Effect of intravenous infusion of growth hormone-releasing hormone on the morphology of rat pituitary somatotrophs

The effect of GRH infusion on rat adenohypophysial morphology was studied by light microscopy, immunocytochemistry, in situ hybridization, and electron microscopy. Synthetic rat GRH was intravenously administered by osmotic minipumps at 14.4, 72, 360 and 720 μg/ day/rat for 1 week. In one group treated for 1 week with a daily dose of 720 μg GRH, the rats were killed 7 days after withdrawal of GRH. Control rats in which GRH was replaced by excipient, or those that received no treatment, were included as well. GRH infusion with daily doses of 360 and 720 μg resulted in a significant increase in pituitary weight and weaker GH immunoreactivity compared with other groups. Ultrastructurally, the somatotrophs were increased in size and became sparsely granulated, and the organelles involved in hormone sythesis were very prominent. The intensity of the GH mRNA signal did not differ from control animals, suggesting the desensitization of somatotrophs to GRH. The highest GRH dose induced an increased number of nuclei immunoreactive for proliferation cell nuclear antigen (PCNA). One week after GRH withdrawal, shrinkage of cytoplasm, involution of RER and Golgi complex, and a decrease of cell attachment sites indicated the reversibility of changes induced by GRH. In conclusion, GRH infusion induced, within days, hypertrophy and proliferation of somatotrophs with ultrastructural features of highly stimulated, sparsely granulated cells. Morphological changes were reversible.Endocr Pathol 4:131–139, 1993.     

Further characterization of the effects of imipramine on plateau membrane currents in guinea-pig ventricular myocytes

Summary The effects of imipramine, a tricyclic antidepressant, on action potential characteristics and plateau membrane currents were studied in isolated guineapig ventricular myocytes, using the whole cell configuration of the patch-clamp technique. Imipramine (1, 5 and 15 mol/l) decreased in a concentration-dependent manner the amplitude and shortened the duration of the action potential, but it had no effect on resting membrane potential. At all three concentrations tested, imipramine decreased the delayed outward potassium current, this effect being apparently voltage-independent since it did not modify the activation curve. Imipramine, 5 and 15 mol/l, also produced an inhibition of the peak high threshold calcium current, but did not change the shape of the current-voltage relationship or the apparent reversal potential of this current. Therefore, imipramine probably decreased the maximum available calcium conductance. However, the inward rectifying potassium current was not affected by any concentration of imipramine tested. Imipramine, 1 and 5 mol/l, shortened the duration of the action potentials elicited in the presence of the inorganic calcium channel blocker cobalt chloride, and at 5, but not at 1 mol/l, also shortened the action potentials obtained in the presence of the sodium channel blocker tetrodotoxin. Washout of imipramine completely reversed all its effects within 15 minutes. All these results suggest that imipramine at a concentration of 1 mol/l produced a shortening in action potential duration by inhibiting the late sodium current flowing during the plateau phase of the action potential. At concentrations of 5 and 15 mol/l the effect of imipramine on action potential duration can also be explained by a blocking effect on the high threshold calcium current. Send offprint requests to E. Delpón at the above address     

Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer

Summary Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m². In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant _1/2, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant _1/2, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant _1/2, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c ₂+62.5×c ₂₄+157.7 (r=0.953).This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd.     

Postural imbalance: An early sign in HIV-1 infected patients

Summary We have recorded postural performance in 50 HIV-infected patients in different stages of the disease (Walter Reed (WR) stages I–VI) by means of a force measuring platform. The results were compared with 50 age-matched controls. A significant instability was particularly evident when standing on an unstable foot support. In patients standing with eyes closed, postural sway was significantly higher in every patient group (WR I–II:P<0.02, WR III–V:P<0.001, WR VI:P<0.001). Patients in stage WR I–II showed no relevant neurological abnormalities. In agreement with other neurophysiological data in the literature we suggest that postural imbalance could be an early sign of central nervous system penetration of HIV. No correlation with electromyographic or cerebrospinal fluid findings could be found.     

Treatment of severe sepsis in bone marrow transplant recipients with teicoplanin in combination with β-lactams and aminoglycosides

Summary We evaluated teicoplanin for suspected gram-positive infections after inadequate response to initial empiric beta-lactam and aminoglycoside combination therapy. All 20 patients included in this study received either an allogeneic (8 patients) or an autologous (12 patients) bone marrow transplant for acute myeloid leucaemia (AML), non-Hodgkin's-lymphoma (NHL, high grade) or other malignant diseases. All patients developing primary septicaemia of unknown origin (18 patients) or catheter-related septicaemia (2 patients) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g i.v., t.i.d.; netilmicin 400 mg once daily). All patients responded to therapy, 19 patients were clinically cured and one patient improved under therapy. The therapeutic regimen was well tolerated; only one adverse drug reaction was observed. We did not observe any delayed take or prolonged neutropenia or thrombocytopenia with this therapeutic regimen when our patients were compared to other bone marrow transplant patients (who did not receive this antimicrobial therapy). Our results suggest that teicoplanin is a potentially effective and well tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.

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Teicoplanin in Kombination mit -Laktamen und Aminoglykosiden bei Knochenmarktransplantatempfängern mit schwerer Sepsis

Zusammenfassung Wir untersuchten Teicoplanin bei vermuteten grampositiven Infektionen nach ungenügendem Ansprechen auf die anfängliche Kombinationstherapie von -Laktam-Antibiotika und Aminoglykosiden. Alle 20 in dieser Studie erfaßten Patienten wurden entweder allogen (8 Patienten) oder autolog (12 Patienten) transplantiert mit folgenden Grundkrankheiten: akute myeloische Leukämie (AML), Non-Hodgkin-Lymphom (NHL) oder andere maligne Erkrankungen. Alle Patienten, die eine primäre Septikämie unbekannten Ursprungs entwickelten (18 Patienten) oder unter einer Katheter-bedingten Septikämie (2 Patienten) litten, wurden mit 400 mg Teicoplanin behandelt. Die Verabreichung von Teicoplanin erfolgte einmal täglich intravenös in Kombination mit einem Cephalosporin und einem Aminoglykosid (Ceftazidim 2 g i.v., 3 ×/die, Netilmicin 400 mg, 1 ×/die). Alle behandelten Patienten sprachen auf diese Therapie an. 19 Patienten wurden klinische geheilt, ein Patient besserte sich unter dieser Therapie. Die Kombinationstherapie wurde gut vertragen, unerwünschte Arzneimittelwirkungen traten während der Studie nicht auf. Wir beobachteten kein verzögertes Angehen des Knochenmarks oder eine Verlängerung der Thrombozytopenie unter dieser Behandlung im Vergleich zu anderen knochenmarktransplantierten Patienten, die diese antimikrobielle Behandlung nicht erhielten. Unsere Ergebnisse zeigen, daß Teicoplanin ein wirksames und gut verträgliches Antibiotikum für knochenmarktransplantierte Patienten ist, die primär nicht auf die Kombinationstherapie mit -Laktam-Antibiotika und Aminoglykosiden ansprechen.

     

Ethylcellulose: a new type of emulsion stabilizer.

Cellulose ethers, in particular hypromellose, represent an interesting alternative when emulsions have to be stabilized avoiding conventional low molecular weight surfactants. So far this option has been only described for the formulation of oil-in-water (o/w) emulsions. Since surfactant-free water-in-oil (w/o) emulsions seem to be also attractive as drug carriers, ethyl cellulose, an oil-soluble cellulose derivative, was studied for its ability to stabilize w/o emulsions. Measurements of the interfacial tension confirmed that ethylcellulose was positively adsorbed at the water/oil interface with diverse lipids. Appearance of model emulsions was dependent on the processing temperature. At low temperatures (15 degrees C) cream-like o/w emulsions were obtained. Processing at 30 degrees C yielded fluid w/o-lotions. Investigation of the microstructure showed that the surface of the emulsion droplets was covered with particles which formed a mechanical barrier. These colloidal particles were shown to be a precipitate of ethylcellulose which forms when the polymer which was dissolved in the lipid phase comes into contact with water. Thus, ethylcellulose was demonstrated to represent a new type of particulate polymeric emulsifier.     

H1-receptor blocker antihistamine, terfenadine durably influences the glucocorticoid receptor, and lymphocyte histamine content of weanling rats.

Hormonal imprinting takes place perinatally when a hormone and its maturing target receptor meet. As a consequence of imprinting the receptor accomplishes its maturation reaching the binding capacity characteristic to the adult age. In this critical period the presence of foreign molecules which are able to bind to the receptor can cause faulty imprinting with life-long consequences. In the recent years it was cleared that not only receptors are influenced by faulty imprinting, however, also the hormone production of the given cell. In addition imprinting was provoked at non-perinatal periods (adolescence and adult age) in cytogenic organs. In the present experiment the prolonged effect of a non-perinatal imprinting by an antihistamine to the histamine content of white blood cells and glucocorticoid receptors of liver and thymus was studied. Two weeks after 3-day terfenadine treatment at weaning, flow cytometry of peritoneal cells and blood lymphocytes for histamine, and receptor kinetic analysis of dexamethasone binding were done. Histamine content of blood lymphocytes and glucocorticoid receptor density of liver cells were significantly decreased. This means that a short treatment with a H(1)-receptor blocker antihistamine durably influences physiological indexes which were not known till now. This means that not only the acute effects, but the prolonged side-effects must be considered.     

Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus–Di?erences in Etiology, Epidemiology and Prevention

Incidence of esophageal carcinoma With more than 300 000 new cases per year, cancerof the esophagus, predominantly squamous cell carcinoma(SCC), is one of the 10 most frequently diagnosed tumortypes. Esophageal cancer occurs often in developing coun-tries and shows great regional di?erences[1]. While in re-cent history the incidence of SCC has decreased slightly inregions of high risk and stayed constant in the USA andWestern Europe, the rate of adenocarcinoma of the esoph-agus (AC) has…     

Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. PATIENTS AND METHODS: We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. RESULTS: Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. CONCLUSION: Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.     

A Systematic Overview of Radiation Therapy Effects in Brain Tumours

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for brain tumours is based on data from 9 randomized trials and 1 meta-analysis. Moreover, data from 2 prospective studies, 3 retrospective studies and 4 other articles were used. In total, 19 scientific articles are included, involving 4 266 patients. The results were compared with those of a similar overview from 1996 including 11 252 patients. The conclusions reached can be summarized as follows: The conclusion from SBU 129/2 that curative treatment is not available for patients with high-grade malignant glioma (grade III and IV) is still valid.The survival benefit from postoperative radiotherapy compared to supportive care only or chemotherapy is about 3-4 months, as demonstrated in earlier randomized studies.

Quality of life is now currently estimated and considered to be of major importance when reporting the outcome of treatment for patients with brain tumours.

There is no scientific evidence that radiotherapy using hyper- and hypofractionation leads to longer survival for patients with high-grade malignant glioma than conventional radiotherapy. There is large documentation, but only one randomized study.There is some documentation to support the view that patients with grade IV glioma and poor prognosis can be treated with hypofractionation and with an outcome similar to that after conventional fractionation. A shorter treatment time should be convenient for the patient.Documentation of the benefit of a radiotherapy boost with brachytherapy is limited and no conclusion can be drawn.There is no scientific evidence that radiotherapy prolongs life for patients with low-grade glioma.There are some data supporting that radiotherapy can be used to treat symptoms in patients with low-grade glioma. As no controlled studies have been reported, no firm conclusion can be drawn.