Biomedical subjects

A Sacristán

Publications and source records attributed to A Sacristán.

At least 19 recordsLinked to original sources

PubMed2003

Chemotherapy versus best supportive care for extensive small cell lung cancer.

BACKGROUND: Combination chemotherapy has been the mainstay of treatment for extensive stage small cell lung cancer (SCLC) over the last 25 years even though it only gives a short prolongation in median survival time. The main goal for these patients, if their survival prognosis is limited, should be adequate palliation with the aim of improving their quality of life. OBJECTIVES: To evaluate the effectiveness of chemotherapy in extensive SCLC compared with best supportive care (BSC) or placebo treatment. SEARCH STRATEGY: Medline (1966-Jan 2003), Embase (1974-Jan 2003), Cancerlit (1993-Jan 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2002) were searched. In addition experts in the field were contacted to identify further studies not found by electronic searches. SELECTION CRITERIA: Randomised controlled trials in which any chemotherapy treatment was compared with a placebo group or best supportive care in patients with extensive stage SCLC. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were undertaken independently by two reviewers and disagreements were resolved by a third author. Additional information on the included studies was obtained from the author of the original studies. MAIN RESULTS: Only two studies (the first published in 1977 and the second in 1982) met the inclusion criteria of the review. A total of 65 patients with extensive disease (33 in the first study and 32 in the second) were randomised to received either placebo treatment or ifosfamide. In the second study a third arm of comparison included ifosfamide plus CCNU. Ifosfamide gave an extra 78.5 days survival (mean survival time) compared with the placebo group. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group. Pooled analysis was not possible because only mean survival time was reported in both studies for patients with extensive disease. REVIEWER'S CONCLUSIONS: Chemotherapeutic treatment prolongs survival in comparison with placebo in patients with advanced SCLC. Nevertheless the impact of chemotherapy on quality of life and in patients with poor prognosis is unknown. Well-designed, controlled trials are needed to further evaluate the risks and benefits of different chemotherapeutic schedules in patients with advanced small cell lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

An organizational model for a primary care program of home health care in Spain: a description of the program.

The National Institute of Health (INSALUD) in Spain has successfully used a model of home care that has two major components, each using the physician as part of the team that provides care at home. The first component is home health care that is provided to chronically ill, terminally ill and homebound patients, whereby professionals of primary care provide care for the patient at home, along with other professionals who provide specialized care as support elements. The second component is hospitalization at home, whereby care is provided to acutely ill patients or patients with a precocious medical or surgical discharge from the hospital. The professionals from the hospital provide the basis of care. and the primary health care professionals are the support elements. Both components incorporate a team of support.

Acute Disease↗

PubMed2000

[Respiratory function in pediatric survivors of malignant neoplasms].

AIM: To evaluate post-treatment pulmonary function in patients with malignant extrapulmonary neoplasia and its relationship with age, type of neoplasty and treatment received. METHODS: Cohort study of 95 pediatric patients after chemotherapy with or without surgery or extrapulmonary thoracic radiotherapy. The patients were in remission without treatment and able to undergo pulmonary function testing. Personal history and exposure to risk factors or toxic habits were evaluated. Clinical examination, chest radiographs, pulmonary gammography, basal and stress pulmometry, forced spirometry, whole body phletismography and carbonmonoxide transfer test were performed. RESULTS: Mean age at diagnosis was 5 +/- 3.3 years. Treatment duration was 2.4 +/- 1.3 years and time without treatment 4.3 +/- 3. 3 years. Thirty-six patients were reviewed two and a half years after the first control. Thirty-nine patients had acute lymphoblastic leukemia and 57 had solid tumors. Sixty percent showed functional restriction due to chest deformity after undergoing chest surgery. The association between functional restriction and radiotherapy (6 patients) did not produce poorer functional results. Forty-three percent showed initial change in TLCO. Nineteen percent showed basal hemoglobin saturation under 93% which in 16% fell after physical exercise. These alterations improved with time. However, restrictive change initially present in 11.5% persisted at the second evaluation. Thoracic surgery was the main cause of thoracic deformity and therefore of restrictive change. The children under 8 years old and those who received longer treatments tended to show the worst TLCO values. The patients with neuroblastoma showed greater restrictive change while the change in TLCO was more frequent in patients with Burkitt s lymphoma and in those treated with cyclophosphamide. CONCLUSIONS: Neither personal or family history of respiratory disease nor the presence of symptoms such as cough served to identify risk of functional change. Restrictive change in pulmonary function was greater in patients who had undergone thoracic surgery. Functional values were worse in patients with neuroblastoma. Pulmonary function should be followed up in pediatric survivors of malignant neoplasia in order to prevent restrictive alterations.

Child↗

PubMed1998

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602).

A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.

Administration, Oral↗

PubMed1998

Efficacy of senna versus lactulose in terminal cancer patients treated with opioids.

The best laxative for terminal cancer patients treated with opioids still remains to be determined. This comparative study was conducted with the objective of determining treatment and cost efficiency for senna and lactulose in terminal cancer patients treated with opioids. The methodology used a randomized, open, parallel group design. The study was conducted in the Palliative Care Unit in one Madrid Health Care District. Ninety-one terminal cancer patients were randomized into two groups: A = treated with senna (starting with 0.4 mL daily), and B = treated with lactulose (starting with 15 mL daily) for a 27-day period. The main outcome measures were defecation-free intervals of 72 hr, days with defecation, general health status, and treatment cost. Laxative efficacy was analyzed through t test and analysis of variance. No difference was found between the laxatives in defecation-free intervals or in days with defecation. The final scores for general health status were similar in both groups. Given that the two treatments have similar efficacy and adverse effects, a recommendation is made for the use of senna because its cost is lower than lactulose.

Adult↗

PubMed1998

Twenty-four-month oral carcinogenicity study of ebrotidine in rats.

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species.

Animals↗

PubMed1997

Synthesis and assessment of formamidines as new histamine H2-receptor antagonists.

Four series of compounds whose substructure contains a formamidine functionalized as a novel group in the chemistry of histamine H2-receptors have been synthesized. Series design, synthesis and pharmacological data including inhibition of histamine-stimulated acid secretion, inhibition of acid secretion p.o. and pA2 are reported. N-[(E)-[[2-[[[2](Diaminomethylene)amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide (ebrotidine, CAS 100981-43-9, FI-3542) was selected for further research.

Amidines↗

PubMed1997

Physicochemical properties, analytical determinations and stability of ebrotidine.

Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) is a new H2-receptor antagonist with a potent antisecretory activity and evidenced gastroprotection. This paper describes its physicochemical properties, spectroscopy for its structural identification, detection methods for its organic and inorganic impurities, purity quantitation and stressed degradation and stability tests in solid and solution forms in order to know the behaviour of the test substance against certain experimental conditions. The results obtained indicate that ebrotidine is stable for over 3 years normal storage conditions (25 degrees C/75% RH). As ebrotidine was not found to be hygroscopic or particularly photosensitive, no special storage precautions are required.

Benzenesulfonates↗

PubMed1997

Histamine H2-receptor antagonist action of ebrotidine. Effects on gastric acid secretion, gastrin levels and NSAID-induced gastrotoxicity in the rat.

The antagonism of histamine H2-receptors by ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) was assessed on isolated guinea-pig right atrium. The dose-response curves obtained by histamine on the positive chronotropic effect in guinea-pig atrium were displaced to the right in parallel depending on the concentration of ebrotidine and ranitidine without change in the maximum response with pA2 values of 7.12 and 7.26, respectively. The slope of the regression line of log (DR-1) against log ebrotidine concentration was not significantly different from unity: 0.96 (95% confidence limits: 0.89-1.03). These results indicate that ebrotidine is a competitive H2-receptor antagonist. Following intravenous administration to rats, ebrotidine inhibited histamine- and pentagastrin-stimulated acid secretion in a dose-dependent manner, ED50 being 0.21 and 0.44 mg/kg, respectively. After oral administration to fasting rats 3 h before their sacrifice, ebrotidine decreased the total acid contents of the stomach in a dose-dependent manner, ED50 being 7.5 mg/kg. After a single dose of 100 mg/kg in fasting rats, ebrotidine increased significantly serum gastrin levels within 2 and 5 h after administration, but 8 h after administration serum gastrin levels returned to normal values. In contrast, ranitidine at a single oral dose of 100 mg/kg increased serum gastrin levels more markedly within 2 and 5 h after administration, while after 8 h, this increase still persisted although without significant differences with respect to control, and after 24 h levels returned to normal values. Both ebrotidine and ranitidine were administered orally at a dose of 100 mg/kg for 26 days showing significant increments in plasma gastrin levels 5 h after administration. Such increments were not so marked after ebrotidine and normal values were attained at 24 h after administration. The results obtained after repeated oral administration for 15 days of ebrotidine and ranitidine at the doses of 15 and 50 mg/kg demonstrated that ebrotidine did not increase significantly serum gastrin levels with respect to control 2 h after administration, and no dose-related effect was observed. In contrast, ranitidine increased serum gastrin levels significantly and in a dose-dependent manner with respect to control group. ED50 values of ebrotidine obtained in the experiments on the prevention of NSAID-induced gastrotoxicity in the rat were 12.2, 12.5, 11.5 and 9.8 mg/kg against diclofenac, ketoprofen, indometacin and naproxen, respectively. ED50 values of ranitidine were of the same order: 20.6, 13.9, > 50 and 15.1 mg/kg.

Animals↗

PubMed1997

Action of ebrotidine, ranitidine and cimetidine on the specific binding to histamine H1- and H2-receptors.

Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)-4-thiazolyl]methyl]thio] ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542), a selective H2-receptor antagonist, has proved to competitively inhibit the positive chronotropism induced by histamine in isolated guinea pig atrium. The affinity of ebrotidine to histamine H1- and H2-receptors through the displacement of 3H-pyrilamine and 3H-thiotidine binding to guinea pig cerebellum and brain cortex membranes was investigated. Ebrotidine displaced 3H-thiotidine specific binding to histamine H2-receptors (Ki: 127.5 nmol/l), showing a higher affinity (p < 0.05) than ranitidine (Ki: 190.0 nmol/l) and cimetidine (Ki: 246.1 nmol/l). None of the three substances displaced 3H-pyrilamine binding to H1-receptors (Ki: > 5000 nmol/l). The results showed that ebrotidine is a drug with a high affinity for H2 receptors, higher than cimetidine and ranitidine.

Animals↗

PubMed1997

Effect of ebrotidine on ethanol-induced gastric mucosal damage in the rat. Comparative study with other H2-receptor antagonists.

Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) is a novel H2-receptor antagonist with additional gastroprotective effect. The gastroprotective effect of oral doses of ebrotidine against ethanol-induced mucosal damage in female rats was compared with the effect of cimetidine, ranitidine and famotidine. Macroscopically, ebrotidine showed dose-dependent inhibition of the lesion, with significant differences from that of controls at doses of > or = 12.50 mg/kg (ED50 was 26.54 mg/kg). None of the other drugs tested showed gastroprotective effect under the same conditions. The histopathological study revealed significant reduction in the number of deep and superficial ulcers in ebrotidine-treated animals. The gastroprotective effect of ebrotidine is patent even in the presence of indometacin suggesting that prostaglandins play a rather negligible role in gastroprotective action. These results suggest that ebrotidine may be more useful than the classically known H2-antagonists in the treatment of peptic ulcers.

Animals↗

PubMed1997

Study on the increment of the amount of gastric mucus in rats after repeated-dose administration of ebrotidine.

Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) is a novel H2-receptor antagonist that also exhibits a potent gastroprotective action against ethanol damage. This study was designed to ascertain under physiological conditions the effect of ebrotidine on the secretion of gastric mucus, probably the main component of the mucosal barrier. Two groups of 20 rats each were given a daily oral dose of 10 or 35 mg/kg ebrotidine, respectively, for 17 days. A third group of 20 rats was used as a control. Once the administration period had concluded, the animals were killed and their stomachs were removed and processed by the periodic acid-Schiff (PAS) histochemical method, selective for mucopolysaccharides. PAS-positive areas exhibited a characteristic carmine colour, allowing morphometric study by computerized image analysis. All the histological sections studied were from the same region of the stomach. A significant increase in the PAS-positive area corresponding to glandular mucus was found in all treated groups. This action is consistent with an increased secretion of mucopolysaccharides and represents one of the main mechanisms of the cytoprotective action of ebrotidine.

Animals↗

PubMed1997

Involvement of endogenous nitric oxide and sulfhydryl compounds in ebrotidine-induced gastroprotection.

The role of endogenous nitric oxide and sulfhydryl compounds in the prevention by ebrotidine (N-[(E)- [[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino] methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) (100 mg/kg i.g.) of ethanol-induced gastric damage in rats was demonstrated. When the animals were pretreated with N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, at the dose of 10 mg/kg i.v., the mucosal lesions were aggravated and the gastroprotective action of ebrotidine decreased from 85% to 24%. This decrease in ebrotidine protection was antagonized by L-arginine (200 mg/kg i.v.), the lesion inhibition rate being 69%. D-arginine (200 mg/kg i.v.) was ineffective and the inhibition afforded by ebrotidine was only 14%. Pretreatment with N-ethylmaleimide, a sulfhydryl blocker, at the dose of 50 mg/kg s.c., increased the mucosal lesion induced by ethanol, and the gastroprotective action of ebrotidine decreased from 75% to 9%. These results suggest that endogenous nitric oxide and sulfhydryl compounds play a crucial role in the gastroprotective activity of ebrotidine.

Animals↗

PubMed1997

In vitro anti-Helicobacter pylori activity of ebrotidine.

The in vitro anti-Helicobacter pylori (H. pylori) activity of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene) amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo- benzenesulfonamide, CAS 100981-43-9, FI-3542) versus ranitidine, and their effect on the susceptibility to the antimicrobial agents used in H. pylori eradication were investigated. Assessment was performed by determining the minimum inhibitory concentrations (MIC) against 9 strains of H. pylori, 8 from clinical source and 1 from the American Type Culture Collection (ATCC 43504), in Mueller-Hinton solid media plus 7% blood. The concentration of inocula was 10(7) CFU/ml, incubation was performed at 37 degrees C in microaerophilic atmosphere, and results were read after 5 days of growth. Ebrotidine gave a mean MIC value of 75 micrograms/ml, while that for ranitidine was > 1000 micrograms/ml. Ebrotidine at 100 micrograms/ml enhanced the activity of the antimicrobials studied as follows: erythromycin 3 times, tetracycline 1.1 times, amoxicillin 3 times, metronidazole-sensitive strains 9 times and clarithromycin 5 times. Ranitidine had no effect on the MIC of the antibiotics even at 500 micrograms/ml.

Amoxicillin↗

PubMed1997

Pharmacokinetics of ebrotidine in rats and dogs.

The pharmacokinetics of ebrotidine (N-[(E)-[[[2-[(diaminomethylene)amino] -4-thiazolyl]methyl]thio]ethyl] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) was studied in the rat and dog. After oral (agar suspension) and intravenous administration at 10 mg/kg to rats, ebrotidine was rapidly absorbed. Cmax values averaged 0.498 microgram/ml attained at tmax = 30 min. Distribution was fitted to a two-compartmental model with t1/2 beta = 1 h (i.v.). Clearance (Cl) was 29 ml/min.kg and volume of distribution (Vdss) was 1852 ml/kg. Absolute bioavailability was 22% of the dose administered. After oral (the same tablet formulation as that used for clinical trials) and intravenous administration at 150 mg and 25 mg, respectively, to dogs, absorption of ebrotidine was relatively rapid. Cmax values averaged 2,170 micrograms/ml attained at tmax = 2 h. Distribution was fitted to a two-compartmental model with t1/2 beta = 2.8 h (i.v.). Clearance (Cl) was 600 ml/h.kg and volume of distribution (Vdss) was 1000 ml/kg. Absolute bioavailability, which is variable in this type of drugs, ranges from 29% to 64% of the dose administered.

Administration, Oral↗

PubMed1997

Metabolism of ebrotidine. A review.

A hypothetical metabolic pathway for ebrotidine (N-[(E)-[[(2-[[[2-[(diaminomethylene]amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) has been proposed on the basis of previous data on the metabolism of other H2-receptor antagonists as well as on in vitro degradation assays of ebrotidine. Its potential metabolites have been synthesized and characterized, and their presence in human urine has been investigated by high-performance liquid chromatography (HPLC). Analytical-scale HPLC allowed the identification of metabolites by means of their retention time and UV spectrum, while semipreparative-scale HPLC allowed their identification through FT-IR and 1H-NMR. Mass spectrometry using atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) for HPLC-MS coupling allowed the identification of all metabolites in human urine. The quantitative determination of ebrotidine and its derivatives has been performed according to a newly designed method which consisted of a liquid-liquid extraction in a basic medium followed by reversed-phase HPLC with ion-pair formation. This method was sensitive, precise and no chromatographic interferences with other drugs which might be administered in combination with ebrotidine were observed. In order to elucidate the excretion of ebrotidine, the analytical method was applied to the analysis of the urine collected from 2 healthy volunteers 96 h after receiving 400 mg of ebrotidine.

Benzenesulfonates↗

PubMed1997

Acute toxicity studies of ebrotidine.

The acute toxicity of two formulations of ebrotidine (N-[N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) was studied in rats and mice by different routes of dosing: oral and intraperitoneal routes in rats and mice (suspension), intravenous and oral routes in mice and intravenous route in rats (injectable solution). LD50 values for the oral route were indeterminable in all cases. For the intraperitoneal route. LD50 values were 316 mg/kg (rat) and 366 mg/kg (mouse), and for the intravenous route LD50 values were 100 mg/kg (rat) and 107 mg/kg (mouse).

Administration, Oral↗

PubMed1997

Subacute toxicity of ebrotidine in rats and dogs.

Subacute toxicity studies of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) were performed in Spragu-Dawley rats and Beagle dogs. Both animal species were administered with the same dose levels (50, 200 and 500 mg/kg) for 4 and 7 weeks, respectively. In a previous 4-week subacute toxicity study in the rat, ranitidine and cimetidine at 500 mg/kg were used as reference drugs. The results indicated that ebrotidine was well tolerated at 50 mg/kg, while there were dose-related effects at 200 and 500 mg/kg. Probably due to its pharmacokinetics, ebrotidine was more toxic in dogs than in rats, since the most severe effects were the death or sacrifice in extremis of two dogs from the high dose group which had undergone rectal prolapse, while no deaths occurred in the rats. The changes that were very likely related to treatment (500 mg/kg) were a lower weight in both species, a slight decrease of hematocrit and red blood cells in rats, single increments of transaminases, alkaline phosphatase and lactate dehydrogenase in dogs (some animals of the 200 mg/kg dose group were also affected) and a higher liver weight. These effects with a few exceptions were found to be common to cimetidine and ranitidine.

Animals↗