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Biomedical subjects

C W Young

Publications and source records attributed to C W Young.

At least 55 records · Page 3Linked to original sources
PubMed1988

Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals.

We have treated 33 patients with different types of advanced cancer by 10-day continuous i.v. infusion courses of hexamethylene bisacetamide (HMBA), a drug that produces differentiation of a variety of transformed cell lines on prolonged exposure in vitro to drug concentrations of 3 to 5 mM. In this dose-finding and pharmacokinetic study, five dosage levels were explored from 12 to 28 g/m2/day. Patients who had not shown progression of disease were given repeat courses of therapy at 28-day intervals. Seventy-two courses of therapy were administered; 17 patients received one course; eight patients received two; six patients received three; and one patient each received four and 17+ courses, respectively. The maximal tolerated dose was 28 g/m2/day for 10 days; the dose-limiting toxic effects were thrombocytopenia with hemorrhage and central nervous system dysfunction manifesting as disorientation and confusion. Based on these studies the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day. Pharmacokinetic studies demonstrated rapid clearance of HMBA from plasma; the decay phase data fit a one compartment model with a mean plasma half-life of 2.5 h and a range from 0.6 to 5.8 h. Mean plasma steady-state levels in our patients were 0.37, 0.58, 0.86, 0.88, and 1.42 mM, at the 12-, 16-, 20-, 24-, and 28-g/m2/day dosage levels, respectively. The data indicate that plasma HMBA concentrations of 1 mM can be maintained for 10 days with acceptable patient tolerance, but that HMBA concentrations in excess of 1.4 mM for 10 days are associated with substantial hematological and central nervous system toxicity. Objective antitumor effects were observed in five patients; one woman with non-small cell lung cancer, who has received 17+ courses over a period of 28+ mo, achieved a partial remission that continues at 28+ mo on therapy. Transient regression of cutaneous metastases was observed in three patients with breast carcinoma and one patient with colorectal carcinoma.

Acetamides↗
PubMed1988

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer.

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.

Adult↗
PubMed1988

Effects of selection for body size on feed efficiency and size of Holsteins.

First lactation records from a herd of Holstein cows bred for either high production and large size or for high production and small size were examined to estimate effects of selection for size and feed efficiency. Selection was among progeny-tested bulls available from the artificial insemination industry. Three rations were fed that differed for ratios of concentrate to milk. After three generations, groups of cows bred for large or small size differed by 50.2 kg in weight, 5.6 cm in wither height, 6.4 cm in length, 2.1 cm in depth, and 5.9 cm in chest circumference; most differences were due to a decrease in the size of the small cows. On the basis of total lactations, cows bred for small size were 2.8% more feed efficient than cows bred for large size. During the first 90 d of lactation cows fed the low concentrate ration were more efficient than those fed the high concentrate ration. Season of calving had an effect on feed efficiency between d 30 and 120 of lactation. During this period cows calving between December and May were more efficient.

Animal Nutritional Physiological Phenomena↗
PubMed1988

Inbreeding of and relationship among registered Holsteins.

Holstein-Friesian Herdbooks (Holstein-Friesian Association of America, Brattleboro, VT) were used to draw random samples of 600 registered females born during each of the yr 1970, 1976, and 1982. A two-line pedigree, one random line of ancestry tracing from the sire and another tracing from the dam to the beginning of the Holstein-Friesian Herdbook, was tabulated for each of these 1800 females. These were used to estimate inbreeding and inter se relationship for the Holstein breed. Estimates of inbreeding were 4.7, 3.8, and 4.3% for 1970, 1976, and 1982. These estimates were not different from one another or from 1928 and 1931 estimates. Estimates of inter se relationship were 5.2, 7.3, and 9.8% for 1970, 1976, and 1982. These estimates were different from one another and from an estimate of 3.4% for 1931. The increase in inter se relationship without corresponding increase in inbreeding indicates that a change in mating strategies has evolved over time. The majority of breeders now apparently mate animals that are less related than if mating was random, whereas in the past there was more of a tendency to mate within the same line. Despite these attempts to avoid inbreeding, it may be only a matter of time until increasing inter se relationship causes an increase in inbreeding. Because of detrimental effects associated with inbreeding, it is important that the Holstein breed be monitored on a regular basis for these parameters. Ancestors that occurred most frequently in the 1982 sample were identified and their direct relationships to the breed tabulated for the years studied.

Animals↗
PubMed1987

Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks.

Trimetrexate, a new antifolate compound, was administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors in a Phase I study. Thrombocytopenia was dose limiting, but highly variable among patients at a given dose level; other toxicity was mild and uncommon. Twenty-three patients participated in pharmacokinetic studies and five patients participated in a study of the effects of trimetrexate on [6-3H]-deoxyuridine incorporation into hematopoietic cell DNA. The median total body clearance of trimetrexate for each dose level was independent of dose but the total body clearance varied widely among patients at a given dose level. The magnitude of the fall in platelet count in individual patients correlated well with the amount of exposure to trimetrexate, but not with the extent of prior therapy. The amount of [6-3H]deoxyuridine incorporation into hematopoietic cell DNA at 72 h after drug administration correlated with the total body clearance of trimetrexate. The total body clearance of trimetrexate was reduced in patients with impaired hepatic synthetic function, as judged by low pretreatment serum albumin concentrations. The recommended Phase II starting dose on this schedule is 130 mg/m2 weekly for 3 weeks; patients with hypoalbuminemia should be treated at lower doses.

Adenocarcinoma↗
PubMed1987

Effects of mild inbreeding on productive and reproductive performance of Guernsey cattle.

Production and reproduction records that spanned a 24-yr period were used to study the effects of low coefficients of inbreeding in two experiment station Guernsey herds. Inbreeding ranged from 0 to 25.3% and averaged 4.1%. Milk and fat yields were all first lactations standardized to a mature equivalent, twice daily milking, and 305 d. Intrasire regressions of production traits on percent inbreeding were -23.8 kg of milk, -1.25 kg of fat, and .002% for fat percentage. Estimates of the effect of inbreeding on reproductive traits had large standard errors but suggested that inbreeding depressed reproductive performance. Age at first calving decreased 3.7 d per 1% increase in inbreeding.

Animals↗
PubMed1987

Genetic relationships and additive genetic variation of productive and reproductive traits in Guernsey dairy cattle.

Data were first lactation production and reproduction records initiated from 1958 to 1981 in two experiment station Guernsey herds. Heritability estimates using paternal half sib groups were .24 +/- .12 for milk yield, .27 +/- .12 for fat yield, and .77 +/- .15 for fat percentage. Heritability estimates for reproductive traits ranged from .01 to .04 for number of services, service period, conception rate, and days open, but were higher for days in milk at first breeding (.12) and age at first calving (.13). Except for age at first calving, coefficients of additive genetic variation were larger for reproductive traits than for productive traits. Genetic correlations between measures of production and reproduction were moderate to large and antagonistic, except that the relationship between production and age at first calving was favorable. Breeding value estimates for milk yield and reproduction were negatively correlated for sires with above average breeding values for milk yield. Huge phenotypic variances for reproductive traits masked substantial additive genetic variation for these traits. When all things are considered it seems unwise to ignore reproductive performance in selection programs for dairy cattle.

Animals↗
PubMed1986

Simultaneous estimation of liquid and solid gastric emptying using radiolabelled egg and water in supine normal subjects.

To develop an additional method for the measurement of gastric emptying in supine subjects, 10 normal subjects were given a test meal containing 99Tc-labelled scrambled egg as the "solid" phase marker and 111In in tapwater as the marker for the "liquid" phase. The mean time for emptying 50% of the "solid" phase (t1/2) was 85 min and 29 min for the "liquid" phase. Three individuals were restudied with a mean difference between the two determinations of 10.8% for the "solid" phase and 6.5% for the "liquid" phase. Twenty-six additional studies attempted have been successfully completed in symptomatic patients with advanced cancer. This method provides a simple and reproducible procedure for the determination of gastric emptying that yields results similar to those reported for other test meals and can be used in debilitated patients.

Adult↗
PubMed1986

Health care of Holsteins selected for large or small body size.

Genetic groups of Holsteins selected for large size or small size were compared for health care needs. Two groups were formed from a paired foundation population. Large group was mated to sires with extreme estimates of transmitting ability for tall height and deep and wide bodies. Small group was similarly mated to extreme sires but to those transmitting short height and shallow and narrow bodies. Predicted Differences for milk and fat of sires were above breed average. Actual expenses for veterinary treatment, health supplies and drugs, and value of labor required of animal attendants were evaluated. Large cows required significantly more health care than small cows. Digestive disorders accounted for much of the group difference, and displaced abomasums were more frequent among large cows. Small cows may have economic advantages over large cows of the same breed.

Animal Husbandry↗
PubMed1986

Phase I trial of taxol given as a 3-hour infusion every 21 days.

Taxol is a unique plant product that promotes in vitro assembly of microtubules. In a phase I trial, adults with advanced solid tumors were given taxol (formulated with cremophor EL and dehydrated alcohol) as a 3-hour iv infusion every 21 days. The total dose administered ranged from 15 to 230 mg/m2 in nine escalation steps. Leukopenia, thrombocytopenia, nausea and vomiting, alopecia, stomatitis, transient rashes, increases in serum triglyceride levels, and hypersensitivity reactions were observed. Hypersensitivity reactions characterized by acute dyspnea, generalized erythema, and hypotension immediately following the initiation of the taxol infusion occurred in three of five patients receiving greater than or equal to 190 mg/m2 (18% of patients overall). No antitumor activity was observed. Hypersensitivity reactions constituted a treatment-limiting toxicity for this preparation of taxol given on this schedule over the dosage range examined. With the severity and unpredictability of the hypersensitivity reactions, further usage of taxol is not indicated with this drug formulation on this administration schedule. Further studies are warranted to uncover ways to permit the safe administration of taxol.

Adult↗
PubMed1986

Potentiation of radiation effects on two murine tumors by lonidamine.

Lonidamine is a potent inhibitor of spermatogenesis and a hyperthermic sensitizer. The principal established locus of biochemical action of lonidamine is a selective inhibitory effect of the energy metabolism either in NAD-linked reactions in germ cell mitochondria, as well as the glycolytic metabolism of a variety of tumor cell lines by means of inhibition of mitochondrially bound hexokinase. We carried out in vivo tumor experiments to determine whether lonidamine when combined with radiation could potentiate the cytotoxic effects of radiation on two murine tumors. The combined effects of single acute lonidamine (100 mg/kg) and single dose X-irradiation were evaluated on the transplanted methylcholanthrene-induced fibrosarcoma in BALB/c mice and on the radiation-induced fibrosarcoma in C3H/He mice. The radiosensitizing effect by lonidamine was maximal when lonidamine was administered immediately prior to or after X-irradiation. The dose modifying factor of lonidamine is estimated to be 1.36 for methylcholanthrene-induced fibrosarcoma tumors and 1.25 for radiation-induced fibrosarcoma tumors. There was no disproportionately enhanced skin reaction following the combined treatments. The present results of the potentiating effects of radiation may be attributed, in part, to the findings of cell culture studies that lonidamine is a potent inhibitor of repair of potentially lethal damage.

Animals↗
PubMed1985

Rationale for glycemic control.

Whether long-term glycemic control will prevent the chronic vascular complications of diabetes mellitus remains unknown. Microangiopathy and accelerated macroangiopathy are prevalent in both type I, or insulin-dependent diabetes mellitus, and type II, or non-insulin-dependent diabetes mellitus. Microangiopathy is predominantly responsible for the excessive morbidity and mortality in type I diabetic patients, whereas accelerated macroangiopathy directly relates to the excessive morbidity and mortality in type II diabetic patients. Institution of euglycemia for short periods will reverse preclinical, functional, renal, and retinal abnormalities, but will not reverse clinical nephropathy and retinopathy. Intensive insulin therapy, although it increases the risk of hypoglycemic encephalopathy, seems rational for type I diabetic patients without vascular complications who can recognize and respond normally to hypoglycemia. In patients with type II diabetes, sulfonylurea therapy, which is associated with fewer adverse reactions than intensive insulin therapy, may lower the risk of atherosclerosis development by correcting hyperglycemia and associated lipid abnormalities.

Basement Membrane↗
PubMed1985

Phase I clinical trial of fludarabine phosphate (F-ara-AMP).

F-Ara-AMP (fludarabine phosphate) is an adenosine analogue that is resistant to deamination; it is a more potent cytotoxic compound than ara-A in experimental tumor systems. F-Ara-AMP was given by continuous IV infusion over 5 days once every 4 weeks to 27 evaluable adult patients with advanced cancer. The median Karnofsky performance status was 70% (range 50%-90%), and the median age was 58 years (range 41-74). In addition to adequate blood counts, a creatinine clearance of at least 60 ml/min was required. The initial dose level was 35 mg/m2/day. Dose-limiting myelosuppression was seen in the first patient. Subsequent patients were treated at lower doses. Myelosuppression was the only major toxicity. Leukopenia was generally more prominent than thrombocytopenia, but 2 patients experienced prolonged thrombocytopenia which prevented further therapy. Nausea was minimal, and neither renal nor neurologic toxicity was encountered. In patients with good renal function a dose of 25 mg/m2/day can be safely administered. However, because of apparent cumulative myelosuppressive effects a lower dose is more appropriate for patients who have had extensive prior chemotherapy or radiotherapy.

Adult↗
PubMed1985

Fluorometric high-performance liquid chromatographic analysis of 10-deazaaminopterin, 10-ethyl-10-deazaaminopterin, and known metabolites.

The antifolate compounds 10-deazaaminopterin (10-dAM) and 10-ethyl-10-deazaaminopterin (10-EdAM) are therapeutically superior to methotrexate in transplanted murine tumor systems and in human tumor xenografts growing in immunodeficient "nude" mice. The increased therapeutic index of these analogs correlates with their selective uptake, retention, and polyglutamation within neoplastic cells. We have developed a fluorescence high-performance liquid chromatographic assay applicable to 10-dAM, 10-EdAM, their polyglutamate anabolites, and their 7-hydroxy (7-OH) and deglutamate catabolites. The assay is based upon the high native fluorescence of pteridine-containing compounds which contain carbon in the 10 position. The assay employs a reverse-phase C-18 column and an ascending acetonitrile gradient in 50 mM phosphate, pH 7.0. The compounds are extracted from plasma and urine with 95 +/- 7% and 98 +/- 2% recoveries, respectively, using C-18 Sep-Paks. The linear range of the assay is, for 10-dAM, 2-100 nM, and for 10-EdAM, 1-100 nM. Polyglutamated metabolites of [3H]10-EdAM isolated from L1210 cells have been separated by HPLC with identification of five derivatives (Glu 1-5) confirmed by enzymatic peak shift using serum conjugase and by quantitative correlation of fluorescence intensity, radioactivity, and titration inhibition of dihydrofolate reductase. The assay has been used successfully in pharmacokinetic analyses of plasma and urine samples from patients receiving 10-dAM and 10-EdAM. In patients who had received 10-EdAM, 7-OH-10-EdAM, and the deglutamate catabolite were also detected. This HPLC fluorescence assay is superior to the dihydrofolate reductase inhibition and binding assays with regard to specificity and precision; moreover, it can provide a means for simultaneous assay of the physiologically important anabolites and catabolites of these new antifolates.

Aminopterin↗
PubMed1985

Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections.

The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.

Adult↗
PubMed1985

A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.

Actuarial Analysis↗