Biomedical subjects
Publications and source records attributed to B Costa.
Examination of the pharmacophoric points of the pyrazolo[1,5-a]pyrimidine derivatives, ligands for BZR, previously published led us to the design of a novel class of 3,6-diaryl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-7-ones and to determine the groups involved in the BZR recognition.
Despite the generalization of induction chemotherapy and a better outcome for chemosensitive diseases, the prognosis of inflammatory breast cancer (IBC) is still poor. In this work, we evaluate response and toxicity of high-dose sequential chemotherapy with repeated blood stem cell (BSC) transplantation administered as initial treatment in 100 women with non-metastatic IBC. Ninety-five patients (five patients were evaluated as non-eligible) of median age 46 years (range 26-56) received four cycles of chemotherapy associating: cyclophosphamide (C) 6 g m(-2) - doxorubicin (D) 75 mg m(-2) cycle 1, C: 3 g m(-2) - D: 75 mg m(-2) cycle 2, C: 3 g m(-2) - D: 75 mg m(-2) - 5 FU 2500 mg m(-2) cycle 3 and 4. BSC were collected after cycle 1 or 2 and reinfused after cycle 3 and 4. rG-CSF was administered after the four cycles. Mastectomy and radiotherapy were planned after chemotherapy completion. Pathological response was considered as the first end point of this trial. A total of 366 cycles of chemotherapy were administered. Eighty-seven patients completed the four cycles and relative dose intensity was respectively 0.97 (range 0.4-1.04) and 0.96 (range 0.25-1.05) for C and D. Main toxicity was haematological with febrile neutropenia ranging from 26% to 51% of cycles; one death occurred during aplasia. Clinical response rate was 90% +/- 6%. Eighty-six patients underwent mastectomy in a median of 3.5 months (range 3-9) after the first cycle of chemotherapy; pathological complete response rate in breast was 32% +/- 10%. All patients were eligible to receive additional radiotherapy. High-dose chemotherapy with repeated BSC transplantation is feasible with acceptable toxicity in IBC. Pathological response rate is encouraging but has to be confirmed by final outcome.
We employed the CB1 cannabinoid receptor antagonist SR 141716A (3 mg/kg, i.p.) to investigate whether behavioural effects induced in rats by anandamide, an endogenous cannabinoid (20 mg/kg, i.p.), were mediated by the cannabinoid CB1 receptor. Anandamide reduced ambulatory (67%) and non-ambulatory activities (rearing and grooming, 84% and 90% respectively), with a strong cataleptic effect, produced hypothermia (about -1 degree C) and hindlimb splaying, and reduced defecation (79%). It did not significantly increase either the tail-flick or hot-plate latencies. Except for the decreased defecation, these responses were all blocked by SR 141716A. Although only single doses of the agonist and antagonist were used, the findings indicate that these behavioural effects are probably mediated by an interaction with cannabinoid CB1 receptors.
AIM: To examine the acute actions of the CB1 cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] on typical behavioral pattern of psychoactive cannabinoids in rats. METHODS: At different time after injection the tail-flick response latency, the rectal temperature, the locomotor activity, and the immobility on a ring as well as the numbers of rears, self-grooming episodes (lasting 5 s), and fecal pellets were measured. RESULTS: Acute administration of SR141716A (3 mg/kg i.p.) induced a significant increase in horizontal locomotor activity assayed by an activity meter, in stereotypic activity (such as rearing and self-grooming) and in defecation, and a decrease in nociceptive threshold recorded as tail-flick latency. This dose had no effect on ring immobility and did not change the body temperature. CONCLUSION: These results demonstrate that this cannabinoid antagonist itself was inducing behavior opposite to that of CB1 receptor agonists.
BACKGROUND: To compare the cost and effectiveness of bedtime intermediate-acting insulin and daytime-sulfonylurea (SU) combination therapy versus the conventional two-daily-dose insulin treatment. SUBJECTS, MATERIAL AND METHODS: A pharmacoeconomical analysis of cost minimization. To prove a similar effectiveness a transversal prospective study was carried out. Patients recently converted to insulin due to oral hypoglycaemic agents failure were recruited. Entry criteria were: age > 40 years-old, more than 3 and 1 years of diagnosed diabetes and follow-up, respectively, current BMI between 20-40 kg/m2, baseline HbA1c > 8.5% and fasting C-peptide > 0.3 nmol/l. BMI, HbA1c, hypoglycaemic crisis, insulin and SU (glicazide and glibenclamide) daily dose were recorded, estimating the cost of both therapies. RESULTS: Sixty-five patients (23 male), 32 in combined therapy (mean daily dose of insulin 19.5 U and 2.4 SU tb t.i.d.) and 33 patients with a two-insulin-injection regimen (38.4 U) were treated during a follow-up period of 2.4 years. The two groups exhibited similar mean age (67.8/67.7y), known diabetes duration (15.9/15.1y), BMI (28.9/28.8/kg/m2), previous HbA1c (8.9/9.1%) and fasting C-peptide (1.6/1.2 nmol/l). No statistical differences in BMI increase (1/1.4 kg/m2), neither in mean HbA1c (7.8/7.9%) nor severe hypoglycaemic crisis (0.03/0.17 episodes/year) were evidenced. Patients in combined therapy reported a lower number of mild hypoglycaemic crisis (0.7/1.9 episodes/month; p < 0.01) and the daily cost was significantly lower (94.5/134.3 ptas./day; p < 0.0001). CONCLUSIONS: Both therapies, two-insulin-injection regimen and insulin and sulfonylurea combination therapy were similarly effective in having an acceptable glycaemic control with similar risk for weight gain or severe hypoglycaemia. Combined therapy was more cost-effective and well-tolerated, thus, comfort and a lower risk of mild hypoglycaemic episodes were evidenced.
OBJECTIVE: To investigate the number of people with intolerance to glucose (ITG) and undiagnosed diabetes (DM) among primary care users at risk. DESIGN: Prospective, selective urban polling of a representative sample of those attended in the city of Reus (88,000 inhabitants). SETTING: Two base health areas (10 Primary Care teams) with an approximate overall reference population of 45,000 inhabitants. PATIENTS AND OTHER PARTICIPANTS: Clinical and examination data were recorded with a pre-designed questionnaire. Diagnoses were established by means of base glycaemia (mmol.l-1 or a 75 g glucose oral overload (0 and 120 minutes) for users over 40 with some Diabetes risk factor. Further tests were HbA1C (%), base peptide-C (nmol.l-1, total cholesterol, HDL cholesterol, triglycerides (mmol.l-1 and 24-hour microalbuminuria (mg). MEASUREMENTS AND MAIN RESULTS: After a year included in the survey, the data of 345 people were evaluated: 151 men, 58 years old (95% CI, 57-60) and BMI of 30.8 (30.3-31.4), with 197 diagnoses (57.1%) of normal tolerance to glucose (52-62%). 82 (23.8%) of ITG (20-28%) and 66 (19.1%) of undiagnosed DM (15-23%). Significant differences between the three were detected in age (56/61.5/61.7 years, p < 0.001), proportion of men (38/50/53%, p < 0.05), diagnosis of hypertension (40.6/59.8/53%, p < 0.01), previous anomaly in tolerance 28.4/45.1/51.5%; p < 0.001), HbA1C (4.6/4.9/5.4; p < 0.001), systolic pressure (140.5/143.6/151 mmHg, p < 0.007). Triglycerides (1.4/1.6/2.1, p < 0.001) and microalbuminuria (16/29/51, p < 0.001). Base peptide-C (3.5/3.8/3.8) showed no statistical differences. CONCLUSIONS: Selective detection in primary care amply exceeds opportunist detection in identifying patients with ITG who might be susceptible to preventive measures. In function of the intolerance level, from normality through to DM, statistical differences were found in HbA1C, systolic pressure, Triglyceridaemia and urinary excretion of albumin. These were not extendable to the rest of the lipid profile or to endogenous insulinaemia.
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Treatment of rabbit brain membranes of the DHP binding sites of L-type Ca2+ channel with lysine-specific reagent resulted in a time- and concentration-dependent loss of [3H]nitrendipine binding activity. Following exposure to the maximum concentration of PLP (100 mM), [3H]nitrendipine binding was inhibited by up to 96.5%. Scatchard analysis of the binding data indicated that treatment with PLP resulted in a loss of [3H]nitrendipine binding sites with no effect on binding affinity. Considerable protection against PLP inactivation was obtained by nifedipine. These results indicate that lysine residue plays a critical role in maintaining the DHP-binding sites in a conformation capable of ligand binding.
We report the characterization of A2a adenosine receptors (A2aARs) in porcine striatal membranes and their solubilization (25%) by the detergent digitonin. After solubilization, the drug specificity and equilibrium [3H]CGS-21680 ([3H]2-(4-(2-carboxyethyl)phenylethylamino)-5'-N-ethyl-carboxamido -adenosine) binding parameters were virtually identical to those obtained in intact membranes, indicating a conservation of the binding site after the removal of receptors from their lipid environment. Gel filtration on a calibrated Superdex 200 HR column revealed a main [3H]CGS-21680 binding peak with an apparent molecular weight of 171,000+/-9000 Da. In membranes, Scatchard analysis of saturation data carried out in a wide range of radioligand concentration (1-100 nM) resulted in a biphasic curve and, in accordance with the two binding sites model, yielded a Kd1 = 7.4+/-0.5 and Kd2 = 53.1+/-3.6 nM, a Bmax1 = 186+/-15 fmol/mg protein and a Bmax2 = 285+/-20 fmol/mg protein, respectively. In the presence of guanosine-5'-O-(3-thiotriphosphate) (GTPgamma[S]) a shift from two affinity states to a single one was evidenced (Kd = 28.5+/-5.9 nM) and a Bmax value of 504+/-10 fmol/mg protein found. In the soluble extract, only one high-affinity state was detected (Kd = 19.3+/-1.1 nM and Bmax = 285+/-20 fmol/mg protein) and, in the presence of GTPgamma[S]), a two site model likewise provided a significantly (P < 0.01) better fit (Kd1 = 13.9+/-1.2 nM and Kd2 = 72.1+/-6.9 nM, Bmax1 = 125+/-10 fmol/mg protein and Bmax2 = 375+/-19 fmol/mg protein, respectively). These results suggest a close relation between the receptor and G protein solubilized as a functional unit and open the way to its purification.
A 69-year-old man was admitted to the Intensive Care Recovery Unit after heart surgery, carrying an intra balloon counterpulsation (IABCP) device inserted percutaneously days before surgery to provide hemodynamic support and which was still required after surgery. Fifteen days after insertion, blood was observed in the safety chamber. Surgical removal of the catheter was required when attempts to remove it manually failed. The balloon was seen to be perforated and clotted blood was found inside. We believe that long-term maintenance of IABCP carries high risk of perforation and entry of blood, which will clot, as well as of catheter entrapment unless removal is prompt.
To assess the efficacy and safety of acarbose as an adjunct to high sulfonylurea (SU) doses in patients with imminent SU failure, a randomised, multicentric, 6 month double-blind, parallel and placebo-controlled trial was performed in primary healthcare. Entry criteria were: NIDDM patients in concomitant dietary follow-up, age > 40 year-old, more than 3 years of diagnosed diabetes, baseline HbAlc levels between 8-12% (N: 4-6%), stable body mass index < 35 kg m-2 and glibenclamide daily dose > 10 mg. After 1 month placebo run-in period all patients were randomly allocated into two groups of treatment (acarbose 100 mg t.i.d. vs placebo). HbAlc levels, the main efficacy variable, lipid profile, fasting and postprandial blood glucose levels were performed and adverse events were also recorded. A total number of 65 patients were randomised, 36 in acarbose and 29 in a placebo group. No statistical differences were found on age (60.2/61.7 year-old), BMI (28.7/27.4 kg m-2), glibenclamide dose (14.5/14.0 mg/day) and baseline HbAlc (9.0/8.8%). Acarbose-treated patients significantly reduced HbAlc levels (9.0/7.9 vs 8.8/8.5%; P < 0.01), based upon a marked decrease, but statistically not significant, in mean postprandial plasma glucose levels (11.9/9.6 vs 12.4/11.1 mmol l-1). No significant differences between fasting plasma glucose and lipid profile were detected. A total of 31 patients (47.7%) reported adverse events, 20 (55.5%) and 11 (37.9%) in acarbose and placebo treatment group respectively. Relationship with drug was estimated as possible or probable in 16 (44.4%) of acarbose-treated patients. None of them were excluded from study participation due to insulin requirement. Only seven patients (10.7%), six with acarbose (16.6%) and one with placebo (3.8%), withdrew the study because of the adverse events. Thus, acarbose seems to be a useful option in order to improve HbAlc levels in non-insulin-dependent diabetes mellitus with imminent sulfonylurea failure.
Diabetes mellitus is a chronic disease that has a major social impact. Proper planning for the management of patients with diabetes mellitus requires consideration of the important costs that diabetes imposes on the health system. Most of the indirect costs (lost productivity as a result of disability, absenteeism, loss of potential productive years of life), are related to diabetic complications, which greatly exceed the rest of the costs, and are also very difficult to classify in a standard manner. Direct costs (pharmacy, hospitalisation, consultations) mostly derive from healthcare strategies that aim to reduce late complications of the condition and maintain day-to-day quality of life. Therefore, it does not seem difficult to estimate pharmaceutical expenditures. The consumption of oral antihyperglycaemic agents, insulin, injection equipment and self-monitoring equipment indicates prescription tendencies and shows the influence on costs, and provides indirect information about the quality of healthcare or patients with diabetes mellitus. Over the last few years, some developed countries have shown a progressive increase in pharmaceutical expenditure on diabetic care, whereas economically depressed countries have experienced a dramatic shortage of basic medicines such as insulin. Considering the increase in consumers, and the international distribution of illnesses, both a hypothetical excess cost (related to consumerism; incurred by the health system and the diabetic population) and an irregular distribution of economic resources are evident. A co-ordinated health plan for patients with diabetes mellitus, involving the collaboration of diabetologists and epidemiologists with the pharmaceutical industry, and appropriate training measures for patients and professionals, would improve pharmacoeconomic efficiency in managing this disorder.
The objective of this study was to investigate the effects of single and repeated administration of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)] on behaviour, energy metabolism and biotransformation. Single intraperitoneal administration to male Sprague-Dawley rats of CP-55,940 (0.4 mg/kg), induced a behavioural response characterized by 'splayed hind limbs', antinociception, hypothermia and a decrease in locomotor activity. Brain and liver mitochondria of the CP-55,940-treated rats exhibited an increase in respiration and no changes in ADP/O and citrate synthase specific activity. Repeated intraperitoneal administration of CP-55,940 (0.4 mg/kg, 11 days) induced behavioural tolerance, disappearance of the increase in the mitochondrial oxygen consumption as well as an increase in the monooxygenase activities and the content of liver microsomal cytochrome P450. Some hepatic metabolizing enzymes of the cytosolic glutathione-centre system were also affected. Previous studies had indicated that the tolerance after chronic administration of CP-55,940 could be due to down-regulation of brain cannabinoid receptors. The present findings demonstrate that the behavioural tolerance occurs together with modified biotransformation activities.
BACKGROUND: The U100 insulin (100 units [U]/ml) in only used in a minority of Spanish hospitals and is not ordinarily evaluated. To study the convenience of converting from U40 (40 U/ml) to U100 insulin in a first level hospital, the procedure, costs and professional acceptance were analyzed after one year of experience. SUBJECTS AND METHODS: The chronology and the transfer method are described making an interannual pharmacoeconomical comparison of costs U40/U100 based on insulin intake and injection material. The primary source of information was the computerized base of admission, pharmacy and supply. The secondary source included the obligatory registries of daily medicine sheets. Nursing staff acceptance of the new system (preloaded U100 syringes) was analyzed with a predesigned quantitative scale questionnaire. RESULTS: In the U40 phase, 69,600 U and 8,260 syringes were used to satisfy 136 diabetics at a mean prescription of 21 U/day for 10.9 days. In the U100 phase, 92,100 U and 1,682 syringes were used for 132 admissions with a mean dose of 20 U during 8.6 days. The insulin prescribed and injected was 45.5% and 24.7%, respectively with the consumption of non injected insulin in the center being 20.8%. On taking only the fraction injected into consideration, the mean daily cost per complete treatment was lower in U100 (116/84 and 1,368/809 pesetas; p < 0.0001) representing 0.53% (U40) and 0.36% (U100) of hospital stay costs. The total cost increased by 44 ptas./patient/day during the first year of conversion. Each section of the 67 questionnaires evaluated scored from 4 (greatest acceptance) to 20 (lowest acceptance). The general mean was 6.8 +/- 1.6 with no significant differences between the section of management/manipulation of U100 devices (6.7 +/- 2.1), learning and protocol (7.3 +/- 2.6) and patient education (6.5 +/- 1.8; p = 0.07, NS). CONCLUSIONS: Current hospital conversion to U100 insulin requires the use of mechanized injection systems which represent a slight extra cost of scarce social relevance and are greatly accepted by users if adequate transfer procedures are applied.
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The binding of [3H]nitrendipine to membrane preparation from turtle and rabbit brain was studied. A single population of [3H]nitrendipine binding sites was detected in both species. [3H]nitrendipine bound with high affinity to brain membrane from both rabbit and turtle, revealing a significant population of binding sites (K(D) values of 0.55 +/- 0.05 nM and 0.56 +/- 0.04 nM and Bmax values of 122 +/- 11 and 275 +/- 18 fmol/mg of protein, respectively). Displacement studies showed a similar order of potency of various unlabeled ligands against [3H]nitrendipine both in rabbit or in turtle: nitrendipine > nifedipine >or= nicardipine >> verapamil >or= diltiazem. Our results show that a two fold increment of [3H]nitrendipine binding sites exists in the turtle brain respect to the rabbit.
The modification of [3H]nitrendipine binding sites in rabbit brain membranes with 2,3-butanedione and diethylpyrocarbonate was investigated. 2,3-Butanedione, an arginine-specific reagent, causes a dose- and time-dependent decrease in the number of [3H]nitrendipine binding sites without altering its dissociation constant. Scatchard analysis of the binding data shows that 50 mM 2,3-butanedione decreases the binding capacity of [3H]nitrendipine from a control value of 71 +/- 6 fmol/mg of protein to 40 +/- 3 fmol/mg of protein. Complete and selective protection against inactivation is provided by nifedipine. No decrease of [3H]nitrendipine binding occurs when membranes are pretreated with selective histidine reagent diethylpyrocarbonate. The results indicate that arginine but not histidine residue in L-type calcium channel domain in critical for [3H]nitrendipine binding.
Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration-related (0.1-0.75 mM) depressant effect on both Adenosine 5'-diphosphate (ADP)-induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl-p-phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)-uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both beta-hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron-sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.