold treatment of rheumatoid arthritis (RA) patients who had already received more than 6 g of this metal, 24 such patients were included in a double-blind trial. Besides this gold group comprising 11 patients who received gold (Auromyose^®) in the same dosage schedule as before the study, the trial included a placebo group comprising 13 patients who received gold in a suspension diluted 1/100. In either group clinical, laboratory, and radiological data did not differ after 6 and 24 months in relation to the results at entry except for the serum gold concentrations, which were lower in the placebo group. We conclude that discontinuation of the treatment in RA patients who have received more than 6 g gold is not harmful to the patients for at least two years after withdrawal.     

Man-in-the-barrel syndrome

In a prospective study of 34 comatose patients who had an episode of systemic hypotension, 11 had the "man-in-the-barrel" syndrome (MIB). They moved both legs spontaneously or in response to pain, but did not move either arm. One of 11 patients (9%) with MIB survived to leave the hospital; 8 of the 23 patients (35%) without MIB recovered. Of patients who moved at least one limb to pain and had intact pupillary, corneal, and oculocephalic reflexes 24 hours after insult, one of nine (11%) patients with MIB survived, compared with six of nine patients (67%) without MIB. MIB is common after cerebral hypoperfusion and carries a poor prognosis.     

The definition of posttraumatic stress disorder in alcoholic Vietnam veterans. Are the DSM-III criteria necessary and sufficient?

The authors evaluated the validities of the DSM-III elements defining posttraumatic stress disorder (PTSD) in alcoholic Vietnam veterans by studying the relationships of each to qualification for a PTSD diagnosis under DSM-III standards, the history of a major stressor (3 or more months of combat), and the presence/absence of enough other problems to meet the symptomatic DSM-III requirements for this diagnosis. Elements dealing with the reexperiencing of traumas, diminished pleasure, detachment from others, hyperalertness, sleep disturbance, guilt over behaviors required for survival, and avoidance of stimuli reminiscent of traumas showed substantial correlations with eligibility for a PTSD diagnosis. However, items dealing with emotional expressiveness, response to intimacy, survival guilt, impaired memory, and trouble concentrating either failed to correlate with qualification for a PTSD diagnosis or yielded marginal results. One ("lacking direction") of 10 additional symptoms sometimes termed as "post-Vietnam syndrome" behaviors correlated with eligibility for a PTSD diagnosis as well. The present results and those described in earlier studies suggest that several modifications in the DSM-III definition of PTSD are desirable.     

A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man

Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:

• 1 Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic?
• 2 Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc.
• 3 Comparison of the formulations.

Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min^?1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.     

Ab initio and PCILO investigations of local anaesthetic-model membrane interactions

A "double zeta" basis set ab initio method was used for investigation of the systems (trimethylamine-dimethylphosphate monoanion)H+, aniline-dimethylphosphate monoanion and formanilide-dimethylphosphate monoanion, which represent the models for associative sites of both local anaesthetics and the phospholipid part of the nerve membrane. According to the authors' calculations, complex I was found to be the most stable with a N+-H...O-hydrogen bond. Further, the PCILO method was used for investigation of the interactions of the polar groups of 1-[2-(2-methoxyphenylcarbamoyloxy)ethyl] piperidine (B) and its cation (BH) with N-methylacetamide, which represents a model of association sites of the lipoprotein part of membrane. The strongest hydrogen bond with the carbonyl group of N-methylacetamide forms a N+-H group of cationic form.