5th Day Of Treatment Research Articles

In vivo activation of lymphocytes in melanoma patients receiving escalating doses of recombinant interleukin 2.

A phase-I study of the recombinant, non-mutagenized interleukin 2 (rIL2, BioleukinTM) was performed in 12 melanoma patients (Pts). From 100 to 800 micrograms/m2 of rIL2 were administered by i.v. bolus injection, TID for 4-8 days. Side-effects included fever, malaise, low serum K+ and Ca++ values, electrocardiographic abnormalities, leukopenia and thrombocytopenia. No major organ toxicity and no significant fluid retention were observed at the administered doses. Treatment induced a rapid depletion of peripheral blood lymphocytes (PBL) with a rebound (2-6 times the pre-treatment values), 24-48 hr after rIL2 discontinuation. PBL obtained between the 5th treatment day and the 2nd post-treatment day showed: (a) enhanced proliferation (II/12 Pts) with stimulation indexes of 6-52; (b) increased cytotoxicity against autologous tumor cells (2/2 Pts), allogeneic melanomas (5/7 Pts), the Daudi (5/6 Pts) and K562 cell lines (7/12 Pts); and (c) increased expression of IL2 receptors (8/12 Pts) and of DR antigens (6/12 Pts). Lymphocytes collected 1-2 days after treatment and activated in vitro with rIL2 showed a more rapid development of tumor cytotoxicity, with an earlier loss of activity. Spontaneous proliferation, autologous or allogeneic tumor cytotoxicity and expression of IL2 receptors obtained after in vivo treatment with rIL2 were significantly weaker than those induced during in vitro stimulation. No major objective responses were detected in these patients.

Effects of 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclosporin A on murine cytomegalovirus infection: Studies of resistance mechanisms

Susceptibility to murine cytomegalovirus (MCMV) was enhanced by treating B 6C 3F 1 and CD-1 mice subcutaneously with 100 mg 7,12-dimethyl-benz[a]anthracene (DMBA)/kg fractionated over a 2 week period prior to sub-lethal infection. Virus-augmented natural killer cell (NKC) activity was depressed in B 6C 3F 1 mice treated with 100 mg DMBA/kg, while serum interferon (IFN) levels were unaffected. Treatment with 50 mg DMBA/kg had no effect on susceptibility to virus or virus-augmented NKC activity. Susceptibility to MCMV was not affected by treating mice with 400 mg benzo[a]pyrene (B[a]P)/kg using the same exposure regimen. Virus-augmented NKC activity was suppressed in B[a]P)-treated mice, but the magnitude of the suppression (18%) was much less than that for DMBA-treated mice (39%). Susceptibility to MCMV, virus-augmented NKC and IFN induction were not affected in mice treated intraperitoneally with 50 mg cyclosporin A (CSA)/kg/day for 5 days and infected on the 5th day of treatment. In contrast, enhanced susceptibility to MCMV and depressed NKC activity were observed in mice treated by the same exposure regimen on days 1–5 post infection. Susceptibility was not affected by CSA given on days 5–9 post infection. The data are useful not only because they show that DMBA and appropriately-timed CSA treatments suppress virus augmented NKC and enhance susceptibility to MCMV, but also because they help to define the relative importance of certain immune responses in defending against the infection, thus improving the usefulness of MCMV as a host resistance model for immunotoxicity testing. The data suggest that chemicals which depress NKC are likely to enhance susceptibility to MCMV, and conversely that effects on NKC should be suspected when chemical exposure enhances susceptibility to MCMV.

Sinusitis maxillaris bei Intensivpatienten

Fever of unknown origin is a major diagnostic problem in traumatologic postoperative intensive care medicine. Even when other causes of fever (wound infection, pneumonia, intravenous catheter contamination) have been ruled out, purulent maxillary sinusitis is rarely considered as the initial focus. The maxillary sinuses of 46 patients admitted to a postoperative intensive care unit were examined using a mobile "A-Scan" ultrasonic scanner. Follow-up examinations were performed on a regular basis. As early as on the 5th day of treatment, the initially, most often nasotracheally intubated and artificially ventilated patients exhibited a high frequency of pathological ultrasonic results, whereas only 10 of the 46 patients within the study demonstrated normal findings throughout the follow-up examinations. As a rule, bilateral involvement was observed. When findings were initially unilateral, the nasally intubated side was most often affected. Early extubation, partial mobilisation and/or administration of antibiotics from the first day of treatment onwards did not prevent the occurrence of pathologic ultrasonic results. Fever and leucocyte count were found to be elevated to a higher level in patients with purulent sinusitis. Thus, affection of the maxillary sinuses appears to be a frequent accompanying disease in intensive care patients, and should therefore always be taken into consideration as the initial focus of fever of unknown origin.

Effects of Captopril on the Urinary Excretion of Prostanoids and Kallikrein in Spontaneously Hypertensive Rats

The possible roles of vasodilatory prostanoids and the kallikrein-kinin system in the antihypertensive action of the angiotensin-converting enzyme (kininase II) inhibitor captopril were examined in spontaneously hypertensive rats. Captopril (20, 50 or 100 mg/kg daily orally) reduced blood pressure markedly and dose-dependently. It also increased water consumption and urine excretion, measured on the 5th day of treatment. The 24-hr urinary excretion of PGE2 was not changed, whereas that of PGF2 alpha and TxB2 tended to be enhanced. A clear increase, significant with all doses of captopril, occurred in the urinary excretion of 6-keto-PGF1 alpha. Kallikrein excretion in urine was suppressed by the two larger doses of captopril. The markedly augmented urinary excretion of 6-keto-PGF1 alpha, the stable metabolite of vasodilatory prostacyclin (PGI2), suggests that increased prostacyclin production may participate in the antihypertensive mechanism of captopril. Vasodilatory kinins can also contribute, since the captopril-induced decrease in kallikrein may reflect accumulation of kinins due to their reduced metabolism.

Treatment of hypothalamically-induced primary amenorrhea with epimestrol

Eleven patients with hypothalamic primary amenorrhoea, aged between 17 and 23 years, were examined. Each patient was given 10 mg epimestrol (E) orally over a period of 10 days followed by a 20-day pause. This regimen was repeated 6 times. Gonadotropin secretory patterns were investigated between 9 a.m. and 2 p.m. before, during (on the 5th day of treatment in the 4th cycle) and 3 weeks after termination of treatment. In addition LHRH double stimulation tests were carried out before and after treatment to evaluate the acute releasable pool of gonadotropins as well as the pituitary synthesis capacity. In 3 patients with low baseline gonadotropin levels no effect of E on the release of gonadotropins could be found. These patients also showed non-pulsatile secretion with low baseline gonadotropin levels and no response in the LHRH stimulation tests. Similar results could be observed in one patient with low baseline LH levels but FSH levels within the normal range. Variable results were found in 7 patients with both LH and FSH in the normal range: 3 women experienced menstrual bleeding during and/or after E treatment; 1 woman stated that spotting had occurred twice. These 4 patients all showed regular pulsatile LH secretion after cessation of E treatment; the duration of the LH pulses was 60 to 120 minutes. Some hypothalamic activity seems to be essential for a positive response to E in patients with primary amenorrhoea. This activity is characterized by a positive gestagen test as well as baseline gonadotropin levels in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oral digoxin on sodium excretion, renin-angiotensin-aldosterone system and blood pressure in normotensive subjects.

The effect of digoxin (0.25 mg t.d.s.) given orally for 5 days, on sodium excretion, plasma renin activity, plasma aldosterone and blood pressure has been studied in 6 normotensive subjects, on a constant sodium intake. Average serum digoxin level measured in 5 subjects on the 5th day of treatment was in the upper range of the therapeutic level (1.92 +/- 0.3 nmol/l). Red cell sodium content increased from 9.75 +/- 1.2 mmol/l of cells in the control period to 15.3 +/- 1.7 mmol/l of cells on the 5th day of digoxin treatment when measured in 4 of the 6 subjects. In spite of this evidence of inhibition of the red cell sodium pump, there was no detectable change in sodium excretion, blood pressure, plasma renin activity and aldosterone.

The action of gossypol on rat germinal cells

AbstractAdult male Sprague‐Dawley rats were fed daily with 25 mg/kg of gossypol acetic acid for 55 days. The examination of the testis revealed the constant integrity of the blood‐testis barrier. The earliest damage to the germinal cells appeared on the 14th day of treatment in spermatids in stage 18‐19, and consisted of mitochondrial swelling and cristae disorganization, which was manifested in an altered assembly of the mitochondrial helix and possible axonemal alterations. It appeared that the target cell was a 30–37‐day‐old spermatid that showed the first alterations 6–14 days later, when it reached stage 18. The mitochondrial and eventual axonemal damage was conserved after the migration into the epididymis, affecting 6% of the total sperm population on the 14th day of treatment and reaching the maximum (100%) on the 25th day of treatment. On the 5th day of treatment, epididymal spermatozoa revealed, moreover, the presence of other tail alterations: lack of half of the axonemal components (also in sperm with unaffected mitochondria), loss of midpiece plasma membrane, and breaking of the outer accessory fibers. The conclusion is that a direct action of gossypol on epididymal spermatozoa is superimposed on the action earlier exerted on the spermatids.

Changes of some biochemical parameters of the lens in galactose-treated weaned rats with and without vitamin E therapy.

We tried to counteract the appearance of galactosemic cataracts in weaned rats by high doses of vitamin E. Rats were fed a diet containing 33% galactose. Cataract development was monitored by biomicroscopy and by several biochemical parameters: K+/Na+ ratio, aldose reductase activity, level of protein and non-protein sulfhydryl (SH) groups. Vitamin E was given parenterally at a dose of 100 mg/kg/day. The K+/Na+ ratio drops after 15 days of galactosemia, while the level of the aldose reductase rises after only 5 days of treatment. The non-protein SH groups lens contents fall from the 5th day of treatment onwards, while protein SH groups are not affected. In short-term experiments vitamin E does not prevent biochemical changes caused by galactosemia. The oxidative insult does not seem to be primarily involved in galactose cataract.

Effect of calcitonin on calcitonin cells, parathyroid glands and serum electrolytes in the house shrew (Suncus murinus).

Porcine calcitonin (CT) (0.5 MRC unit daily) was administered intraperitoneally to house shrews, Suncus murinus, for 42 days. The changes in serum calcium and phosphate levels as well as the light microscopical alterations of the parathyroid and calcitonin cells (C cells) between the 1st and 42nd day of treatment were recorded. The serum calcium level shows a fall up to the 7th day of treatment and thereafter it increases to normal values. The hypophosphataemic effect of CT increases progressively throughout the experiment continuing even after the loss of the hypocalcaemic effect. CT administration inhibits the release of secretory granules of C cells up to 21 days. Hyperplasia and degranulation of C cells is observed at 28, 35 and 42 days of treatment. C cells with collapsed membrane are also encountered in the lumina of the thyroid follicles. From the 28th day onwards the parathyroid chief cells of treated animals show hypertrophy and loss of staining reaction.

Plasma xanthine levels in low birthweight infants treated or not treated with theophylline.

The use of theophylline in the management of apnoea in the newborn was studied in 33 preterm infants. Infants received a dose of 3 mg/kg, 13 of them every six hours, the remaining 20 every eight hours. All the infants had significantly fewer apnoeic episodes. In a pharmacokinetic study, the half life of theophylline was 30.3 +/- 7.2 hours and the clearance rate was 23.9 +/- 5.06 ml/kg per hour (means and SD). The plasma theophylline level remained constant at between 13 and 15 mg/l from the 5th day of treatment but, at the same time, the plasma levels of caffeine rose to a mean level of 4.4 mg/l. Caffeine was detectable in plasma at birth, and in preterm infants not receiving theophylline; plasma levels of caffeine tended to be similar to the levels in their mothers' milk. These observations have led to clear conclusions on the optimum timing and dosage of theophylline, and on the need to monitor plasma levels of both theophylline and caffeine in newborn infants treated with theophylline.

Tratamento da Doença de Chagas pelo Nifurtimox (Bayer 2502)

Foram tratados 77 pacientes com doença de Chagas pelo nifurtimox, subdivididos em quatro grupos. Grupo I, com 30 pacientes na fase aguda. Somente oito doentes usaram a droga durante 120 dias, na dose inicial de 15 mg/kg de peso corporal e posteriormente de 10 mg. Vinte e dois pacientes tomaram dose insuficiente. Em quatro doentes (50%) o xenodiagnóstico tornou-se negativo pós-tratamento; destes, três fizeram reação de Machado Guerreiro, a qual estava negativa. Houve um óbito por insuficiência cardíaca no 59 dia de tratamento. Seis pacientes apresentaram polineuropatia periférica. Grupo II, com 15 pacientes na fase crônica, tratados em ambulatório. Oito abandonaram o tratamento, mas cinco em dez que tomaram placebo fizeram o mesmo. Dos seis que tomaram a droga durante 120 dias e fizeram pelo menos um xenodiagnóstico pós-tratamento, havia quatro que estavam com os exames negativos. O tratamento não alterou o eletrocardiograma, a área cardíaca ou a radiografia do esôfago dos doentes e não evitou que um paciente viesse a desenvolver insuficiência cardíaca e um outro arritmia. Grupo III, com 15 pacientes na fase crônica, tratados com 10 mg/kg, durante 120 dias. Fizeram 12 xenodiagnósticos mensalmente, cada um com oito caixas contendo 10 T. infestans após o tratamento e somente 28,5% dos pacientes apresentaram todos os exames negativos. Houve acentuada redução da parasitemia, mesmo nos doentes não curados. O número de xenos positivos passou de 43% antes do tratamento para 24,4% após o mesmo e o número de caixas positivas caiu de 29,6% para 7%. Grupo IV, com 17 pacientes na fase crônica, tratados com 8 mg/kg ao dia, sendo que em oito durante 120 dias, em cinco durante 100 dias e em quatro durante 60 dias. A percentagem de doentes com os 12 xenos negativos pós-tratamento foi de 56,25. Também neste grupo houve redução de parasitemia, caindo a percentagem de xenos positivos de 76,5 antes do tratamento para 10,3 e a de caixas positivas de 28,6 para 3,1. Não há vantagem em se prolongar o uso do nifurtimox por mais de dois meses. As percentagens de cura são bem inferiores as obtidas na Argentina, Chile e Rio Grande do Sul. A droga produz muitas reações, sendo a mais importante a polineuropatia periférica.

Kinetic studies on rifampicin

To aid interpretation of the fall in the serum concentrations of rifampicin observed in the early phase of continuous treatment, the distribution of the antibiotic was assessed simultaneously in the serum, bile, and urine of patients treated for one week. Transfer constants between these compartments were calculated on the 1st and 7th day of treatment by multicompartmental kinetic analysis. — The results obtained suggest that the decrease in serum concentrations is due to enhanced biliary excretion; no significant change was observed in the amount of antibiotic excreted in the urine. The increased capacity of the liver to excrete rifampicin in bile might result from enzyme induction by the antibiotic in hepatocytes.

Correlated morphometric and biochemical studies on the liver cell. II. Effects of phenobarbital on rat hepatocytes.

The changes occurring in rat hepatocytes during a 5 day period of treatment with phenobarbital were determined by morphometric and biochemical methods, particular attention being paid to the endoplasmic reticulum. The hepatocytic cytoplasm played an overwhelming part in the liver hypertrophy, while the hepatocytic nuclei contributed to only a moderate extent. The endoplasmic reticulum accounted for more than half of the increase in cytoplasmic volume. The increase in the volume and number of hepatocytic nuclei in the course of phenobarbital treatment was associated with changes in the ploidy pattern. Until the 2nd day of treatment both the rough-surfaced endoplasmic reticulum (RER) and the smooth-surfaced endoplasmic reticulum (SER) participated in the increase in volume and surface of the whole endoplasmic reticulum (ER). Subsequently, the values for RER fell again to control levels, whereas those for SER continued to increase, with the result that by the 5th day of treatment the SER constituted the dominant cytoplasmic element. The specific volume of mitochondria and microbodies (peroxisomes) remained constant throughout the duration of the experiment, while that of the dense bodies increased. The specific number of mitochondria and microbodies displayed a significant increase, associated with a decrease in their mean volume. The phenobarbital-induced increase in the phospholipid and cytochrome P-450 content of the microsomes, as well as in the activities of microsomal reduced nicotinamide-adenine dinucleotide phosphate-cytochrome c reductase and N-demethylase, was correlated with the morphometric data on the endoplasmic reticulum.

Central Mining--Rand Mines Group. Report for the year 1947

The use of theophylline in the management of apnoea in the newborn was studied in 33 preterm infants. Infants received a dose of 3 mg/kg, 13 of them every six hours, the remaining 20 every eight hours. All the infants had significantly fewer apnoeic episodes. In a pharmacokinetic study, the half life of theophylline was 30.3 +/- 7.2 hours and the clearance rate was 23.9 +/- 5.06 ml/kg per hour (means and SD). The plasma theophylline level remained constant at between 13 and 15 mg/l from the 5th day of treatment but, at the same time, the plasma levels of caffeine rose to a mean level of 4.4 mg/l. Caffeine was detectable in plasma at birth, and in preterm infants not receiving theophylline; plasma levels of caffeine tended to be similar to the levels in their mothers9 milk. These observations have led to clear conclusions on the optimum timing and dosage of theophylline, and on the need to monitor plasma levels of both theophylline and caffeine in newborn infants treated with theophylline.