Biomedical subjects
Publications and source records attributed to T Davila.
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The present experiments were designed to investigate the effect of methylprednisolone and dexamethasone on tritiated metaraminol uptake in the whole animal. Rats received i.p. injections of methylprednisolone (5, 10 and 20 mg kg-1) or dexamethasone (1, 2 and 4 mg kg-1) on each of 3 consecutive days. Under light ether anaesthesia 5 min before death the rats received radioactive metaraminol (3 microgram kg-1) via the femoral vein. Samples of various organs were removed and prepared for scintillation counting. The highest radioactivity was observed in the lungs and heart, followed by the kidney medulla, aorta, kidney cortex and submaxillary gland. Both steroids significantly inhibited uptake of metaraminol in the tissues examined. Dexamethasone seems to be more potent that methylprednisolone. It is concluded that these steroids may modify the uptake mechanism responsible for inactivation of the sympathomimetic neurotransmitter.
The interaction between thiazide diuretics and contractile responses produced by 5-hydroxytryptamine, acetylcholine, noradrenaline and angiotensin II, has been examined on isolated rat uterus and guinea pig aorta. Hydrochlorothiazide, polythiazide and cyclopenthiazide inhibited the contraction of isolated tissue induced by the spasmogens. These data demonstrated that the tested diuretics possess antagonistic activity on contractions induced by various spasmogens.
Urinary prostaglandin E2 (PGE2) and PGF2 excretion was previously found to be inversely related to sodium intake in the rabbit. Renal prostaglandin (PG) synthesis might therefore be involved in the renal handling of sodium. This possibility was tested by studying sodium excretion during inhibition of renal PG synthesis with four different nonsteroidal anti-inflammatory drugs in unanaesthetized, female rabbits. The rabbits n = 5-6) were kept in metabolic cages and chronically maintained on different sodium containing diets. On a medium salt diet (0.4% NaCl), neither treatment with indomethacin (1.5 mg/kg x 2 or 3 mg/kg x 2) nor diclofenac (1.5 mg/kg x 2) for three days changed the urinary excretion of sodium and water although the mean excretion of immunoreactive PGE2 (iPGE2) and iPGF2 were reduced by between 43-78%. On a very low salt diet (0.05% NaCl), two days treatment with aspirin (30 mg/kg x 2), diclofenac (3 mg/kg x 2), indomethacin (3.5 mg/kg x 2) or naproxen (10 mg/kg x 2) did not alter sodium excretion in any significant direction. The mean urinary PGE2 and PGF2 excretion was reduced by 35-63% and 63-85%, respectively. These results do not support a major role of PGs in the chronic regulation of sodium balance in the rabbit. The possible influence of mineralocorticoids on renal PG synthesis was studied by administration of aldosterone (100 microgram/kg x 2) for two days to rabbits on a high salt diet (2% NaCl) and cancrenoate (10 mg/kg x 2), an aldosterone antagonist, to rabbits on the very low salt diet. However, neither drug significantly changed the urinary excretion of PGF2 alpha, indicating that renal PG synthesis is not influenced by mineralocorticoids in the rabbit.
The influence of dietary sodium chloride on the urinary excretion of prostaglandins (PGs) was studied in unanesthetized female rabbits housed in metabolic cages. Urinary PG levels were determined by radioimmunoassay, bioassay and gas chromatography-mass spectrometry. In the first experiment rabbits were fed at high (2.5%) and later a low (0.25%) sodium chloride diet ad libitum. A 2--5 fold increase in excretion of immunoreactive PGF2alpha (iPGF2alpha) and iPGE2 was noticed when animals were given the low salt diet. Since it could not be excluded that dietary factors other than sodium chloride contributed to the changes a second, more controlled experiment was undertaken. Rabbits were fed 30 g/kg per day of diets offering only in the content of sodium chloride, 2% and 0.37% respectively. On the high salt diet the rabbits excreted 0.1 +/- 0.04 microgram/day of PGE2 and 2.0 +/- 0.5 microgram/day of iPGF2alpha. After equilibration on the low salt diet the PGE2 excretion rate increased to 1.5 +/- 0.3 microgram/day (p less than 0.001) and that of iPGF2alpha to 3.4 +/- 0.4 microgram/day (p less than 0.01). These results thus point to an inverse relationship between renal sodium excretion and the activity of the renal prostaglandin system.
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Uptake of 14C-labelled 5-hydroxytryptamine (14C-5-HT) has been investigated by perfusion of the rat brain ventricular system. When angiotensin II was present during perfusion, a dose-dependent inhibition of 14C-5-HT uptake in rat brain was observed. A similar effect was obtained with angiotensin II analogs (8-alanine angiotensin II or 1-dimethylglycine, 8-isoleucine angiotensin II). The inhibitory effect of angiotensin II can be almost completely blocked with 1-dimethylglycine, 8-isoleucine angiotensin II. In washout experiments, the radioactivity remaining in the brain was greater in the presence of angiotensin II.
The accumulation of 3H-metaraminol in incubated lung tissue of the rat was examined in vitro. Lung tissue concentrated tritium after incubation with 3H-metaraminol. This uptake proceeds against a concentration gradient and shows saturation kinetics (Km 12.5 X 10(-7) M and Vmax 2.105 nM/g/15 min.) with great affinity for 3H-metaraminol. The accumulation of 3H-metaraminol is dependent of temperature and energy supply, and requires the presence of sodium ions. The loss of accumulated radioactivity showed the possibility that a small fraction of metaraminol is apparently firmly boune (e.g. neuronal sites), while a greater portion is taken up by extraneuronal structures (e.g. capillary endothelial cells). The first localization could represent uptake-1 and the second uptake-2. The results obtained also confirm the important role of the lungs as an organ which participates in the fate of endogenous substances and drugs.
Uptake and release of 3H-metaraminol was measured in vitro incubating rat lung tissue in the presence of ouabain (1.5-45 mug/ml), cocaine (1-30 mug/ml), tyramine (0.1-3 mug/ml, reserpine (0.05-1.5 mug/ml), imipramine (0.1-3 mug/ml) and desipramine (0.3-10 mug/ml. All drugs significantly inhibited uptake and release of 3H-metaraminol from lung tissue. This blockade most probably occurs at membrane levels of both neuronal uptake-1 sites and extraneuronal uptake-2 sites. These results further emphasize the importance of the lung in the fate of drugs and endogenous substances.
A potential novel therapy for prostate cancer is the induction of immune responses to normal prostate-associated antigens (PAA). One approach is to use synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hurdle when using normal PAA for this type of therapy is the tolerance that the immune system may already have for PAA. To evaluate mechanisms for overcoming tolerance, the authors assessed the level of tolerance to SV40T antigen in a transgenic mouse. The SV40T antigen is selectively expressed in the prostates of mice from the transgenic adenocarcinoma mouse prostate (TRAMP) model. The authors have shown that TRAMP mice are tolerant to a dominant cytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with nontransgenic littermates. The tolerance was exhibited as early as 4 weeks and as late as 24 weeks. The use of multiple injections of an oligonucleotide that contains an unmethylated CpG induced high levels of hematopoiesis but did not overcome the tolerance. Injection of an antibody to activate CD40 increased the CTL response in normal mice but also did not overcome tolerance. However, tolerance in the TRAMP mice was avoided when an epitope that had previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to induce prostatitis and antitumor responses. The results of this work should facilitate the development of immune-based therapies for prostate cancer.
Following a short review of penetration of drugs through the skin (a bilayer membrane which consists of the stratum corneum and the viable epidermis), transdermal therapeutic systems (TTS) are described. These systems are special pharmaceutical preparations capable of delivery of some drugs (e.g. very potent drugs, with narrow therapeutic index, short biological half-life) via skin under well controlled conditions. After their application drug passes directly into the systemic circulation avoiding the effect of first-pass hepatic metabolism. At the same time, their advantages and disadvantages are presented. Finally, currently existing TTS in the market containing e.g. scopolamine (motion sickness), nitroglycerin (angina pectoris), estradiol (postmenopause), clonidine (hypertension) and systems in the development are briefly reported. These transdermal therapeutic systems are considered as a new approach to improve the usage of drugs in terms of better dosage control, increased safety and easier application.