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Biomedical subjects

R Adam

Publications and source records attributed to R Adam.

At least 91 records · Page 5Linked to original sources
PubMed1997

A 41-kDa antigen of the rodent filaria Acanthocheilonema viteae with homologies to tropomyosin induces host-protective immune responses.

A purified 41-kDa protein of the rodent filaria Acanthocheilonema viteae was shown to protect jirds against a challenge infection. Subcutaneous immunization with the protein reduced the number of adult worms by up to 65% and the number of circulating microfilariae declined by up to 93% in these animals. The protein is located in the muscle tissues of adult worms and was identified as tropomyosin by N-terminal sequencing of the purified protein.

Amino Acid Sequence↗
PubMed1997

Aneuploidy in twin gestations: when is maternal age advanced?

OBJECTIVE: To determine the maternal age at which twin gestations have a risk of fetal aneuploidy comparable to that of singleton pregnancies at maternal age 35, accounting for variation in dizygotic twinning rates by maternal age and race. METHODS: Known aneuploidy risks and rates of dizygotic twinning by maternal age and race were used to calculate the risk of fetal aneuploidy at term and in the second trimester by maternal age and race in twin gestations, using previously published calculations. RESULTS: The risk of at least one aneuploid twin at term is 1/193 at maternal age 31 for both white and African-American women, which is comparable to the risk of 1/192 for an aneuploid singleton term pregnancy at maternal age 35. The risk of at least one aneuploid twin at amniocentesis at maternal age 31 is 1/190 for white and 1/187 for African-American women, which is slightly lower than the rate in singletons of 1/135. CONCLUSION: Invasive prenatal diagnosis for detection of fetal aneuploidy should be offered to all women with twin gestations at age 31, regardless of race.

Adult↗
PubMed1997

Place of cryosurgery in the treatment of malignant liver tumors.

OBJECTIVE: The authors evaluate the results of cryosurgery in malignant liver tumors. SUMMARY BACKGROUND DATA: The outcome of primary or secondary liver tumors is poor when resection can not be achieved. Encouraging results of cryosurgery have been reported in unresectable liver tumors, but this treatment needs further evaluation of its efficacy in homogeneous groups of patients. METHODS: From 63 patients with malignant liver tumors with various histology treated by cryosurgery in a 2.5-year period, the authors evaluated the results of 34 patients with nonresectable hepatocellular carcinoma (9 patients) or nonresectable metastases from colorectal cancer (25 patients). Cryosurgery was used either as a single treatment (4 hepatocellular carcinomas, 5 metastases) or in association with liver resection (5 hepatocellular carcinomas, 20 metastases). Systemic chemotherapy was used routinely before surgery and after surgery. RESULTS: There was no intraoperative mortality. Mortality within 2 months was 3% and was unrelated to the procedure. Postoperative morbidity consisted of one sterile fluid collection and one biliary fistula (8%). At a mean follow-up of 16 months, (range, 2-27) local recurrence rate was 0% for hepatocellular carcinoma and 44% for metastases. Cumulative survival at 24 months was 63% and 52%, respectively, with 6 patients (67%) and 5 patients (20%) currently disease free. In the group of patients with metastases, survival was related to the size of the treated tumor (p = 0.06) and the absence of residual disease (p = 0.03). CONCLUSIONS: Cryosurgery is safe and increases the number of patients with unresectable liver malignancies in whom surgery can aim at eradicating the tumor. Local recurrence is observed more frequently for metastases than for hepatocellular carcinoma. The benefit in survival is related to the complete treatment of the tumoral disease.

Adult↗
PubMed1997

Repeat hepatectomy for colorectal liver metastases.

OBJECTIVE: The authors assess the long-term results of repeat hepatectomies for recurrent metastases of colorectal cancer and determine the factors that can predict survival. SUMMARY BACKGROUND DATA: Safer techniques of hepatic resection have allowed surgeons to consider repeat hepatectomy for colorectal metastases in an increasing number of patients. However, higher operative bleeding and increased morbidity have been reported after repeat hepatectomies, and the long-term benefit of these procedures needs to be evaluated. STUDY POPULATION: Sixty-four patients from a group of 243 patients resected for colorectal liver metastases were submitted to 83 repeat hepatectomies (64 second, 15 third, and 4 fourth hepatectomies). Combined extrahepatic surgery was performed in 21 (25%) of these 83 repeat hepatectomies. RESULTS: There was no intraoperative or postoperative mortality. Operative bleeding was not significantly increased in repeat hepatectomies as compared to first resections. Morbidity and duration of hospital stay were comparable to first hepatectomies. Overall and disease-free survival after a second hepatectomy were 60% and 42%, respectively, at 3 years and 41% and 26%, respectively, at 5 years. Factors of prognostic value on univariate analysis included the curative nature of first and second hepatectomies (p = 0.04 and p = 0.002, respectively), an interval between the two procedures of more than 1 year (p = 0.003), the number of recurrent tumors (p = 0.002), serum carcinoembryonic antigen levels (p = 0.03), and the presence of extrahepatic disease (p = 0.03). Only the curative nature of the second hepatectomy and an interval of more than 1 year between the two procedures were independently related to survival on multivariate analysis. CONCLUSIONS: Repeat hepatectomies can provide long-term survival rates similar to those of first hepatectomies, with no mortality and comparable morbidity. Combined extrahepatic surgery can be required to achieve tumor eradication. Repeat hepatectomies appear worthwhile when potentially curative.

Adult↗
PubMed1997

Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis.

OBJECTIVE: To investigate the impact of preoperative transarterial lipiodol chemoembolization (TACE) in the management of patients undergoing liver resection or liver transplantation for hepatocellular carcinoma. PATIENTS AND METHODS: TACE was performed before surgery in 49 of 76 patients undergoing resection and in 54 of 111 patients undergoing liver transplantation. Results were retrospectively analyzed with regard to the response to treatment, the type of procedure performed, the incidence of complications, the incidence and pattern of recurrence, and survival. RESULTS: In liver resection, downstaging of the tumor by TACE (21 of 49 patients [42%]) and total necrosis (24 of 49 patients [50%]) were associated with a better disease-free survival than either no response to TACE or no TACE (downstaging, 29% vs. 10% and 11 % at 5 years, p = 0.08 and 0.10; necrosis, 22% vs. 13% and 11% at 5 years, p = 0.1 and 0.3). Five patients (10%) with previously unresectable tumors could be resected after downstaging. In liver transplantation, downstaging of tumors >3 cm (19 of 35 patients [54%]) and total necrosis (15 of 54 patients [28%]) were associated with better disease-free survival than either incomplete response to TACE or no TACE (downstaging, 71 % vs. 29% and 49% at 5 years, p = 0.01 and 0.09; necrosis, 87% vs. 47% and 60% at 5 years, p = 0.03 and 0.14). Multivariate analysis of the factors associated with response to TACE showed that downstaging occurred more frequently for tumors >5 cm. CONCLUSIONS: Downstaging or total necrosis of the tumor induced by TACE occurred in 62% of the cases and was associated with improved disease-free survival both after liver resection and transplantation. In liver resection, TACE was also useful to improve the resectability of primarily unresectable tumors. In liver transplantation, downstaging in patients with tumors >3 cm was associated with survival similar to that in patients with less extensive disease.

Aged↗
PubMed1997

[Vascular clamping of the liver. Indications and limits].

Control of bleeding during liver surgery is an essential prognostic factor for postoperative morbidity and mortality. Several well defined methods are currently available to ensure vascular occlusion, ranging from selective clamping of a segmental pedicle to total vascular exclusion of the liver. These methods of vascular control each have specific indications. However, they can induce ischaemia of the liver whose functional consequences, such as postoperative liver failure, are particularly severe in the case of prolonged ischaemia, affecting the remaining liver and in the presence of histological or functional alterations of the hepatic parenchyma. Selective methods of vascular control, only affecting the part of the liver to be resected, can be used systematically. In contrast, when the occlusion is not selective, they must be used sparingly, essentially in the case of bleeding from the parenchymal section, adopting the principal objective of the briefest possible total ischaemia. Minimization of bleeding must be weighed up against the consequences of ischaemia on the remaining liver, especially in the case of extensive hepatectomy, prolonged clamping and pathological non-neoplastic liver.

Blood Loss, Surgical↗
PubMed1996

Beneficial effects of Eurocollins as aortic flush for the procurement of human livers.

A review of 550 consecutively transplanted liver grafts stored in University of Wisconsin solution (UW) was performed during a 4-year period to ascertain whether graft function was impaired by flushing the aorta with Eurocollins (EC) rather than UW during the harvesting. The outcome of 255 liver grafts flushed with UW in both the aorta and portal vein (group UW/UW) was compared with 295 liver grafts flushed with EC through the aorta and UW through the portal vein (group ECUW). Liver grafts in both groups were flushed with 1 L of UW during the back table procedure and subsequently stored in UW at 4 degrees C before transport. Donor and recipient characteristics, cold and warm ischemia times, and methods of transplantation were similar in both groups, except that the recipient prothrombin time (PT) before liver transplantation (LT) was lower in the UW/UW group. There was no significant difference between the groups with peak transaminases aspartate aminotransferase (AST) and alanine aminotransferase, maximum value of serum bilirubin within 10 days following LT, incidence of primary nonfunction, need for retransplantation, and patient and graft survival at 1 month. Results were improved, however, in the EC/UW group in regard to PT after LT, operative bleeding and proportion of grafts with histologic lesions at the reperfusion biopsy (P<0.001). These better results in the EC/UW group were confirmed when grafts transplanted in urgent situations were excluded from analysis and by multivariate analysis assessing the effects of pretransplant PT and AST values of the recipients combined with the method of liver cooling with each of the aforementioned criteria. In conclusion, the method of using EC for the aortic flush during liver procurement reduces the amount of UW solution by 50% with improved graft function. This method seems justified in that it is less expensive while affording improved graft function.

Adenosine↗
PubMed1996

Identification of chitinase as the immunodominant filarial antigen recognized by sera of vaccinated rodents.

Acanthocheilonema viteae is a parasitic nematode of rodents. We identified the chitinase of A. viteae infective stage larvae (L3) as the main target of the humoral immune response of jirds, which were protected against challenge infection after vaccination with irradiation attenuated L3. The cDNA of the L3 chitinase has been sequenced, and the deduced amino acid sequence shows significant homologies to chitinases of Brugia malayi microfilariae, insects, yeast, bacteria, and Streptomyces sp. The protein has been characterized by monoclonal antibodies and substrate activity gels. The chitinase of L3 may contribute to degrading the nematode cuticle during molting and thus represents a target of protective immune responses in a phase where the parasite is highly vulnerable. In addition, it has been shown that a similar enzyme exists in uterine microfilariae, which probably has a role in casting the egg shell.

Amino Acid Sequence↗
PubMed1996

Beneficial effect of alanine on metabolic recovery of fasted livers submitted to cold ischemia.

The aim of this study was to investigate the possible beneficial effect on perfused mouse liver of alanine as an exogenous substrate for gluconeogenesis. Livers from fed and fasted animals were perfused with oxygenated Krebs' Henseleit buffer for 30 min, then stored at 4 degrees C in University of Wisconsin solution for 48 h. Then reperfusion at 37 degrees C was performed according to two protocols. In the first one, reperfusion with alanine-free Krebs' Henseleit buffer was used for 1 h. 8 mM (3-(13)C) alanine was then added and perfusion was prolonged for a second hour. In the second one, the first hour of perfusion was omitted and the organs were reperfused directly for an hour in the presence of 8 mM (3-(13)C)alanine. 31P NMR was used to measure the NTP recovery of the livers. At the end of the reperfusions, 13C and 1H NMR spectra of perfusates and of glutamine extracted from these perfusates by HPLC were recorded. These data were analysed according to a model of liver metabolism assuming that the only substrate of the liver was (3-(13)C)alanine and endogenous substrates were metabolizable only through pyruvate. It was found that in the absence of initial alanine at reperfusion, livers from fasted mice recovered less NTP than those of fed ones (40 +/- 4% vs 60 +/- 5%, p <0.01), but not if this substrate is present at the beginning of reperfusion (61 +/- 5% vs 60 +/- 5%). This was confirmed by the amount of labelled metabolites produced. However, the dilution of 13C labelled metabolites by unlabelled ones did not indicate a larger concentration of endogenous substrates in livers from fed mice. The conclusion reached was that the lower pyruvate dehydrogenase activity of livers from fasted mice relatively to that from fed mice could be compensated for by the greater pyruvate concentration provided by alanine for the initial production of NTP after cold ischemia and warm reperfusion.

Alanine↗
PubMed1996

Urinary thromboxane B2 as an indicator of acute rejection in human liver transplantation.

Urinary thromboxane B2 (u-TXB2) was measured and analyzed after a human liver transplantation in 28 patients (30 transplantations) who underwent an orthotopic liver transplantation. Our results showed that the u-TXB2 levels exceeded 3.0 micrograms/mmol creatinine in only 2 of the 13 cases that had a favorable postoperative course. In 10 of the 11 episodes of acute rejection, the u-TXB2 levels exceeded 3.0 micrograms/mmol creatinine. In 6 episodes of acute rejection, the TXB2 levels were more than 5.0. In 4 out of 6 episodes of infection unassociated with rejection, the u-TXB2 values were between 3.0 and 4.9 micrograms/mmol creatinine. In 2 episodes of liver necrosis the TXB2 value reached 5.3 in one and 0.9 in the other. In conclusion, the u-TXB2 level was observed to be elevated in cases of acute rejection, infection, or necrosis. The diagnosis of acute rejection on the basis of u-TXB2 showed a sensitivity of 58.8%, a specificity of 93.3%, and an accuracy of 75.0% for a threshold level of 3.0 micrograms/mmol creatinine, and a sensitivity of 85.7%, a specificity of 79.2%, and an accuracy of 80.6% for a threshold level of TXB2 of 5.0 micrograms/mmol creatinine. These results indicate that the serial determination of u-TXB2 is a useful diagnostic means for predicting acute rejection after liver transplantation.

Adolescent↗
PubMed1996

Teaching effectiveness of the advanced trauma life support program as demonstrated by an objective structured clinical examination for practicing physicians.

Although the Advanced Trauma Life Support (ATLS) course is now taught internationally, its teaching effectiveness still requires confirmation. The Objective Structured Clinical Examination (OSCE) reliably assesses clinical performance by utilizing standardized patients. An OSCE of eight 15 minute trauma patient stations and two 40 item MCQ tests were used to test the teaching effectiveness of the ATLS program in 32 practicing physicians who applied for an ATLS program in Trinidad and Tobago. The physicians were randomly assigned to an ATLS group (n = 16) that completed the ATLS course and a non-ATLS group (n = 16). Before and after the ATLS course, all physicians completed MCQ tests and trauma OSCE. Mean (+/- SD) OSCE scores (standardized to 20) ranged from 9.8 +/- 1.7 to 10.0 +/- 1.7 and 9.5 +/- 1.8 to 10.8 +/- 1.3 in the ATLS and non-ATLS groups, respectively, prior to the ATLS course (NS). Post-ATLS OSCE scores ranged from 15.9 +/- 1.7 to 17.6 +/- 1.7 in the ATLS group (p < 0.05 compared to pre-ATLS) and 9.5 +/- 1.4 to 10.1 +/- 1.3 in the non-ATLS group, which did not improve their OSCE scores. Adherence to priorities was graded 1 to 7 with the pre-ATLS grades of 1.7 +/- 0.6 (ATLS) and 1.8 +/- 0.7 (non-ATLS) and post-ATLS grades of 6.4 +/- 1.1 (ATLS) and 2.1 +/- 0.6 (non-ATLS). Organized approach to trauma was graded 1 to 5 with pre-ATLS grades of 1.6 +/- 0.5 (ATLS) and 1.7 +/- 0.6 (non-ATLS) and post-ATLS grades of 4.5 +/- 0.6 (ATLS) and 1.9 +/- 0.6 (non-ATLS). Pre-ATLS MCQ scores (%) were similar: 53.1 +/- 8.4 (ATLS) and 57.3 +/- 5.4 (non-ATLS), but post-ATLS scores were greater in the ATLS group: 85.8 +/- 7.1 (ATLS) and 64.2 +/- 3.6 (non-ATLS). Our data support the teaching effectiveness of the ATLS program among practicing physicians as measured by improvement in OSCE scores, adherence to trauma priorities, maintenance of an organized approach to trauma care, and cognitive performance in MCQ examinations.

Clinical Competence↗
PubMed1996

Chitinase genes expressed by infective larvae of the filarial nematodes, Acanthocheilonema viteae and Onchocerca volvulus.

State-specific products of 220 and 75 kDa were identified by metabolic labelling of infective larvae of the filarial nematode Acanthocheilonema viteae in ticks. Synthesis was temperature sensitive, occurring at 27 degrees C but not at 37 degrees C. These products were secreted 3-6 days after leaving the vector during post-infective development, but subsequent expression was not detected. The smaller protein with a pI of 6.2, was purified by two-dimensional electrophoresis and the N-terminal amino acid sequence was derived. This provisionally identified the protein as a chitinase, which was confirmed biochemically by glycol-chitin substrate gel electrophoresis. The polymerase chain reaction was used to amplify a product from a cDNA library of A. viteae infective larvae. The nucleotide sequence codes for a putative signal peptide of 20 amino acids and a mature protein of 504 residues (Mr 56 kDa), exhibiting 69% identity (81% similarity allowing for conservative substitutions) with the MF1 chitinase described from microfilariae of Brugia malayi. N-linked glycosylation may account for some, or all, of the discrepancy in Mr between the predicted polypeptide and the native parasite product (75 kDa). Primers based on the A. viteae sequence were used to amplify a related sequence from a cDNA library of Onchocerca volvulus infective larvae. The O. volvulus cDNA codes for a 20-amino acid signal peptide followed by 477 residues with an Mr of 54 kDa, and shares 67% identity with the A. viteae chitinase (80% similarity allowing for conservative substitutions) and 69% identity with the B. malayi MF1 molecule. It is proposed that chitinases expressed by infective stages of these filarial nematodes may play a role in ecdysis during post-infective development.

Amino Acid Sequence↗
PubMed1996

Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.

OBJECTIVE: The authors discuss the technique and evaluate the results of an aggressive surgical approach in patients with primarily unresectable colorectal liver metastases that were downstaged by chronomodulated chemotherapy. BACKGROUND: Resection is the best treatment of colorectal liver metastases, but it may be achieved in only 10% of patients. In the remaining 90%, survival is poor, even after partial response to chemotherapy. Little is known about the results of curative hepatectomy in patients whose metastases are downstaged by chemotherapy. PATIENTS AND METHODS: Fifty-three patients with colorectal liver metastases initially unresectable because of ill located (8), large (8), multinodular (24) lesions, or because of extrahepatic disease (13) were downstaged by a systemic chronomodulated chemotherapy associating 5-fluorouracil, folinic acid and Oxaliplatin to the point that operation could be performed. This consisted of a major hepatectomy in 37 patients and a minor resection in 16. Associated procedures (including 5 two-stage hepatectomies and 3 pulmonary resections) were performed in 25 patients. RESULTS: There was no operative mortality. Complications occurred in 14 patients. The cumulative 3- and 5-year survival rates were 54% and 40% (according to the type of lesions: ill-located, 75% and 48%; large, 62% and 62%; multinodular, 54% and 40%; extrahepatic, 43% and 14%). Hepatic recurrence (34 patients, 64%) was amenable to repeat surgery in 15 cases. CONCLUSIONS: Liver resection may be achieved in some previously unresectable patients with the help of an effective chemotherapy. The benefit in survival seems comparable to that obtained with primary liver resection (40% at 5 years). This therapeutic strategy involves a multimodal approach, including repeat hepatectomies and extrahepatic surgery.

Aged↗
PubMed1996

Split-liver transplantation. The Paul Brousse policy.

OBJECTIVE: The authors objective is to report their recent experience with split-liver transplantation, focusing on the results and the impact on organ shortage. SUMMARY BACKGROUND DATA: There is an insufficient number of organs for liver transplantation. Split-liver transplantation is a method to increase the number of grafts, but the procedure is slow to gain wide acceptance because of its complexity and the poor results reported in previous series. METHODS: During the year 1995, the authors split 20 of 83 transplantable livers allocated to the authors' center, generating 40 grafts: 23 were transplanted locally and 17 were given to partner centers. During the same period, the authors accepted four split-liver grafts proposed to them by other centers. Overall, 27 split-liver transplantations were done in the authors' unit, accounting for 30% of the 90 transplants performed in 1995. RESULTS: One-year patient and graft survival rates for split-liver transplantation were 79.4% and 78.5%, respectively. Arterial and biliary complications rates were 15% and 22%, respectively, with none leading to graft loss. Primary nonfunction occurred in one case (4%). By splitting 24 of 87 transplantable livers (4 of which were in partner units), a total of 111 transplantations were performed, increasing graft availability by 28%. CONCLUSIONS: Split-liver transplantation is achieving graft and patient survival rates similar to that of whole liver transplantation despite a higher incidence of complications, which could become less frequent as experience is gained with this procedure. A wider acceptance of split-liver transplantation could markedly increase the supply of liver grafts.

Adult↗
PubMed1996

Attrition of cognitive and trauma management skills after the Advanced Trauma Life Support (ATLS) course.

OBJECTIVE: To test the attrition of cognitive and trauma management skills among practising physicians after the Advanced Trauma Life Support (ATLS) course. DESIGN, MATERIALS, AND METHODS: Sixty practising physicians who completed the ATLS course had comparative assessment of cognitive skills (with multiple choice questions, MCQ) pre-ATLS, immediately post-ATLS, at 6 months (group A), 2 years (group B), 4 years (group C), and 6 years (group D) after the course. Trauma management skills were also compared using eight Objective Structured Clinical Examination (OSCE) trauma stations completed by the four groups of physicians. MEASUREMENTS AND MAIN RESULTS: Pre-ATLS MCQ scores (54.2 +/- 4.2 to 59.8 +/- 5.3%) and immediately post-ATLS MCQ scores (85.9 +/- 5.1 to 87.7 +/- 5.3%) were similar in all four groups. Follow-up MCQ scores were 77.8 +/- 3.6% at 6 months 70.6. +/- 1.9% at 2 years, 69.4 +/- 1.7% at 4 years, and 68.9 +/- 2.0% at 6 years. OSCE scores out of a maximum of 20 were 16.8 +/- 0.3 at 6 months, 13.9 +/- 0.1 at 2 years, 12.0 +/- 0.1 at 4 years, and 11.9 +/- 0.1 at 6 years. Adherence-to-priorities scores (maximum, 7) were 6.6 +/- 0.2 at 6 months, 6.8 +/- 0.1 at 2 years, 6.6 +/- 0.1 at 4 years, and 6.6 +/- 0.1 at 6 years. Organized-approach scores (maximum, 5) were 4.8 +/- 0.1 at 6 months, 4.6 +/- 0.2 at 2 years, 4.7 +/- 0.2 at 4 years, and 4.6 +/- 0.2 at 6 years. Using the MCQ 80% pass mark criterion, at least 50% of physicians fail by 6 months and all fail this cognitive test thereafter. CONCLUSIONS: Whereas cognitive and trauma management skills decline after the ATLS, these skills are maintained at similar levels between 4 and 6 years after ATLS. A 50% failure rate occurs within 6 months and maximum attrition of cognitive skills occurs within 2 years of ATLS completion. Major principles of adherence to priorities and maintenance of an organized approach to trauma care are preserved for at least 6 years after ATLS.

Adult↗
PubMed1996

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Adolescent↗
PubMed1996

Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. II. Pharmacological profile.

The pharmacological profile of befloxatone, a reversible, selective and competitive inhibitor of monoamine oxidase-A has been investigated in rodents. In mice, befloxatone was more active at potentiating generalized tremors induced by L-5-hydroxytryptophan (ED50, 0.21 mg/kg p.o.) than phenylethylamine-induced stereotypies (ED50, 58 mg/kg p.o.), indicating a very high in vivo selectivity for inhibition of the A form of monoamine oxidase. Befloxatone showed potent activity in behavioral models in rodents predictive of antidepressant activity (forced swimming test, learned helplessness and reserpine reversal) with minimal effective doses of 0.1 to 0.2 mg/kg p.o. In these tests, befloxatone was much more potent (10- to 500-fold) than reference antidepressant compounds (reversible and irreversible monoamine oxidase inhibitors and monoamine reuptake inhibitors). In rats, befloxatone increased rapid eye movement sleep latency and decreased rapid eye movement sleep duration, without rebound effects. Potential anxiolytic activity was observed in the elevated-plus maze test in rats (minimal effective dose, 1-2 mg/kg p.o.). Befloxatone had no effect on motor performance, did not induce sedative or stimulant activity up to doses of 200 mg/kg p.o. and was devoid of anticholinergic activity in mice. Interaction studies with p.o. dietary tyramine (12 mg/kg), carried out in freely moving rats, demonstrated that, in contrast to irreversible monoamine oxidase inhibitors, befloxatone did not potentiate the pressor effect of this amine in the range of doses which showed pharmacological activity in antidepressant behavioral models. Furthermore, of the compounds tested (moclobemide, brofaromine, nialamide and phenelzine), comparison of doses active in antidepressant models and doses potentiating the pressor effects of tyramine demonstrated that befloxatone had the best therapeutic index. The results suggest that befloxatone will show clinical antidepressant activity at low doses and will be devoid of the side effects associated with irreversible monoamine oxidase inhibitors.

Animals↗