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Biomedical subjects

J Clark

Publications and source records attributed to J Clark.

At least 235 records · Page 13Linked to original sources
PubMed1994

Toxicokinetics of oxazepam in rats and mice.

The comparative toxicokinetics of oxazepam were studied in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an i.v. dose of 20 mg/kg and oral gavage doses of 50, 200, and 400 mg/kg. In addition, the toxicokinetics of oxazepam in a 3-week dosed-feed study of male B6C3F1 mice at 125 and 2500 ppm were also investigated. Results indicated that the elimination of oxazepam from plasma after i.v. injection in both rats and mice were first-order and could be best described by a two-compartment model with a terminal elimination half-life of 4-5 h for rats and 5-7 h for mice. After oral gavage dosing the peak oxazepam plasma concentrations in most rodents were reached within 2-3.5 h. At all doses studied, female rodents had significantly higher plasma concentrations than males. Absorption of oxazepam was significantly extended at higher oral doses of 200 and 400 mg/kg. At 50 mg/kg, the bioavailability of oxazepam in rats (< 50%) was lower than in Swiss-Webster mice (> 80%). The bioavailability of oxazepam in both B6C3F1 and Swiss-Webster mice decreased with increasing dose. A dose proportionality of Cmax was not observed in rats and mice after gavage doses of 50, 200, and 400 mg/kg. Plasma concentrations of oxazepam in the dosed-feed study increased with the concentration of oxazepam in the feed, a quasi-steady-state of plasma concentrations of oxazepam was reached after approximately 4 days ad libitum exposure. In B6C3F1 mice, the estimated relative bioavailability of oxazepam from dosed feed (relative to gavage study at 50 mg/kg) was about 43%.

Animals↗
PubMed1994

Pretherapy dental status of patients with malignant conditions of the head and neck.

Maxillofacial problems after radiotherapy to this region are common and have at least a temporal relationship to preexisting odontogenic disease. This study was undertaken to determine the dental status of patients before multimodality therapy for head and neck cancer. One hundred thirty-one patients were examined during their initial visit to a head and neck tumor clinic. The majority of dentulous patients were noncompliant with routine dental care (76%) and oral hygiene (65%). There was a high incidence of alveolar bone loss (66%), clinical caries (71%), and failing restorations (91%). Overall, 73 (97%) of the dentulous patients needed dental care before radiotherapy; however, follow-up visits revealed that 59 (81%) of these patients did not seek the indicated treatment. These data suggest that thorough oral examinations should be performed on all patients before radiotherapy that involves the oral cavity.

Adolescent↗
PubMed1994

Diagnostic accuracy of predicting coronary artery disease related to patients' characteristics.

Patients' demographic and clinical characteristics may affect diagnostic accuracy of cardiologists. We asked a group of experienced cardiologists from three institutions to estimate the pretest probability of coronary artery disease in 257 patients referred for diagnostic coronary angiography and with no history of previous myocardial infarction nor valvular heart disease. Physicians pretest estimates were compared with the diagnostic findings of coronary angiography. We tested the influence of five variables on the accuracy of the pretest estimates: age, sex, chest pain characteristics, rest electrocardiogram and electrocardiographic exercise test result. Cardiologists tended to overestimate the presence of coronary artery disease and this tendency was particularly remarkable in the group of patients showing a negative exercise test. Pretest diagnostic accuracy was 0.72 when the test result was negative and 0.85 when the test result was positive (95% confidence interval of the difference 0.03 to 0.23; p < 0.001). The diagnosis of coronary artery disease was also more accurate for male than for female patients (0.81 vs 0.70; 95% confidence interval of the difference 0.02 to 0.21; p < 0.02). Characteristics of chest pain, age and rest electrocardiogram did not affect the level of pretest diagnostic accuracy. Cardiologists should be cognizant of correctly interpreting a negative exercise test and the clinical data of female patients; in both cases, they should move circumspect of the diagnosis of coronary artery disease.

Age Factors↗
PubMed1994

The results of modified use of chemotherapy for patients with metastatic breast cancer.

We investigated whether modifying standard chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) could improve the outcome of patients with advanced breast carcinoma. We changed the conventional FAC treatment as follows: firstly, we administered oestrogens during the delivery of chemotherapy. Secondly, we administered 5-fluorouracil by continuous infusion. Thirdly, we limited chemotherapy treatment to 12 cycles and did not continue treatment during remissions. We evaluated this modified treatment in 63 patients and compared its results to other treatments results given at this institution. We found that the modified treatment improved the quality of life and survival of premenopausal breast cancer patients.

Adult↗
PubMed1994

Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma.

Human synovial sarcomas contain a recurrent and specific chromosomal translocation t(X;18)(p11.2;q11.2). By screening a synovial sarcoma cDNA library with a yeast artificial chromosome spanning the X chromosome breakpoint, we have identified a hybrid transcript that contains 5' sequences (designated SYT) mapping to chromosome 18 and 3' sequences (designated SSX) mapping to chromosome X. An SYT probe detected genomic rearrangements in 10/13 synovial sarcomas. Sequencing of cDNA clones shows that the normal SYT gene encodes a protein rich in glutamine, proline and glycine, and indicates that in synovial sarcoma rearrangement of the SYT gene results in the formation of an SYT-SSX fusion protein. Both SYT and SSX failed to exhibit significant homology to known gene sequences.

Amino Acid Sequence↗
PubMed1994

Expression of a dominant allele of human ARF1 inhibits membrane traffic in vivo.

ADP-ribosylation factor (ARF) proteins and inhibitory peptides derived from ARFs have demonstrated activities in a number of in vitro assays that measure ER-to-Golgi and intra-Golgi transport and endosome fusion. To better understand the roles of ARF proteins in vivo, stable cell lines were obtained from normal rat kidney (NRK) cells transfected with either wild-type or a dominant activating allele ([Q71L]) of the human ARF1 gene under the control of the interferon-inducible mouse Mx1 promoter. Upon addition of interferon, expression of ARF1 proteins increased with a half-time of 7-8 h, as determined by immunoblot analysis. Induction of mutant ARF1, but not wild-type ARF1, led to an inhibition of protein secretion with kinetics similar to that observed for induction of protein expression. Examination of the Golgi apparatus and the ER by indirect immunofluorescence or transmission electron microscopy revealed that expression of low levels of mutant ARF1 protein correlated with a dramatic increase in vesiculation of the Golgi apparatus and expansion of the ER lumen, while expression of substantially higher levels of wild-type ARF1 had no discernible effect. Endocytosis was also inhibited by expression of mutant ARF1, but not by the wild-type protein. Finally, the expression of [Q71L]ARF1, but not wild-type ARF1, antagonized the actions of brefeldin A, as determined by the delayed loss of ARF and beta-COP from Golgi membranes and disruption of the Golgi apparatus. General models for the actions of ARF1 in membrane traffic events are discussed.

ADP-Ribosylation Factor 1↗
PubMed1994

Antibiotic policies--relevance to general practitioner prescribing. Family Health Services Authority, Great Britain.

In the UK rational antimicrobial prescribing in General Practice requires effective communication between the Family Health Services Authority (FHSA), microbiologists and General Practitioners (GPs). Many FHSAs now have a Pharmaceutical Adviser to assist the FHSA Medical Adviser in providing pharmaceutical advice, setting and monitoring of indicative prescribing amounts and fundholding drug budgets. They are also increasingly involved in developing practice formularies. Reviews of local prescribing often show significant differences between antimicrobial usage and local recommendations from microbiologists which are generally based on their interpretation of local laboratory susceptibility data. The efforts of two FHSAs working with local microbiologists to communicate a rational antimicrobial policy are described. This has involved conducting prescribing audit, publishing guidelines, practice visits and arranging meetings between GPs, microbiologists and FHSA staff.

Anti-Bacterial Agents↗
PubMed1994

Melphalan uptake, hyperthermic synergism and drug resistance in a human cell culture model for the isolated limb perfusion of melanoma.

Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines; (b) prolonging the treatment time beyond 1 h had little additional toxicity; and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines; pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan; (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours; and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1994

An audit of morphine prescribing in a specialist cancer hospital.

The object of this study was to assess the quantity and quality of morphine prescribing in a specialist cancer hospital. An audit of prescription charts of all patients was performed using palliative care unit recommendations as the standard. The major weaknesses identified in morphine prescription were a lack of provision of breakthrough doses, the use of 'as required' (prn) oral morphine in the absence of regular oral morphine, and the lack of reference in the unit guidelines to co-prescription of aperients, antiemetics and night sedation. These deficiencies were targeted in an education programme and the survey was repeated to complete the audit cycle. Although some improvement in prescribing practice was shown, persistent problems have illustrated the need for an ongoing hospital-wide education programme.

Analgesics↗
PubMed1994

Home antibiotic therapy for low-risk cancer patients with fever and neutropenia: a pilot study of 30 patients based on a validated prediction rule.

PURPOSE: To assess the feasibility of early discharge to home therapy with standard intravenous antibiotics in 30 patients with fever and neutropenia at low risk by a validated clinical decision rule. PATIENTS AND METHODS: Newly admitted outpatients with fever and neutropenia were evaluated for home therapy during 2 days of inpatient observation. To evaluate enrolled patients' acceptance of home care, we assessed patient attitudes and quality of life before and after home therapy. To assess economic effects, we compared the medical charges of patients treated at home with those of medically eligible patients who remained in the hospital. RESULTS: Of the first 84 patients, 50 (60%) were medically ineligible, and neutropenia was resolved in another eight (10%) during the observation period. Only nine patients of the remaining 26 who were medically eligible (35%) were enrolled in the home-therapy trial. Thereafter, 21 of 31 medically eligible patients (68%) were enrolled. The 30 patients treated at home were neutropenic for a median of 6 days (mean, 8.2). Four had medical complications, and five others were readmitted for observation. Patients' quality of life improved during home therapy, and favorable attitudes toward home care persisted after treatment. Medically eligible patients not enrolled had briefer neutropenia than patients treated at home, but had 44% higher daily medical charges and equivalent overall charges despite treatment half as long. CONCLUSION: We conclude that early discharge of low-risk patients to home intravenous antibiotic therapy is feasible, is well received by patients, and may prove to be cost-saving. However, these conclusions must be validated in a large randomized trial.

Adolescent↗
PubMed1994

Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered weekly on an outpatient basis with concurrent thoracic radiation to patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase I clinical trial, paclitaxel was administered as a 3-hour intravenous (IV) infusion, repeated every week for 6 weeks. The starting dose of paclitaxel was 10 mg/m2. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients if tolerated. Unacceptable toxicity was defined as grade 3 nonhematologic toxicity, excluding nausea and vomiting, and grade 4 hematologic toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Twenty-seven patients were entered onto this study through seven dose escalations (from 10 mg/m2/wk to 70 mg/m2/wk for 6 weeks). Severe esophagitis occurred at 70 mg/m2 (two patients with grade 4 disease and one patient with grade 2). One of six patients at 60 mg/m2 developed grade 3 esophagitis and three of seven patients had grade 2 esophagitis. One of 27 patients developed a hypersensitivity reaction. One of 27 patients developed grade 3 neutropenia. CONCLUSION: Esophagitis is the principle dose-limiting toxicity of weekly paclitaxel and thoracic radiation in the outpatient setting. A phase II trial using concurrent radiation and paclitaxel at the MTD of 60 mg/m2/wk is underway.

Adult↗
PubMed1994

Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.

L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Toxicokinetics of pentachlorophenol in the F344 rat. Gavage and dosed feed studies.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in the Fischer 344 rat using i.v. and oral (gavage, dosed feed) routes of exposure. 2. Only minor sex differences were observed in the elimination kinetics of PCP after i.v. administration at 5 mg/kg. 3. Absorption of PCP from the gastrointestinal tract after gavage doses of 9.5 and 38 mg/kg in aqueous methylcellulose vehicles was first order with an absorption half-life of about 1.3 h. 4. The absorption rate constant of PCP from doses feed was comparable with that obtained from aqueous methylcellulose gavage formulations. 5. Bioavailability of PCP administered in dosed feed was significantly lower than the bioavailability of PCP administered by gavage. 6. Dose proportionality was established to a dosage of at least 38 mg/kg. 7. Daily fluctuation of PCP plasma concentrations was observed during the dosed feed study with peak and trough concentrations occurring in early morning and late afternoon, respectively. 8. The time course of PCP plasma concentrations during the dosed feed study were simulated using a computer model based on linear theory. The simulations were comparable with the experimentally determined concentrations.

Animals↗
PubMed1994

Reconstruction of major segmental loss of the proximal femur in revision total hip arthroplasty.

Reconstruction of major proximal femoral segmental defects is one of the most difficult challenges in revision total hip arthroplasty (THA). One technique that has been successful is the use of a modular, long-stemmed prosthesis, cemented to an allograft proximal femur and press-fit to the host bone. Since July 1989, the authors have used this technique in 30 hips (29 patients). The trochanteric slide approach was used in all cases. Sixty pounds of weight bearing was encouraged for six weeks, then full weight bearing as tolerated. The mean follow-up period was 22 months (range, two to 46 months). All but two grafts united to the host bone clinically and radiographically. Complications included five dislocations, one graft-host nonunion, one graft resorption, and one deep infection requiring resection arthroplasty. The latter patient was subsequently reconstructed successfully using the same technique. Although the follow-up period is short, the authors have been encouraged by the early success of these allograft-prosthetic composites. Advantages of this approach include rapid return to weight bearing, physiologic loading of the distal femur, and reconstitution of vital proximal bone stock.

Adult↗