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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
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↗
PubMed1996

Re-resection for colorectal liver metastasis.

With the decreasing mortality and morbidity of liver resection in the last 10 years, a more aggressive approach has emerged against liver metastases of colorectal cancer. Repeat liver resection is being performed for patients with isolated liver recurrence following a first hepatectomy. Based on a 2-year experience of 55 repeat hepatic resections performed in 44 patients, the authors observed no operative mortality and a postoperative morbidity of 15% similar to that of first hepatectomies. Five-year survival rate is 44% following second hepatectomy. These results combined with the review of the literature demonstrate that rehapectomy may be performed safely and may provide the only chance of long-term remission in patients presenting with technically resectable liver recurrence in the absence of widespread extrahepatic disease.

Colonic Neoplasms↗
PubMed1995

Modulation of the receptor binding affinity of amphiregulin by modification of its carboxyl terminal tail.

Amphiregulin (AR), a heparin-binding, epidermal growth factor (EGF) receptor ligand has homology with EGF but exhibits a lower affinity for the EGF receptor than EGF. As the mature form of AR is truncated at the C terminus and lacks a conserved leucine residue known to be essential for high affinity binding of EGF to the EGF receptor, wild-type AR (AR1-84), a C-terminally extended AR construct incorporating six residues from the predicted coding sequence of AR (AR1-90) and a similarly extended construct with a Met86 to Leu substitution (AR1-90(leu86)) were expressed as recombinant proteins in yeast, purified by heparin affinity and C18 reverse phase chromatography and their relative biological activities determined. The growth factors were tested in mitogenesis and EGF receptor autophosphorylation assays and their relative order of potencies was found to be leu86 > met86 > wt. The AR1-90(leu86) construct was found to be 50- to 100-fold more active than wild type AR1-84 consistent with previously reported studies of the role of the equivalent C-terminal leucine in EGF or TGF alpha. Significantly, the C-terminally extended form of AR, AR1-90, which utilized six residues from the predicted coding sequence, was 10-times more active than wild type AR1-84. This difference in activity of the C-terminally extended form of AR may be of biological significance since differential proteolytic processing of the AR precursor in vivo could result in production of multiple forms of the growth factor with differing affinities for the EGF receptor and hence differing biological potencies.

Amphiregulin↗
PubMed1995

Molecular cloning and characterization of the filarial LIM domain proteins AvL3-1 and OvL3-1.

A full-length cDNA of the filarial nematode Acanthocheilonema viteae was isolated from a cDNA library of female worms, using a partial cDNA of the OvL3-1 gene of Onchocerca volvulus as a probe. The AvL3-1 cDNA contained an open reading frame which encoded for a protein with a theoretical molecular weight of 64 kDa. The deduced protein contained a predicted signal sequence, a short repetitive motive of unknown function, and three LIM domains. The structure of the LIM domains was identical to those of zyxin, a cytoskeleton-associated protein of chicken fibroblasts, suggesting that AvL3-1 has a similar role in filarial nematodes. The sequence information was used to isolate the homologous cDNA of O. volvulus by PCR from a cDNA library of female O. volvulus, which showed an overall identity of 76.9% to AvL3-1 on the protein level. AvL3-1 was expressed in Escherichia coli and the affinity-purified fusion free protein was used to immunized jirds (Meriones unguiculatus). Immunization together with the adjuvant STP or with Freund's adjuvant induced IgG and IgM antibody responses, but no significant protection against a challenge infection with L3 of A. viteae, compared to appropriate control groups.

Amino Acid Sequence↗
PubMed1995

Morphology and ultrastructure of the digestive gland of Bithynia siamensis goniomphalus (Prosobranchia: Bithyniidae) and alterations induced by infection with the liver fluke Opisthorchis viverrini (Trematoda: Digenea).

The morphology and ultrastructure of the digestive gland of Bithynia siamensis goniomphalus and its alteration by infection with Opisthorchis viverrini were investigated by light and electron microscopy. The digestive gland of B. s. goniomphalus was composed of three different cell types: digestive cells, excretory cells, and narrow cells. In infected animals the number of excretory cells increased dramatically. Cellular injury in digestive cells as well as in excretory cells following the infection could be observed at the ultrastructural level.

Animals↗
PubMed1995

[Results of posterior chamber lens implantation with trans-scleral sulcus suture fixation].

BACKGROUND: Transscleral fixation of a posterior chamber intraocular lens has been proposed in eyes lacking adequate posterior capsular support. METHODS: We performed a retrospective review of 38 eyes of 38 patients who had a 12 months follow-up. Visual acuity, intraocular pressure and complications have been studied. We performed a transscleral fixation of posterior chamber lens with the following indications: 1. planned intraocular cataract extraction; 2. following intraoperative complications of phacoemulsification; 3. in combination with perforating keratoplasty; 4. in combination with parsplana vitrectomy. RESULTS: There were no serious intra- or shortly postoperative complications. 34% of the implanted lenses were not perfectly positioned. Up to 12 months, there were only minor problems in the anterior segment (suture erosions, anterior synechiae, iris capture). As longterm postoperative complications one patient developed retinal detachment, 3 others proliferative vitreoretinopathy after previous retinal detachment surgery. Two patients developed new onset glaucoma, and 3 glaucoma patients showed a medically uncontrollable intraocular pressure postoperatively. CONCLUSIONS: The transscleral fixation of a posterior chamber intraocular lens has been performed in combination with a vitrectomy in order to minimize postoperative complications. Especially in combination with a pars-plana vitrectomy and silicone oil filing the transsclerally fixated posterior chamber intraocular lens is superior to the anterior chamber IOLs.

Follow-Up Studies↗
PubMed1995

Combined liver and kidney transplantation in patients with chronic nephritis associated with end-stage liver disease.

A variety of renal diseases can be associated with end-stage liver diseases requiring orthotopic liver transplantation (OLT), including cirrhosis-associated glomerulonephritis (GN), and nephropathy unrelated to the liver disease. A retrospective survey showed that nine patients undergoing liver transplantation in our centre had histologically proven GN or interstitial nephritis with renal failure and/or nephrotic-range proteinuria, and experienced severe complications post-OLT since nephrotoxic immunosuppressive drugs (CsA and FK506) could not be adequately given. Four of the nine patients died. Therefore, combined liver-kidney transplantation has been suggested as first choice treatment in such patients. From January 1990 to February 1994, in patients with end-stage liver disease referred for OLT, and who presented with unexplained renal function impairment and/or significant proteinuria, severe nephropathy was confirmed by renal biopsy in nine: four mesangiocapillary GN with immune deposits, one membranous nephropathy, two diabetic glomerulosclerosis and two interstitial nephritis. All underwent liver transplantation immediately followed by kidney transplantation. The postoperative period was uneventful, and neither death nor renal failure were recorded. Combined transplantation resulted in all patients in the normalization of renal function, and in the disappearance of proteinuria within the first postoperative month. From 6 months to 4 years post-transplant, the renal function remained within normal ranges in all patients. Routine renal transplant biopsy was performed in two patients with pre-transplant cirrhosis-associated GN, and showed no evidence of recurrence of the original nephropathy. We conclude that combined liver-kidney transplantation is an adequate therapeutic option in patients with end-stage liver disease associated with advanced kidney disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.

OBJECTIVE: The authors report on the experience of orthotopic liver transplantation in fulminant hepatitis at Paul Brousse Hospital. SUMMARY BACKGROUND DATA: Liver transplantation is a breakthrough in the treatment of patients with fulminant hepatitis. However, the indications, the timing for transplantation, the type of transplantation, and the use of ABO incompatible grafts in this setting still are debated. METHODS: Transplantation was indicated in patients with confusion or coma and factor V less than 20%, younger than 30 years of age, and confusion or coma and factor V less than 30% older than 30 years of age. RESULTS: Among 139 patients who met the aforementioned criteria for transplantation, 1 recovered, 22 died before transplantation, and 116 underwent transplants with a 1-year survival of 68%. Survival was 83% in patients with grade 1 and 2 comas at transplantation versus 56% (p < 0.001) in those with grade 3 comas; it was 51% versus 81% (p < 0.001) in those transplanted with high risk (ABO-incompatible, split, or steatotic) and low-risk grafts, respectively. In a multivariate analysis, steatotic and partial grafts were predictive of poorer patient survival, and ABO incompatibility was predictive of poorer graft survival. CONCLUSIONS: Orthotopic liver transplantation is an effective treatment in fulminant hepatitis. Use of high-risk grafts permitted transplantation of 83% of patients, but was responsible for higher mortality.

ABO Blood-Group System↗
PubMed1995

Morphology and ultrastructure of the redia and pre-emergent cercaria of Opisthorchis viverrini (Trematoda: Digenea) in the intermediate host Bithynia siamensis goniomphalus (Prosobranchia: Bithyniidae).

The intramolluscan stages of the human liver fluke Opisthorchis viverrini were investigated by light, scanning, and transmission electron microscopy. The morphology of the tegument, and the excretory system of the redia and pre-emergent cercaria as well as glandular cells, tail structure, and the eye spots of the cercarial stage are described. Possible environmental adaptations are discussed. The redia is characterized by a tegument which is folded concentrically and covered with densely arranged microvilli. This tegument is composed of a typical syncytium with submerged tegumental cells. The pre-emergent cercaria is characterized by a long tail with prominent fin folds and obliquely striated muscles. The oral sucker is well developed and protrusible, whereas the ventral sucker is faintly developed. Proteinaceous tegumental spines which are arranged transversally and different kinds of presumed sensory structures cover the cercarial body surface. Two well pigmented eye spots with rhabdomeric photoreceptors are located in the anterior part of the body. An extended protonephridial system is connected to a voluminous excretory bladder. The excretory tube opens at the end of the body and does not lead into the tail. Three types of glandular cells could be differentiated according to their vesicles, which are shed into the syncytial layer.

Animals↗
PubMed1995

[Liver transplantation in the treatment strategy of portal hypertension].

We reviewed 1000 consecutive liver transplants over a 10 year period with special attention to a pre-transplant history of portal hypertension revealed by variceal hemorrhage. Of 730 primary transplanted patients with chronic liver disease 186 (26%) experienced variceal bleeding prior to transplantation of which 130 (70%) required interventional therapy to palliate the bleeding. Sclerotherapy was performed in 93 (50%), surgical portal diversion in 27 (15%) and TIPSS in 10 (5%) patients. Moderate to severe liver dysfunction accounted for 91% of the patients with bleeding complications. The impact of both bleeding and treatment modality utilized in the pre-transplant period was analyzed in a way to integrate liver transplantation into the multimodality treatment of portal hypertension. The overall survival for all patients was 76% at five years. Previous history of variceal bleeding did not affect the outcome of patients following liver transplantation. The patients treated by initial sclerotherapy demonstrated no difference with either graft or patient survival. The patients who had TIPSS to control hemorrhage had lower, but insignificant, graft and patient survival. The group of patients with variceal hemorrhage who had prior surgical shunt did, however, demonstrate a significant increased survival of 96% when compared to the non-shunted group which had a 73% survival (p < 0.007). The strategy in treating these potential transplant patients is critical to the success of the subsequent transplant.

Adult↗
PubMed1995

A phase I-II trial of five-day continuous intravenous infusion of 5-fluorouracil delivered at circadian rhythm modulated rate in patients with metastatic colorectal cancer.

The toxicity of 5-fluorouracil (5-FU) was decreased by two to eight-fold if this drug was injected in mice near the middle of the day (rest span) rather than in the middle of the night (activity span). If the rhythm in 5-FU toxicity is linked to the sleep-wakefulness endogenous circadian cycle across species, the least toxic time in man would correspond to 4.00 hours at night. The availability of a single-reservoir programmable-in-time external ambulatory pump (Chronopump, Autosyringe, Hooksett, USA) allowed us to perform a first test of this hypothesis. Five-FU was infused for 5 consecutive days, via an implanted venous access port, with peak drug delivery at 4.00 hours and no infusion from 18.00 to 22.00 hours. Each course was repeated after a free interval of 16 days. Intrapatient dose escalation was planned from 4 to 9 g/m2/course (800 to 1800 mg/m2/day x 5 days) if toxicity was less than grade 2 according to the World Health Organization (W.H.O.). Thirty-five patients with metastatic colorectal cancer were treated; 15 (41%) had received previous therapy, 22 (63%) had W.H.O. performance status of 2 or greater, and 19 (54%) had two or more sites involved. Grade 2 or greater toxicity was encountered in less than 5% of the courses, indicating an adequate control of toxicity via dose adjustment. Oral mucositis, diarrhea, and/or hand-foot syndrome limited dose escalation, and their incidence was dose dependent. Median maximal tolerated dose was 7.5 mg/m2/course in 30 patients assessed for this endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗