John R. Luderer

Plasma prostaglandins in hypercalcemic patients with neoplastic disease

Peripheral plasma prostaglandin E (PGE) determinations were performed on a series of 79 patients with solid tumor neoplasms and correlated with their serum calcium levels. Fourteen patients were hypercalcemic and 11 of these had significant elevations in circulating plasma PGE. Ten of the hypercalcemic group had extensive metastases to bone. These findings support the recently developed hypothesis that prostaglandins are causally related to the genesis of hypercalcemia in malignancy.

Familial essential thrombocythemia

Primary or essential thrombocythemia is rarely observed in childhood, and familial occurrence has been reported only once. In this study, essential thrombocythemia is documented in five members of both sexes from two to 62 years of age in three successive generations. The propositus had a persistent elevation of the platelet count, splenomegaly, a normal hemoglobin level, a normal white blood cell count, and abnormal platelet aggregation. Platelet arachidonic acid metabolites assayed by high-performance liquid chromatography and serum thrombopoietin levels were normal. Megakaryocytes were increased in number and size. Both mature and early immature megakaryocytes, but no atypical megakaryocytes, were identified by surface immunofluorescence. Bone marrow cultures showed normal myeloid and erythroid colony formation, and chromosome studies revealed a normal female karyotype. These findings support the concept that familial essential thrombocythemia is a myeloproliferative disorder that is transmitted by an autosomal dominant mode of inheritance, and that untreated young women and children with essential thrombocythemia have long survival.

THE RELEASE OF THROMBOXANE A2 AND PROSTACYCLIN FOLLOWING EXPERIMENTAL ACUTE PULMONARY EMBOLISM

The contributions of thromboxane A2 (TXA2) and prostacyclin (PGI2) to the effects of acute pulmonary embolism were evaluated in 18 open-chest rabbits. All rabbits received autologous whole-blood-clot embolus (.4 cc) by way of a catheter in the right ventricle. Pulmonary artery (PA) and left atrial (LA) pressures, and aortic flow (AOQ) were recorded. The stable metabolites of TXA2 (TXB2) and PGI2 (6-Keto PGF1) were assayed by radioimmunoassay at pre- and post-embolization periods (+5, +10, +20, +30, and +40 minutes). Significant elevations of pulmonary vascular resistance (PVR) (normalized), PA pressure, and reduction of AOQ were noted comparing pre-embolus to +5 minute time intervals. A negative correlation was reached between PGI2 and AOQ at +40 minutes (p less than .05). Five of the 13 rabbits died prematurely. At +5 minutes these 5 rabbits had higher PVR (p less than .001) and lower AOQ (p less than .01) than their living counterparts. At +10 minutes AOQ was still significantly lower (p less than .005) and TXB2 was higher (p less than .05) in the premature death group. We conclude that TXB2 is significantly but transiently elevated early following acute pulmonary embolism and may contribute to mortality. In contrast PGI2 does not appear to play an immediate role in the hemodynamic events following embolization but does rise to significant levels later in the course possibly in an attempt to compensate for reduced flow.

Captopril-Induced Skin Eruptions

Abstract: Seven of 23 hypertensive patients treated with captopril (SQ 14,225), an orally active converting enzyme inhibitor, developed a pruritic, erythematous, macular, and papular eruption of the trunk, face, and proximal extremities. The eruption appeared one to 31 weeks after initiation of captopril therapy and was associated with diarrhea (three patients), fever (two patients), and generalized arthralgias (one patient). Six patients had an increased percentage of band cells (5 to 34 per cent) on peripheral smear without an associated leukocytosis. In one patient, the skin rash was associated with a peripheral eosinophilia (20 per cent), Coombs‐positive hemolytic anemia, and acute renal failure with eosinophiluria. There were no changes in BUN, creatinine, or urinalyses in the remaining patients. Four patients showed a transient rise in plasma PGE without concomitant changes in plasma PFG2α or 6‐keto PGF1α, and three patients had slight elevations in the erythrocyte sedimentation rate. Skin biopsies revealed a perivascular and perifollicular lymphocytic and histiocytic infiltrate with negative immunofluorescence to IgG, IgM, IgA, and β1C. The skin eruption and associated symptoms resolved in all patients, even though captopril administration was continued in six of the seven patients.

Elevated Prostaglandin E in Idiopathic Intestinal Pseudo-Obstruction

The syndrome of idiopathic intestinal pseudoobstruction, described by Naish et al. in 1960,1 consists of repeated bouts of idiopathic intestinal pseudo-obstruction accompanied by diarrhea and at ti...

Dazoxiben, a thromboxane synthetase inhibitor, in Raynaud's phenomenon

Dazoxiben, a specific thromboxane synthetase inhibitor, was evaluated in 21 patients with Raynauds phenomenon in a double‐blind, placebo‐controlled crossover experiment. Total fingertip blood flows were measured by plethysmography and capillary blood flows were measured by 133Xe disappearance rate. Subjects were studied in both a warm (28°) and a cold (20°) room. Arteriovenous (AV) shunt flow was estimated by subtraction of capillary flow from total flow. Ex vivo production of thromboxane B2 (TXB2) and 6‐keto PGF1α was determined by specific radioimmunoassay in serum from venous blood incubated for 1 hr (37°). Plasma concentrations of TXB2 and 6‐keto PGF1α were also monitored. Dazoxiben (100 mg 4 times a day for 14 days) inhibited ex vivo TXB2 production (from 463.1 ± 69.9 to 101.8 ± 13.4 ng/ml/hr; (X̄ ± SE)), enhanced ex vivo 6‐keto PGF1α production (from 1.38 ± 0.05 to 3.76 ± 0.18 ng/ml/hr), reduced plasma TXB2 concentration (from 88.1 ± 13.9 to 38.8 ± 5.9 pg/ml). There were no changes in plasma concentration of 6‐keto PGF1α. Dazoxiben did not improve total digital blood flow, capillary flow, AV shunt flow, or forearm blood flow at 28° or 20°. There was no subjective improvement in frequency or severity of Raynauds attacks (assessed by patient diaries). It is concluded that dazoxiben is a potent and specific thromboxane synthetase inhibitor capable of altering arachidonic acid metabolism, but is of little or no benefit in the treatment of Raynauds phenomenon.

Effects of nadolol and propranolol on plasma lidocaine clearance

Nadolol and propranolol effects on lidocaine elimination were followed in six healthy men and women. Each received three separate 30‐hr infusions of lidocaine (2 mg/min): one alone, one after 3 days pretreatment with nadolol (160 mg daily), and one after 3 days pretreatment with propranolol (80 mg every 8 hr). Liver blood flow was determined by the systemic clearance of indocyanine green. Steady‐state plasma lidocaine levels were increased by nadolol (2.1 ± 0.2 to 2.7 ± 0.3 μg/ml) and by propranolol (2.1 ± 0.2 to 2.5 ± 0.3 μg/ml). Lidocaine plasma clearance was decreased by nadolol (1030 ± 81 to 850 ± 82 ml/min) and by propranolol (1030 ± 81 to 866 ± 75 ml/min). Hepatic blood flow was decreased by nadolol (1275 ± 77 to 902 ± 102 ml/min) and propranolol (1275 ± 77 to 957 ± 119 ml/min). The hepatic extraction ratio for lidocaine was increased by nadolol (0.86 ± 0.06 to 0.91 ± 0.05) and by propranolol (0.86 ± 0.06 to 0.90 ± 0.06). Lidocaine intrinsic clearance was not changed by nadolol (8.19 ± 1.87 to 9.52 ± 2.36 l/min) or propranolol (8.19 ± 1.87 to 9.50 ± 3.13 l/min). Our data indicate that both nadolol and propranolol reduce lidocaine clearance by their effects on hepatic blood flow and not by inhibition of lidocaine metabolism.

Converting enzyme inhibition with captopril in patients with primary hyperaldosteronism

The humoral and hemodynamic effects of converting enzyme inhibition with captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (±SEM) plasma renin activity (PRA) rose from 5.0 ± 1.4 to 35.3 ± 5.3 ng/ml/hr (P < 0.001) and mean (±SEM) plasma aldosterone (PA) declined from 25.8 ± 2.9 to 15.1 ± 1.9 ng/ml (P < 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone‐producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive.

Immunosuppression and human cancer: Role of prostaglandins

Prostaglandins, unsaturated fatty acid derivatives with diversified pharmacologic activity, have been implicated in the pathophysiology of many diseases. Prostaglandin E (PGE) levels were measured by radioimmunoassay in the plasma of 41 normocalcemic patients with various stages of malignancies. Delayed hypersensitivity was assessed by a battery of six recall skin test antigens (ST) and by Dinitrochlorobenzene (DNCB) sensitization and challenge. Twenty‐five patients with one or more positive skin tests had a mean PGE level of 87 ± 8 pg/ml, whereas 16 patients with negative ST had a mean PGE level of 96 ± 12 pg/ml. Twenty‐one DNCB negative patients had a mean PGE level of 98 ± 12 pg/ml and eight totally anergic patients had a mean PGE of 96 ± 12 pg/ml. All PGE values were within the normal range and there was no statistical difference between the four groups, (p < 0.1). We concluded that circulating PGE does not correlate with the non‐specific immunosuppression seen in cancer patients.

The Effect of Itazigrel and Aspirin on the Mucosa of the Esophagus, Stomach, and Duodenum of Normal Subjects

The effects of aspirin, itazigrel (U‐53,059; a new antiplatelet drug), and placebo on the mucosa of the esophagus, stomach, and duodenum were evaluated in this double‐blind, randomized, placebo‐controlled study. Six normal male subjects were included in each of five treatment groups: aspirin (325 mg each morning for five doses), aspirin (325 mg tid for 12 doses), itazigrel (25 mg each morning for five doses), itazigrel (50 mg tid for 12 doses), and placebo. Aspirin and itazigrel, at all doses investigated, significantly inhibited ex vivo, ionophore (A23187)‐stimulated thromboxane B2 synthesis. Collagen‐induced platelet aggregation was significantly inhibited on day 3 (P = .021) and day 5 (P = .002) in both aspirin and itazigrel groups as compared with placebo. Upper gastrointestinal endoscopy was performed before the first dose of drug (day 1) and two hours after the last dose (day 5) for each subject. A rating scale was used to score the amount of mucosal damage. The baseline (day 1) endoscopic scores revealed no significant differences between groups. On day 5, neither placebo nor itazigrel treatment groups showed any significant change compared with baseline. On day 5, both aspirin groups had significantly (P < .001) more mucosal damage than the placebo group and either itazigrel group. It is concluded that in this relatively acute study, at doses that produce comparable inhibition of platelet aggregation and platelet cyclo‐oxygenase, itazigrel was superior to aspirin in terms of toxicity to the upper gastrointestinal tract.