Israeli A. Jaffe

Adverse effects profile of sulfhydryl compounds in man

Many of the adverse reactions produced by penicillamine and other compounds with an active sulfhydryl group form a distinctive pattern when viewed as a class. Alterations in taste perception, mucocutaneous lesions, proteinuria due to immune-complex membranous glomerulopathy, and pemphigus are adverse reactions that have been encountered with all of the compounds discussed herein. Hematologic reactions such as neutropenia and thrombocytopenia occur rarely and with variable frequency. The angiotension converting enzyme inhibitor captopril has an active sulfhydryl group. When it was first given in high doses to patients with severe hypertension, adverse effects similar in pattern to those just outlined were reported. With reduced doses and more careful patient selection, the more serious reactions are no longer found, but disturbances of taste perception, rash, and oral mucosal ulcers are still encountered.

GONADAL FUNCTION AND THE DEVELOPMENT OF CORONARY HEART DISEASE.

THERE IS an almost universal clinical impression that coronary heart disease and myocardial infaretion are more common in men than in women, particularly in the younger age groups. The over-all male-female ratios are commonly given as between 3 to 1 and 5 to 1, while in the under 40 age group, ratios between 15 to 1 and 30 to 1 have been reported. lA considerable body of evidence derived from animal and human studies suggests that estrogenic hormones may play a major role in retarding the development of coronary heart disease in young females.6 This concept has been greatly reinforced by the observations that serum lipid patterns and levels of serum cholesterol may be altered by the administration of estrogens.7-9 If functioning ovaries provide protection against coronary heart disease, a group of noneastrated women would be expected to develop less coronary heart disease than a castrated group. To test this hypothesis, the prevalerice of coronary heart disease was determnined for a group of bilaterally oophoreetomized women, representing castrates, and a group of hysterectomized women, representing noneastrates. Methods The primary comparisons made in this study are between a group of bilaterally oophorectomized women who had had surgical removal of both ovaries with or without hysterectomy and a group of hysterectomized women. In a later phase of the investigation a group of women with no history of major gynecologic surgery were also studied. These were sisters of women in the two primary groups.

Penicillamine-associated pemphigus: is it really pemphigus?

Penicillamine-associated bullous eruptions share with spontaneously occurring pemphigus intraepidermal acantholysis, epidermal intercellular deposition of immunoglobulin, and circulating serum antibody against the intercellular regions of the epidermis. We report the case of a penicillamine-associated bullous eruption in which there were some of the histologic features of pemphigus, but none of the immunofluorescent features. Instead, the immunofluorescent findings of bullous pemphigoid were demonstrated. Review of the literature reveals that clinical and histologic features of penicillamine-associated bullous eruptions differ in important respects from those of spontaneously occurring pemphigus. Our report adds immunologic data to evidence that the penicillamine-associated bullous eruptions may not be the same disease as spontaneously occurring pemphigus.

Penicillamine‐induced myasthenia gravis: Effects of penicillamine on acetylcholine receptor

Autoimmune diseases, including myasthenia gravis, occur in patients treated with D-penicillamine. Because D-penicillamine might induce autoantibodies by the mechanism of antigenic alteration, we studied the reaction of D-penicillamine with purified acetylcholine receptor from Torpedo californica. We found that brief exposure to D-penicillamine resulted in its covalent attachment to two receptor subunits, alpha (40,000 daltons) and gamma (59,000 Daltons), presumably by reduction and formation of mixed disulfides. Furthermore, D-penicillamine treatment resulted in a dramatic modification of the equilibrium acetylcholine binding properties of both purified receptor and receptor-rich membrane fragments.

Triethylene melamine in clinical cancer chemotherapy

F OLLOWING the introduction of nitrogen mustard (HN2) as a chemotherapeutic agent for the management of disseminated malignant lymphomas and inoperable bronchogenie carcinoma in 1943, hundreds of closely related compounds have been synthesized and studied experimentally. Although a small number of these demonstrated certain advantages over HN2 in the laboratory, clinical evaluation failed to justify their substitution for the commonly employed nitrogen mustard. Recently. however, a related chemical compound has been examined both in the laboratory and in clinical therapy which offers significant advantages over HN2 in selected cases. This drug, triethylene melamine, is effective after oral administration and the incidence of immediate toxic manifestations is appreciably less than with the intravenous nitrogen mustard. perience of this clinic in forty-four cases treated during the past two years. At the outset it can be stated that the drug does not cure any malignant disease. Emphasis will be placed on the indications, limitations, dosage and toxicity. The experimental observations which provided the basis for clinical trial have been reported by Rose’ and Philips, 2 and detailed discussion of the drug in cancer chemotherapy has been presented by Karnofsky et a1.3 and Wright et al.”

Protein‐Bound Homocyst(e)ine in Patients With Rheumatoid Arthritis Undergoing D‐Penicillamine Treatment

Protein‐bound homocyst(e)ine was measured in the plasma of 38 nonhomocystinuric patients with rheumatoid arthritis. Nineteen of them were treated orally with d‐penicillamine 100‐1,500 mg/d for a period of one month to 15 years. For these patients, the mean ± standard deviation level of plasma protein‐bound homocyst(e)ine was 1.95 ± 1.07 nmol/mL. In contrast, the mean plasma level of protein‐bound homocyst(e)ine was 4.72 ± 1.11 nmol/mL in the 19 patients who had not been treated with oral d‐penicillamine. There was a statistically significant difference (P < .0001) in the plasma protein‐bound homocyst(e)ine concentrations between patients with and without oral d‐penicillamine therapy. Thus, it may be speculated that oral d‐penicillamine may be beneficial in protecting patients from the development of thromboembolism and arteriosclerosis.

Penicillamine in Rheumatoid Arthritis: Clinical Pharmacology and Biochemical Properties

The current status of the clinical pharmacology of penicillamine was reviewed. Its indications in the therapy of RA were defined, and current principles of dosage were presented. The autoimmune side effects were discussed in the light of their possible implication with regard to a locus of action of the drug on the immunological system. A comparison was presented of the biochemical properties of penicillamine and 5-thiopyridoxine, another mercaptan compound which appears to demonstrate a penicillamine-like action in patients with RA. It was found that 5-thiopyridoxine did not possess copper chelating properties, it failed to form a mixed disulfide with cystine, it did not induce dermolathyrism in the weanling rat, and it was not a vitamin B6 antagonist. If both of these compounds do work by a common mechanism in RA, then the aforementioned biochemical properties of penicillamine must be presumed to be not relevant to its fundamental action in this disease.