Effect of caerulein in patients with biliary colic pain.

A randomized placebo-controlled double-blind trial was carried out in 24 patients with biliary colic pain in order to evaluate the analgesic effect of caerulein (CRL). Caerulein (1 ng/kg . min infused intravenously over 15 min) showed an analgesic effect that was significantly higher than placebo (p less than 0.001). The analgesic action of CRL was not inhibited by naloxone (0.4 mg intravenously, administered two times). Further, the effect of i.v. CRL or saline on artificially induced biliary tree hypertension was studied in 7 patients with a T-tube common bile duct drainage. During saline intravenous administration, increasing biliary tree pressure resulted in pain in 5 patients, with the threshold for pain being 40 cmH2O. During CRL intravenous infusion, significantly higher perfusion pressures were required to achieve a given common bile duct pressure and the pressure threshold for pain was not reached. Consequently, pain was prevented in all patients. These data suggest that CRL relieves biliary colic pain by reducing biliary tract pressure.

Ceruletide increases dose dependently both jejunal motor activity and threshold and tolerance to experimentally induced pain in healthy man.

The effects of ceruletide on jejunal motility and experimentally induced pain were studied in 16 healthy men, who participated each in four experiments and received in random double blind fashion 5, 10, or 20 micrograms ceruletide intramuscularly or placebo. Jejunal pressures were recorded by three perfused catheters with orifices between 10 and 20 cm aboral of the ligament of Treitz. Ceruletide dose dependently diminished phase I and increased phase II type activity and tended to reduce the number, but not the duration, of activity fronts. The number and amplitude of contractions as well as the area under the curve increased significantly and dose dependently as did threshold and tolerance to electrically and threshold to thermally induced pain. Only mild sedative and other side effects occurred.

Metergoline in the management of hyperprolactinemic amenorrhea and anovulation.

84 patients with elevated serum PRL levels, ranging from 25 to 253 ng/ml, were treated with an antiserotonin agent, metergoline, at the dose of 12 mg/day for 90 days. The clinical complaint was of amenorrhea in 70 cases (plus galactorrhea in 44 cases) and of anovulation in 14 cases (plus galactorrhea in 6 cases). Hyperprolactinemia was due to a pituitary adenoma in 18 cases; in 53 cases it was of unknown origin, while in 7 cases it followed treatment with neuroleptics or with oral contraceptives and in 6 cases it followed a puerperium. In patients with amenorrhea, metergoline induced the appearance of menses in 61 cases (94%), and of ovulation in 46 cases (82%). In 13 of the 14 patients with anovulation, ovulation was restored. Galactorrhea disappeared in 40 out of 50 patients. Metergoline normalized serum PRL levels (less than 20 ng/ml) in 46 cases and significantly reduced serum PRL levels in all but 3 of the remaining patients. In spite of suggested nonhormonal contraceptive measures, 14 patients became pregnant; 2 had abortions and the remaining 12 patients completed by vaginal delivery, uneventful pregnancies. These results indicate metergoline as a safe and effective drug in the management of hyperprolactinemic amenorrhea and anovulation. 49 patients were followed for 2 additional months, receiving no treatment (24 cases) or metergoline at a reduced daily dosage (8 mg/day, 25 cases). Within 60 days, 60% of the first group had relapse of the clinical condition and a rebound elevation of serum PRL levels while only 20% of the second group experienced relapse of amenorrhea and rebound elevation of serum PRL levels (p less than 0.01).

Selective mitochondrial alterations induced by a single dose of daunorubicin or 4-demethoxydaunorubicin in mouse ventricular myocardium.

The ventricular myocardium of CD1 mice given a single high dose (LD50) of daunorubicin (DNR) or its derivative, 4-demethoxydaunorubicin (4DD), was studied under the electron microscope. Severe degenerative alterations were observed, but only in the mitochondria in myocardial tissue samples taken 3 and 7 days after treatment. This suggests that mitochondrial lesions might play an important role in the pathogenesis of anthracycline myocardipathy. Furthermore, the nucleolar segregation phenomenon, already described in experimental doxorubicin myocardiopathy, was not observed in the myocardial samples taken 1 and 3 h after DNR or 4DD injection: this fact may be interpreted, without excluding a possible DNA-mediated toxic mechanism, as the result of different kinetic behaviour of DNR and 4DD compared to doxorubicin.

Cardiac toxicity from antitumor therapy.

A review is made concerning cardiac toxicity from antitumor agents. The pattern, clinical course and fate of cardiac drug-related phenomena are considered. Special attention is drawn to new attempts to better understand, and possibly prevent, such a treatment limiting side-effect.

Adriamycin cardiotoxicity: a survey of 1273 patients.

Valuable information was collected on the medical history and clinical course of 1273 patients entered in clinical trials with Adriamycin (ADR) carried out in 12 European cancer centers. A coded patient form was used for the data collection carried out in each center by a qualified physician following a guideline which was discussed and accepted by all of the participants. The aim of the study was to define the incidence, characteristics, and possible co-factors of the cardiomyopathy (CMP) in patients treated with combination chemotherapy regimens including ADR. The mean total dose of ADR was 268 mg/m2 (range, 15--1251 mg/m2), and 5.1% of the patients received a total dose of greater than 550 mg/m2. A "definite" ADR-related CMP was observed in 1.7% of the cases; another 3% of the cases were reported as "possible" ADR-CMP since the role played by the drug could not be clearly defined. "Definite" ADR-CMP was fatal in eight patients (0.6%) while "possible" ADR-CMP was fatal in 13 patients (1.0%). Among the possible co-factors examined, the following ones were found to be significantly associated with the occurrence of a "definite" ADR-CMP: (a) total dose of ADR; (b) vincristine when given both before and concomitantly with ADR; (c) bleomycin when given before ADR; and (d) radiotherapy to the mediastinum when given concomitantly with ADR. Furthermore, none of 182 patients receiving ADR by slow infusion developed a "definite" ADR-CMP, while 2% of the patients treated by bolus injection did so. The occurrence of a "possible" ADR-CMP was found to be significantly associated with two pre-existing pathologic conditions (electrocardiogram [ECG] abnormalities and hypertension) but not with the treatment-related co-factors for the "definite" ADR-CMP mentioned above. Other variables examined, such as sex, age, cancer type, baseline liver function, and cyclophosphamide treatment, did not seem to influence the risk of ADR-CMP. Data on ECG changes occurring during ADR treatment were also reported and their incidence was found to be strictly related to the frequency of the ECG monitoring.

[Nicergoline and platelet aggregation. A review of experimental and clinical studies (author's transl)]. / Nicergolin und Thrombozytenaggregation. Ein Uberblick über experimentelle und klinische Studien.

10-Methoxy-1,6-dimethyl-ergoline-8 beta-methanol-(5-bromonicotinate) (nicergoline, Sermion), an ergoline derivative in clinical use for syndromes related to cerebral and peripheral vascular insufficiency, displays a platelet antiaggregating effect which may be important for its therapeutic effect. This paper reviews the present experimental and clinical evidence relating to the platelet antiaggregating activity of nicergoline and its mechanisms of action is discussed in detail. Since the platelet antiaggregating effect of nicergoline is mainly related to its alpha-adrenolytic activity, the importance of catecholamines for the behaviour of both human platelets and endothelium as well as their interference with the prostaglandin/prostacycline system is also discussed.

Ultrastructural alterations of atrial myocardium induced by adriamycin in chronically treated animals.

The clinical use of adriamycin (AM) is limited by a possible dose-dependent myocardiopathy. Severe lesions of ventricular myocardium widely described by electron microscopy have been correlated to irreversible congestive heart failure. On the other hand, the atrial contractile elements which differ from the ventricular ones because of the presence of the so-called specific granules have rarely been considered. In the work described in this paper, adriamycin was injected into rabbits and mice according to schedules of chronic toxicity. At the end of the treatment the atrial myocells presented diffuse ultrastructural lesions of mitochondria, sarcoplasmic reticulum and myofibrillar bundles. These alterations might be caused by the ribonucleoprotein synthesis inhibition, by a direct drug toxicity or by an energetic crisis due to early mitochondrial lesions. Besides, adriamycin produces a decrease of the specific atrial granules that play a hypothetic role in the metabolism of myocardial cells. However, lack of information about the contents and the exact function of atrial granules does not allow us to conclude that their decrease in treated animals has a pathogenetic significance in myocardiopathy induced by adriamycin.

Platelet aggregometry and anti-platelet isoantibodies.

102 sera from polytransfused patients have been screened in platelet aggregometry. Anti-human platelet isoantibodies, tested against 'responsive' human platelets in PRP, give in the aggregometer a decrease in optical density recorded as a sigmoidal curve. In the first step of reaction PF3 availability suggests that the primary action of antibody is to damage the platelet membrane. The second step might be a true aggregation (an ADP-mediated platelet clumping) or a platelet lysis, depending on the type and the potency of antibody, on the type of platelets (normal or thrombasthenic) and on some experimental conditions. These conclusions, confirmed by electron microscopy findings, suggest that aggregometry is a very rapid and simple method of detecting platelet antibodies.

Human platelet aggregation by mixed cryoglobulins.

Glomerulonephritis in idiopatic mixed cryoglobulinemia represents perhaps a glomerular damage by immune complexes. In this study, a sigmoidal-like curve was obtained after addition of 13 different mixed cryoglobulins to both autologous and isologous platelet-rich plasma, tested in platelet aggregometer. The lag phase of the curve corresponds to platelet phagocytosis of cryoglobulin-binding ferritin, as shown in electron microscopy and the optical density decrease phase corresponds to the aggregation of platelets that shows the same ultrastructural characteristics of ADP-induced platelet aggregation. This platelet aggregation is inhibited by different drugs. Intraglomerular platelet aggregation by cryoglobulins might play a key role in determining the glomerular damage in cryoglobulinemia by the release of nucleotides and vasoactive amines.

Anti-heparin activity of a macroglobulin from a patient with breast adenocarcinoma.

We describe a case of IgM paraproteinemia, whose macroblogulin reacted anomalously with heparin. Anti-heparin activity of the paraprotein was suggested by insensibility of the patient's plasma to heparin in heparin-thrombin clotting time. Moreover, the presence of heparin in the medium markedly reduced the inhibitory effect of the paraprotein on platelet aggregation by ADP.