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Biomedical subjects

R Walker

Publications and source records attributed to R Walker.

At least 343 records · Page 19Linked to original sources
PubMed1986

Phase I study of carboplatin (CBDCA) in children with cancer.

A phase I study of carboplatin (CBDCA) was performed in 40 children with advanced cancer. A single course of CBDCA consisted of 4 weekly 1-hour infusions followed by a 2-week rest. The starting dose of 100 mg/m2/week was 66% of the maximum tolerated dose in adults. Escalated dose levels given were: 125, 150, 175, and 210 mg/m2. Myelosuppression was dose limiting, with thrombocytopenia more pronounced than leukopenia. There was no evidence of cumulative toxicity. The maximum tolerated dose for children with solid tumors was 210 mg/m2/week X 4. Other side effects included transient nausea and vomiting at the higher dose levels and non-dose-related, reversible changes in creatinine clearance. One patient developed hives. No hepatic toxicity was seen. Among the 28 evaluable patients with solid tumors, one of ten with osteogenic sarcoma had complete disappearance of a lung nodule for 15+ months. Two of four patients with medulloblastoma had partial responses by clinical and computerized tomographic scan for 4 and 10 months. All three responders had received prior cisplatin therapy. CBDCA has major advantages over cisplatin in terms of reduced toxicity. Responses observed in patients previously treated with cisplatin are encouraging. The recommended phase II dose for children with solid tumors is 175 mg/m2/week X 4 with a 2-week rest.

Adolescent↗
PubMed1985

Solubilisation, purification and reconstitution of hepatic microsomal azoreductase activity.

Microsomal NADPH-cytochrome c (P-450) reductase and cytochrome P-450 were purified from the livers of phenobarbitone-treated rats. Purified NADPH-cytochrome c (P-450) reductase effected the NADPH-dependent reduction of FMN and FAD under anaerobic conditions in a non-enzymic manner, but was unable to reduce directly the azo dye, amaranth. In the presence of FMN, the purified reductase effected reduction of amaranth through the production of reduced FMN. Incorporation of NADPH-cytochrome c (P-450) reductase into the microsomal fraction increased the azoreductase activity of liver preparations from phenobarbitone-treated rats, but had no effect on azoreductase activity in preparations from control animals. Azoreductase activity was reconstituted into dilauroyl phosphatidylcholine vesicles containing purified cytochrome P-450 and purified NADPH-cytochrome c (P-450) reductase. In the absence of supplementary FMN, amaranth reduction was completely dependent upon all three components, but in the presence of FMN, the omission of any one component failed to abolish completely azoreductase activity.

Amaranth Dye↗
PubMed1985

Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations in the pancreatic infiltrate and expression of rat MHC class II molecules in endocrine cells.

Use of monoclonal antibodies specific for rat lymphocyte subsets and an anti-insulin marker has allowed us to document the following sequence of events leading to the development of clinical diabetes in this animal model. The first change observed in the pancreas is increased expression of MHC class II molecules on vascular endothelium and this precedes lymphocytic infiltration. Next, T cells of the T helper phenotype infiltrate the pancreas around blood vessels. Many of the infiltrating T cells show class II expression indicating that they are activated. A few cytotoxic and suppressor cells and B lymphocytes are also present and their numbers increase proportionately with rat age. Some macrophages are also seen. Finally, at a late stage class II MHC molecules can be detected in partially destroyed islets on beta cells which are still actively synthesising insulin. We have never observed expression of class II molecules on glucagon or somatostatin secreting cells which are invariably well preserved.

Animals↗
PubMed1985

Chemotherapy trials in recurrent primary intracranial germ cell tumors.

Gonadal germ cell tumors respond favorably to chemotherapy either at diagnosis or when they recur. Histologically similar tumors may arise in the CNS usually in the pineal or suprasellar regions. Although radiation therapy may produce a 5 year disease-free survival in excess of 60% in localized pure germinoma, germ cell tumors of other histology tend to recur. We have conducted 14 chemotherapy trials in 8 patients with recurrent CNS germ cell tumors using 3 different single agent and 2 multi-agent chemotherapy regimens. The histologic diagnoses of the patients were germinoma (4), endodermal sinus tumor (2), embryonal carcinoma (1), and mixed tumor - germinoma plus choriocarcinoma (1). There were 7 males and 1 female with a median age of 13 years. The primary tumor arose in the pineal region in 6 and was multicentric in 2. Seven patients had local recurrences and one developed an initial recurrence in the spinal canal. Three patients had CNS metastases at relapse and 2 had systemic metastases. Objective responses were documented in 7 of 14 trials (50%). Responses were observed with cyclophosphamide (80 mg/kg) in 3 of 4 patients for 2+, 3, and 5 mos, cisplatin (120 mg/m2) in 1 of 2 patients for 2+ mos, and the VAB 6 protocol (vinblastine, bleomycin, cyclophosphamide, actinomycin-d, cisplatin) in 3 of 5 patients for 5, 8, and 18 mos. The median duration of response was 5 mos. (2+-18). High doses of single chemotherapy agents such as cyclophosphamide and cisplatin as well as VAB 6 regimen have definite activity in recurrent CNS germ cell tumors, especially germinoma. Good palliation may be achieved with chemotherapy alone with acceptable morbidity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Metabolism of the 1-13 sequence of gastrin 17 in humans and failure to influence acid secretion.

The metabolism and action on basal and gastrin 17 (G-17)-stimulated acid secretion of the N-terminal 1-13 sequence of G-17 was studied in human volunteers. Basal acid secretion was not changed by infusion of 1-13 G-17 in doses of 75-1000 pmol X kg-1 X h-1 which gave plasma concentrations of N-terminal G-17 immunoreactivity of 150-2020 pmol X L-1. In addition the acid response to G-17 in a dose that stimulated about 50% maximal acid output was not influenced by 1-13 G-17 (75 and 1000 pmol X kg-1 X h-1). The mean half-time for disappearance of N-terminal immunoreactivity after stopping infusion of 1-13 G-17 was 9.8 +/- 0.5 min. Gel filtration indicated a single peak of N-terminal immunoreactivity in plasma during infusion of 1-13 G-17. Ion exchange chromatography on diethylaminoethyl cellulose, however, revealed two peaks of immunoreactivity. One corresponded to 1-13 G-17, the other eluted earlier. In samples taken after stopping the infusion, the variant predominated. On high-pressure liquid chromatography the variant was resolved into a major component, which had a retention time less than 1-13 G-17, and two minor components. The variants were not produced by incubation of 1-13 G-17 with plasma in vitro. It is concluded that 1-13 G-17 is converted in the circulation to new forms with longer half-lives. Because plasma enzymes cannot account for the formation of these variants, it is possible that enzymes present on cell walls, for example, on capillaries, may be responsible.

Adult↗
PubMed1985

The use of pergolide and lisuride, two experimental dopamine agonists, in patients with advanced Parkinson disease.

Pergolide, an experimental dopamine agonist, was administered to 56 patients with advanced Parkinson disease who were no longer satisfactorily responding to levodopa, including 45 patients with diurnal oscillations in performance: "on-off" phenomena. Lisuride, an experimental dopamine agonist was administered to 63 patients with advanced Parkinson disease. Pergolide or lisuride, when added to levodopa, resulted in a significant decrease in disability in both the "on" and the "off" period, and an increase in the number of hours in which patients were "on". Forty-one of 56 patients (73%) improved on Pergolide. Thirty-seven of 63 patients (59%) improved on lisuride. Mean dose of pergolide was 2.5 mg. (range 0.2 to 10.0 mg.). Mean dose of lisuride was 2.6 mg. (range 0.2 to 5.0 mg.). Pergolide was discontinued in 18 patients because of adverse effects, including an organic confusional syndrome (six patients), dyskinesias (four patients) and cardiovascular abnormalities (three patients). Lisuride was discontinued in 26 patients because of adverse effects, including an organic confusional syndrome (15 patients), dyskinesias (five patients) and vasospasm (two patients). Pergolide was discontinued in nine patients and lisuride in 12 because of a lack of effect or a declining effect. Both drugs are equally useful in patients with advanced Parkinson disease.

Adult↗
PubMed1985

Inadequate tetanus protection among the rural elderly.

Three cases of tetanus occurring in a community in southern West Virginia in five years prompted a survey of the immunization status of the population of this region. An immunization history was obtained from 540 consecutive patients seen at three different health care facilities. Of these, 386 (71.5%) had received prior tetanus protection, 65 (12%) had never been immunized, and 89 (16.5%) were uncertain or had received incomplete immunization. Of the 65 nonimmunized patients, 54 (83%) were older than 50 and only 11 (17%) were younger. Compared to the total group sampled, significantly more nonimmunized patients (both male and female) were older than 50 (P less than .001). Also, significantly more of these never immunized individuals lived in rural areas (P less than .001). In a group of 222 patients identified as being at increased risk of having tetanus, 65 (29%) had never been immunized, 89 (40%) were of uncertain or incomplete status, and 68 (30.5%) had been immunized more than ten years previously. One hundred twenty (54%) high-risk patients were older than 50 and 103 (46%) were younger. Compared to the entire population sampled, high-risk patients included significantly more who were older than 50 (P less than .001). Also, significantly more high-risk patients lived in rural areas (P less than .007). When treating injured patients, it is important to recall that many older adults living in rural areas are not adequately immunized against tetanus. Such patients should receive human tetanus immunoglobulin, as well as tetanus toxoid.

Adolescent↗
PubMed1985

Acid and gastrin responses during intragastric titration in normal subjects and duodenal ulcer patients with G-cell hyperfunction.

Amino acid induced acid and gastrin responses during intragastric titration at pH 2.5 and 5.5 were compared in normal subjects and duodenal ulcer patients with G-cell hyperfunction. The latter were identified on the basis of raised basal or maximal acid outputs and increased gastrin responses to feeding. In normal subjects the mixed amino acid meal stimulated only modest increases in serum gastrin, and the highest observed increase was about 30% that after a standard meal. In contrast, in the G-cell hyperfunction group the highest gastrin concentrations were similar to those after a standard meal. In the G-cell hyperfunction group the increment in serum gastrin at pH 2.5 expressed as a proportion of that at pH 5.5 was 0.29 indicating that the capacity of acid to inhibit gastrin release was well established in these patients. Acid secretory rates were close to maximal at both pH 2.5 and 5.5 during intragastric titration in the ulcer patients, but in normal subjects acid output was about 50% maximal at 2.5 and close to maximal at 5.5. The results suggest that the enhanced gastrin response to feeding in G-cell hyperfunction patients is because of increased sensitivity to amino acid stimulation rather than to diminished acid-inhibitory mechanisms.

Adult↗
PubMed1985

Metabolism of heptadecapeptide gastrin in humans studied by region-specific antisera.

The metabolism of synthetic human heptadecapeptide gastrin (G17) in vivo, and in serum in vitro, was studied by radioimmunoassay using region specific antisera, gel filtration, ion exchange chromatography, and high performance liquid chromatography. After infusion of G17 intravenously in normal human volunteers, COOH-terminal and NH2-terminal immunoreactive G17 fragments were generated. At a steady state, approximately 15% of COOH-terminal immunoreactivity was attributable to G14-like material and up to 25% of total NH2-terminal immunoreactivity was attributable to two NH2-terminal fragments; one had the chromatographic properties of 1-13 G17, and the other was less acidic and less hydrophobic. After stopping the infusion of G17, the latter fragments accounted for progressively greater proportions of total gastrin activity. When G17 was incubated in serum in vitro, there was time-dependent and temperature-dependent loss of immunoreactivity, and again COOH-terminal and NH2-terminal immunoreactive fragments were formed. Removal of the NH2-terminal pyroglutamic acid was probably the rate limiting step because synthetic 2-17 G17 was degraded more rapidly in serum (t1/2, 2-3 h) than G17 (t1/2, 3-5 h). EDTA blocked degradation at the COOH-terminus of both 2-17 G17 and G17 but cleavage at the NH2-terminus still occurred, giving rise to a G14-like peptide. The rate of conversion of G17 in serum was not enough to account for the production of fragments in vivo, and it is proposed that these are formed when G17 encounters enzymes on cell surfaces, perhaps during passage through the capillary circulation. The production of these fragments needs to be considered in interpreting studies of the identity, metabolism, and release of gastrin in health and disease.

Adult↗
PubMed1984

The cooperative effect of the satin and beige mutations in the suppression of NK and CTL activities in mice.

The functional activity of natural killer (NK) cells has been found to be modulated by several point mutations associated with coat color. The most commonly studied gene, beige (Bg), has been found to block a postrecognition event in the lytic cycle. Four other coat color mutations in the mouse (satin, leaden, fuzzy, pale ears) were studied for their effect on NK cell function, and only one, satin (Sa), was found to be suppressive. When both the Sa and Bg mutations were present in the same animal, their effects were synergistic in the suppression of NK levels. Normal numbers of NK cells were present in these double mutants, as determined by the frequency of IgG2b binding cells and by antiasialo GM1 staining. The ability of Sa/Bg NK cells to recognize and bind targets suggests that the defect is localized in the postbinding cytolytic pathway. These genes were not specific for NK cells and also suppressed alloimmune cytolytic T lymphocyte function. Since Sa/Bg mice are much more suppressed in NK function than Bg mice, we suggest that this double mutant may be a better model for NK deficiency in vivo.

Animals↗
PubMed1984

Sustained induction of hepatic xenobiotic metabolising enzyme activities by phenobarbitone in C3H/He mice: relevance to nodule formation.

Phenobarbitone (PB) was administered to male C3H/He mice at a dose of 85 mg/kg/day in a semisynthetic diet for up to 90 weeks. Throughout the treatment period a sustained induction of a number of parameters of hepatic Phase I and Phase II xenobiotic metabolism was observed. Histological examination revealed hypertrophy of the centrilobular cells of the liver lobule in PB treated mice and after 25 weeks small basophilic nodules were found in control and PB treated animals. In addition eosinophilic nodules, which were often large, developed in PB treated mice. Xenobiotic metabolising enzyme activities in large excised nodules after 70 or 90 weeks of PB treatment were either similar to or greater than those present in surrounding host tissue. Both phenobarbitone- and polycyclic hydrocarbon-type mixed function oxidase enzyme activities were induced in large nodules. In conclusion, PB produced a sustained induction of xenobiotic metabolising enzymes both in host tissue and in large eosinophilic nodules. The formation of these nodules in C3H/He mice was thus not associated with any failure of induction of hepatic xenobiotic metabolism.

Animals↗
PubMed1984

Long-term treatment with pergolide: decreased efficacy with time.

We studied the effect of pergolide (combined with levodopa) in 17 patients with Parkinson's disease, including 15 with "wearing off" or on-off phenomena, who had been taking pergolide for at least 2 years. Mean duration of the study was 27.8 months. All 17 patients improved initially, but the improvement later faded. Mean disability score, which decreased initially by 60% (significant), was decreased only by 20% after 2 years (not significant). Wearing off and on-off phenomena, which improved initially, became prominent again. Four patients lost all the improvement, nine patients lost much of the improvement, and four maintained much of the improvement. Mean dose of pergolide was 2.2 mg (range, 0.8 to 5.0 mg).

Aged↗
PubMed1984

Combined use of benserazide and carbidopa in Parkinson's disease.

The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa. Peak dopa levels are higher, occur sooner, but decline more rapidly with benserazide. Although many patients respond better to one drug than the other, we sought to exploit the differences in pharmacokinetics by giving both drugs to the same patient. Benserazide was combined with carbidopa in 38 patients who were experiencing a diminished response to carbidopa, including 22 patients with diurnal oscillations in performance, "wearing off" or on-off phenomena. Previous attempts to change the dose, sequence, or ratio of levodopa to carbidopa in these patients had been unrewarding. Ten of the patients improved on the combination of benserazide and carbidopa, with a 30% decline in disability. The mean dose of levodopa:carbidopa before benserazide was 910:100 (9 to 1 ratio); the mean dose of levodopa:benserazide was 355:90 (4 to 1 ratio). The mean dose of levodopa:carbidopa + benserazide was 925:155 (6 to 1 ratio). The combination of carbidopa with benserazide is useful in some parkinsonian patients.

Adult↗