Dependency on sex and stimulus quality of nociceptive behavior in a conscious visceral pain rat model.

Visceral pain may be influenced by many factors. The aim of this study was to analyze the impact of sex and quality of intracolonic mechanical stimulus on the behavioral manifestations of visceral pain in a preclinical model. Male and female young adult Wistar rats were sedated, and a 5 cm long latex balloon was inserted into the colon. Sedation was reverted and behavior was recorded. The pressure of the intracolonic balloon was gradually increased using a sphygmomanometer. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation. Two different types of stimulation were used: tonic and phasic. Phasic stimulation consisted of repeating several times (3x) the same short stimulus (20 s) within a 5 min interval allowing a 1 min break between individual stimuli. For tonic stimulation the stimulus was maintained throughout the whole 5 min interval. Both phasic and tonic stimulation produced a pressure-dependent increase of abdominal contractions. The abdominal response was more intense under phasic than under tonic stimulation, but with differences depending on the sex of the animals: females exhibited more contractions than males and of similar duration at all pressures, whereas duration of contractions pressure-dependently increased in males. The duration of tonically stimulated contractions was lower and not sex- or pressure-dependent. In the rat, responses to colonic distension depend on the quality of the stimulus, which also produces sex-dependent differences that must be taken into account in the development of models of pathology and visceral pain treatments.

[Arterial Hypertension register in private clinics in Venezuela: RHAVEN Study]. / Registro de Hipertensión Arterial en consultas privadas en Venezuela: Estudio RHAVEN.

INTRODUCTION: In Venezuela, no large studies have been conducted to determine the level of control of hypertension (HT). OBJECTIVE: The primary objective was to know the prevalence of controlled HT among hypertensive patients treated pharmacologically. MATERIALS AND METHODS: A cross-section study was conducted on patients 18years and older. RESULTS: A total of 4,320 patients were included. The prevalence of controlled hypertension was 52.6% (95%CI: 51.1-54.1%). The lack of control of HT was associated with diabetes (P<.001), hypertensive heart disease (P<.001), chronic kidney disease (P<.001), and peripheral arterial disease (P=.02). Non-compliance of treatment was also associated with uncontrolled HT (5.1% [117/2,274] in the controlled versus 43.2% [885/2,046] in the uncontrolled; (P<.001). CONCLUSION: The prevalence detected of controlled hypertension was 52.6%.

Preclinical evaluation of the effects on the gastrointestinal tract of the antineoplastic drug vincristine repeatedly administered to rats.

BACKGROUND: Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and motility or its long-term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects. METHODS: Rats received saline or vincristine (0.1 mg kg-1 , ip) daily for 10 days. Evaluations were performed during treatment and 2-6 weeks after. Somatic mechano-sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole-mount myenteric plexus preparations. KEY RESULTS: Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS-immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization. CONCLUSIONS AND INFERENCES: Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine-induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long-lasting.

Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer.

PURPOSE: To evaluate the feasibility, toxicity and efficacy of the combination regimen consisting of gemcitabine-FDR infusion plus erlotinib, in ACP patients. METHODS: Forty-two patients with histologically confirmed, locally advanced or metastatic pancreatic cancer were included in this phase II trial. Main objectives were to assess the efficacy and safety of this regimen. Therapeutic regimen consisted of gemcitabine 1,200 mg/m(2) in 120-min infusion on days 1, 8 and 15, plus erlotinib 100 mg orally once daily. Cycles were repeated every 28 days. RESULTS: A total of 160 courses of gemcitabine-FDR erlotinib were administered (median 3.8 courses per patient). The most common grade 3-4 AEs were neutropenia (21%), thrombocytopenia (10%), skin rash (10%) and asthenia (10%). Complete response was achieved in one patient (2%) and 11 (26%) achieved a partial response. Stable disease and progression disease were observed in 11 patients (26%) and 19 (45%), respectively. Median time to progression was 5 months (95%CI: 3.9-5.8 months) and median overall survival was 8 months (95% CI: 5.1-10.8). One-year survival rate was 35%. CONCLUSIONS: A regimen consisting of gemcitabine-FDR infusion plus erlotinib is active and well tolerated in APC patients. However, the results do not justify the conduct of a Phase III trial.

XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer.

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged > or = 70 years received oxaliplatin 130 mg m(-2) on day 1 followed by oral capecitabine 1000 mg m(-2) twice daily on days 1-14 every 3 weeks. Patients with creatinine clearance 30-50 ml min(-1) received a reduced dose of capecitabine (750 mg m(-2) twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28-49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9-7.8 months) and 13.2 months (95% CI, 7.6-16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand-foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.

Phase II randomised trial of raltitrexed-oxaliplatin vs raltitrexed-irinotecan as first-line treatment in advanced colorectal cancer.

The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m(-2) followed by oxaliplatin 130 mg m(-2) on day 1 (arm A), or CPT-11 350 mg m(-2) followed by raltitrexed 3 mg m(-2) (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5-57.7%) for arm A, and 34% (95% CI, 19.8-48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1-2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3-4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (P<0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3-4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.

Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study.

To evaluate the efficacy and toxicity of irinotecan (CPT-11) in combination with raltitrexed as first-line treatment of advanced colorectal cancer (CRC). A total of 91 previously untreated patients with advanced CRC and measurable disease were enrolled in this phase II study. The median age was 62 years (range 31-77); male/female 54/37; ECOG performance status was 0 in 50 patients (55%), one in 39 (43%) and two in two (2%). Treatment consisted of CPT-11 350 mg x m(-2) in a 30-min intravenous infusion on day 1, followed after 30 min by a 15-min infusion of raltitrexed 3 mg x m(-2). Measurements of efficacy included the following: response rate, time to disease progression and overall survival. Of the 83 evaluable patients valuable to objective response, there were five complete responses (6%) and 23 partial responses (28%), for an overall response rate of 34% (95% CI: 25.9-46.5%). In all, 36 patients (43%) had stable disease, whereas 19 (23%) had a progression. The median time to progression was 11.1 months and the median overall survival was 15.6 months. A total of 487 cycles of chemotherapy were delivered with a median of five per patient. Grade 3-4 WHO toxicities were as follows: diarrhoea in 13 patients (15%), nausea/vomiting in four (4%), transaminase increase in six (7%), stomatitis in two (2%), febrile neutropenia in three (3%), anaemia in five (6%) and asthenia in three (3%). The combination CPT-11-raltitrexed is an effective, well-tolerated and convenient regimen as front-line treatment of advanced CRC.

Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas.

BACKGROUND: The objectives of this study were to evaluate the efficacy and toxicity of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur (UFT) in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-three chemotherapy-naïve patients with adenocarcinoma of the pancreas were included in this phase II study. All of whom had a Karnofsky performance status >or=50 and bi-dimensionally measurable disease (either advanced non-resectable or metastatic); median age 59 years (range 39-77); male:female ratio 29:14. Eight patients (19%) had locally advanced disease and 35 (81%) distant metastases. Treatment consisted of gemcitabine 1200 mg/m(2) given as a 120-min infusion weekly for 3 consecutive weeks, plus oral UFT 400 mg/m(2)/day (in 2-3 doses per day) on days 1-21, cycles were given every 28 days. Measurements of efficacy included response rate, clinical benefit response, time to disease progression and overall survival. RESULTS: A total of 192 cycles of chemotherapy were delivered with a median of four per patient. There were two complete responses (5%) and 12 partial responses (28%), producing an overall response rate of 33% [95% confidence interval (CI) 16% to 49%]. Thirteen patients (30%) had stable disease, whereas 16 (37%) had a progression. The median time to progression was 6 months and the median overall survival was 11 months. Twenty-five patients (64%, 95% CI 47% to 78%) experienced a clinical benefit response. Grade 3-4 WHO toxicities were: neutropenia in nine patients (21%); thrombocytopenia in four (9%); anaemia in five (12%); diarrhoea in four (9%); and asthenia in one (2%). CONCLUSIONS: A fixed dose-rate infusion of gemcitabine associated with UFT was well tolerated and showed promising activity in patients with locally advanced or metastatic carcinoma of the pancreas. This is an appropriate palliative treatment in this setting.

Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group.

BACKGROUND: Use of chemotherapy for advanced pancreatic carcinoma (APC) pursues a palliative objective. Gemcitabine is active against this tumor and shows in vitro synergism with 5-fluorouracil. UFT is a combination of tegafur (a prodrug of 5-flouorouracil) and uracil that can be given orally. The administration of UFT for several weeks may simulate the effects of a continuous infusion of 5-fluorouracil. The objective of the current study was to assess the efficacy and toxicity of the combination gemcitabine-UFT-leucovorin in the treatment of APC. METHODS: Forty-two patients with bidimensionally measurable APC were included. The study regimen consisted of gemcitabine 1000 mg/m(2) once weekly for 3 consecutive weeks, followed by a 1-week rest, intravenous 6S-steroisomer of leucovorin (6SLV) 250 mg/m(2) in 2 hours on Day 1, oral 6SLV 7.5 mg/12 hours on Days 2-14, and oral UFT 390 mg/m(2)/day (in 2 doses) on Days 1-14. Cycles were repeated every 4 weeks for a minimum of 3 per patient unless progressive disease was detected. RESULTS: One hundred eighty-three courses were given, with a median of 4 per patient. World Health Organization Grade 3-4 toxicity was: diarrhea in 7 patients (17%), leucopenia in 2 (5%), nausea/vomiting in 2 (5%), and anemia in 1 (4%). Among 38 patients evaluable for response, 6 achieved a partial response (16%; 95% confidence interval (CI), 6-31. 4), 15 had stable disease (39%), and 17 had progression (45%). Improvement in performance status and symptoms (pain, analgesic consumption, and weight) was present in 11 (29%) and 17 (45%) patients, respectively. Eighteen patients (47%; 95% CI, 31.5-54.5) experienced a clinical benefit response. CONCLUSIONS: The combination of gemcitabine-UFT-6SLV is convenient and moderately active and shows a low toxicity for the palliative treatment of patients with APC.

[Early assessment in perinatal hypoxia. Prognostic markers]. / Evaluación precoz en la hipoxia perinatal. Marcadores pronósticos.

INTRODUCTION: Perinatal asphyxia and its neurological signs are the most important cause of brain damage and neurological sequelae in full term newborn babies. Neuroprotection treatments currently being investigated promise to reduce such sequelae, but these treatments are not without risk and the patients involved should be selected. OBJECTIVE: To analyze a scale composed of variables recorded from the start of delivery until the fourth hour of life, comparing the neurological evolution of the patients. By means of this scale we aim to establish a criterion for the selection of neonates with acute perinatal asphyxia, who would benefit from neuroprotector treatment. PATIENTS AND METHODS: A retrospective study was made of 50 patients with the diagnosis of perinatal asphyxia. Our scale was formed of the following variables: intrauterine meconiorrhexis, pathological cardiotocographic recordings, resuscitation at birth, Apgar score at five minutes, pH of the umbilical artery blood, neurological examination, multisystemic involvement, seizures, persistent metabolic acidosis and need for mechanical ventilation during the first hours of life. The patients were followed up for at least one year by means of periodical studies (neurological examination and evaluation of psychomotor development according to the Brunnet Lezinne test). For statistical analysis we used the chi squared test, Fisher's exact test, Kruskal-Wallis test and the area beneath the ROC curve. RESULTS AND CONCLUSIONS: The scale presented constitutes a rapid, easy method which is statistically significant for the selection of perinatal asphyxia of high neurological risk which would benefit from neuroprotector treatment after the event.

Gemcitabine plus vinorelbine in nonsmall cell lung carcinoma patients age 70 years or older or patients who cannot receive cisplatin. Oncopaz Cooperative Group.

BACKGROUND: Although the prevalence of nonsmall cell lung carcinoma (NSCLC) is high among elderly patients, few data are available regarding the efficacy and toxicity of chemotherapy in this group of patients. Recent reports indicate that single agent therapy with vinorelbine (VNB) or gemcitabine (GEM) may obtain a response rate of 20-30% in elderly patients, with acceptable toxicity and improvement in symptoms and quality of life. In the current study the efficacy and toxicity of the combination of GEM and VNB in elderly patients with advanced NSCLC or those with some contraindication to receiving cisplatin were assessed. METHODS: Forty-nine patients with advanced NSCLC were included, 38 of whom were age >/= 70 years and 11 were age < 70 years but who had some contraindication to receiving cisplatin. All patients were evaluable for response and toxicity. Treatment was comprised of VNB, 25 mg/m(2), plus GEM, 1000 mg/m(2), both on Days 1, 8, and 15 every 28 days. Patients received a minimum of three courses unless progressive disease was detected. RESULTS: One hundred sixty-five courses were administered, with a median of 3. 6 courses per patient. The overall response rate was 26% (95% confidence interval, 15-41%). Two patients attained a complete response (4%) and 11 patients (22%) achieved a partial response. Eastern Cooperative Oncology Group performance status improved in 35% of those patients with an initial value > 0, whereas relief of at least 1 symptom without worsening of other symptoms was noted in 27 patients (55%). The median time to progression was 16 weeks and the 1-year survival rate was 33%. Toxicity was mild. Six patients (12%) had World Health Organization Grade 3-4 neutropenia, 2 patients (4%) had Grade 3-4 thrombocytopenia, and 2 patients (4%) had Grade 3 neurotoxicity. Three patients with severe neutropenia (6%) died of sepsis. The median age of those patients developing Grade 3-4 neutropenia was significantly higher than that of the remaining patients (75 years vs. 72 years; P = 0.047). CONCLUSIONS: The combination of GEM and VNB is moderately active and well tolerated except in patients age >/= 75 years. This age group had an increased risk of myelosuppression. Therefore the prophylactic use of granulocyte-colony stimulating factor should be considered with this treatment. New chemotherapy combinations with higher activity and lower toxicity are needed for elderly patients with advanced NSCLC.

Treatment of superior and inferior vena cava syndromes of malignant cause with Wallstent catheter placed percutaneously.

Superior vena cava syndrome (SVCS) and inferior vena cava syndrome (IVCS) represent a severe symptomatic complication of some malignant tumors. Although radiation therapy and chemotherapy are elective, symptomatic relief takes 7-10 days to be achieved, and poor symptomatic benefit can be obtained in relapsed or resistant tumors. We report on a palliative approach using Wallstent catheters placed percutaneously in a series of 16 patients. Results obtained in relief of symptoms were excellent (complete response of cephalea, jugular enlargement, and collateral circulation achieved in 100% [16/16] of patients; complete response of edema obtained in 93% [15/16] of patients). Achievement of symptomatic response was obtained for all symptoms during the first 24 h poststenting, except for edema and dyspnea. Mean duration of patency of the stents was 6.4 months (range 2-17 months). Rates of morbidity and complications were very low. Dyspnea was a quite resistant symptom, and only four of 13 patients (31%) obtained complete response, while partial improvement was obtained in the other nine (79%). However, placement of the stents does not preclude the use of radiation therapy or chemotherapy. We think that these results and those from other studies warrant larger multicentric trials.

Radiosurgery of epilepsy. Long-term results.

Based on experimental research, since 1982 until 1991 a series of 11 patients diagnosed as suffering from idiopathic focal epilepsy have been treated with stereotactic radiosurgery. Focus location was determined with cortical electrodes and confirmed by stereotactically placed deep electrodes. Stereotactic radiosurgery was performed with photons from a cobalt source with a dose of 10 to 20 Gy, except in two cases in whom a betatron was used. The results were: complete cessation of seizures in four cases and a significant reduction in the number of seizures in five additional cases. Seizures began to decrease gradually after a period of three months of one year, except in two cases in whom there was an immediate response after treatment. In two cases there was no change. No complication related to the irradiation was recorded. The gradual and delayed effect, obtained with low doses, may favour the hypothesis that non-descructive permanent structural changes, possibly related to the neuronal plasticity phenomenon, constitute the mechanism underlying these facts. Although the number of cases so far is too small, the absence of side-effects may make this bloodless method the one of choice specially in those cases in whom eloquent areas are involved.

Stereotactic radiosurgery may be effective in the treatment of idiopathic epilepsy: report on the methods and results in a series of eleven cases.

Between 1982 and 1991, 11 patients (4 male, 7 female) ranging in age from 16 to 42 years who had been diagnosed with idiopathic focal epilepsy resistant to medication, were treated with stereotactic radiosurgery. The preoperative symptomatic period was 3-24 years. The process of localizing epileptic focus was based on chronic electrocorticography with flexible electrodes introduced into the subarachnoid space through single burr holes, and left in place during a maximum of 7 days until a clinical seizure was recorded. In most cases the procedure had to be repeated until localization was clear. This process was aided by a computer-assisted automatic analysis procedure. Final confirmation of focus location was done with depth electrode recording in most cases. Stereotactic radiosurgery was performed with a 60Co gamma source using 10 mm collimators, except in two cases in which a betatron was used. The estimated dose was 10-20 Gy at the isocenter. Four of the 11 patients (36%) were medication- and seizure-free after a mean follow-up of 102.5 months. Five patients (45%) presented a reduction of seizures of 98, 89, 86, 75 and 75%, respectively. Two patients did not respond to treatment. Seizure reduction began after a delay period of 2-12 months except in 2 patients and in most cases seizure rate decreased progressively during several months (range: 3-48) postoperatively until stabilization. No complications related to irradiation were recorded. Doses effective for epilepsy are much lower than those for producing cerebral lesions, so the mechanism is not destruction of the focus of the pathways spreading the epileptic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiosurgery of epilepsy.

Since 1982 a series of 11 epileptic patients have been treated with stereotactic radiosurgery. Patients were intracranially recorded with cortical and deep electrodes until the location of the epileptogenic focus was determined. A deep electrode was stereotactically placed at this point to confirm the accuracy of the location. All patients received radiosurgery with a gamma source and a dose of 10 to 20 Gy, except two of them in which a betatron was used. The results were: Total disappearance of the crises and withdrawal of medication: 4 cases (36%). More than 80% reduction of crises: 3 cases (27%). More than 50% reduction of crises: 2 cases (18%). Less than 50% reduction of crises: 2 cases (18%). No complications were observed, even in those cases in which the focus was located near critical areas of the brain. The efficacy of the low doses used accounts for non-destructive mechanisms, probably mediated by a neuronal plasticity phenomenon, as experimental studies suggest. The lack of complications can make this therapeutic approach an alternative to be considered when critical areas are involved.