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Biomedical subjects

G Clark

Publications and source records attributed to G Clark.

At least 109 records · Page 6Linked to original sources
PubMed1987

Replacement of the anterior cruciate ligament with a bone-ligament-bone anterior cruciate ligament allograft in dogs.

Acute replacement of the canine anterior cruciate ligament (ACL) with a frozen, bone-ligament-bone anterior cruciate ligament preparation was studied using biochemical, immunologic, and biomechanical testing methods. Nine dogs were used for the study, six dogs received allografts and three received autografts. No tissue antigen matching was performed. All nine dogs were killed nine months after surgery. Necropsy examination revealed that the ACL was not present in three joints (one autograft, two allografts). The two autograft and four allograft ligaments available for mechanical testing sustained mean maximum loads that were 10% and 14%, respectively, of the mean maximum loads sustained by the contralateral ACL. Autoradiography indicated that cellular activity was more pronounced in the autograft specimens. Hydroxyproline uptake was 200% and 45% of normal in the autograft and allograft ligaments, respectively. Both autograft and allograft specimens were producing Type I collagen at the time of killing. Antidonor dog leukocyte antigen (DLA) antibody was detected in the synovial fluid taken at the time of killing from six of six dogs that received allografts and in zero of three dogs that received autografts.

Animals↗
PubMed1986

1-amino-3,7,8-trichlorodibenzo-p-dioxin: a specific antagonist for TCDD-induced myelotoxicity.

It was recently reported that suppression of murine bone marrow hematopoiesis is a very sensitive indicator for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity (1). We report here that a structural analog of TCDD, 1-NH2-3,7,8-trichlorodibenzo-p-dioxin (NH2-TriCDD), is a specific and effective antagonist for TCDD-induced myelotoxicity and enzyme induction. When administered to mice or added directly into culture at a 100-fold excess, relative to TCDD, NH2-TriCDD completely abrogated the ability of TCDD to inhibit granulocyte-macrophage progenitor cells (CFU-C) formation, an indicator of hematopoiesis. Further, NH2-TriCDD inhibited TCDD-induced activation of cytochrome P1-450 monooxygenase activity. Studies designed to measure specific binding of TCDD to the cytosolic Ah receptor indicated that NH2-TriCDD effectively inhibited binding of TCDD to the receptor by acting as a competitive antagonist (Ki = 0.72 nM).

Animals↗
PubMed1986

Pharmacokinetic study of fludarabine phosphate (NSC 312887).

Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily X 5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentration-time curves yielded an average distribution half-life (t1/2 alpha) of 0.60 h and a terminal half-life (t1/2 beta) of 9.3 h. The estimated plasma clearance was 9.07 +/- 3.77 l/h per m2 and the steady state volume of distribution, 96.2 +/- 26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r = -0.94, P less than 0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r = 0.828; P less than 0.1). Approximately 24% +/- 3% of 2-FLAA was excreted renally over the 5-day course of drug administration.

Agranulocytosis↗
PubMed1985

Acute myelotoxic responses in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Blood cells are derived from a multitiered system of progenitor stem cells that lose their capacity for proliferation and self-renewal as they continue along pathways of differentiation. Since these hematopoietic events can be readily monitored in vivo and in vitro in the mouse, we have utilized this system to examine altered cellular differentiation associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. Progenitor cells were suppressed following acute exposure of mice to TCDD at doses as low as 1.0 micrograms/kg body wt. In vitro studies demonstrated that myelotoxicity occurs by a direct inhibition of proliferating stem cells. Genetic studies indicated that the myelotoxic responses to TCDD, both in vivo and in vitro, segregate with the Ah locus. In addition, the in vitro myelotoxicity of various polyhalogenated aromatic hydrocarbon congeners correlated with their previously reported ability to induce hepatic microsomal enzyme activity and to bind to an intracellular receptor for TCDD. TCDD was also found to bind specifically to bone marrow cells from Ah-responsive, but not nonresponsive mice, indicating that bone marrow cells possess a specific receptor for TCDD. These data indicate that the myelotoxic response to TCDD is regulated by the Ah receptor present in the target tissue and demonstrates the utility of this system for examining the cellular and molecular events associated with the toxicity of polyhalogenated aromatic hydrocarbons, the prototype for which is TCDD.

Animals↗
PubMed1985

Pancreatic enzyme synthesis in pancreatic disease.

In a prospective evaluation of patients suspected of having chronic pancreatitis, synthesis of pancreatic enzymes was measured by means of the incorporation of selenium-75-labelled methionine into the proteins of duodenal aspirate during stimulation of pancreatic secretion with secretin (1 CU X kg-1 X h-1) plus cholecystokinin (CCK) (1 IDU X kg-1 X h-1). The rate of pancreatic enzyme synthesis was increased in patients with chronic pancreatitis. Measurement of pancreatic enzyme synthesis was more sensitive in the detection of chronic pancreatitis than either the bicarbonate or the trypsin secretory response to secretin plus CCK. A combination of the bicarbonate secretory response with measurement of the rate of enzyme synthesis provided a positive predictive power of 100% when both tests were abnormal and a negative predictive power of 100% when both tests were normal, so that the combined test can be recommended both for excluding and confirming the presence of chronic pancreatitis.

Adult↗
PubMed1984

Pancreas divisum and its association with choledochal sphincter stenosis. Diagnosis by endoscopic retrograde cholangiopancreatography and endoscopic biliary manometry.

Choledochal sphincter stenosis was demonstrated in 37 of 90 patients with pancreas divisum. In 21 of the patients, stenosis was diagnosed during ERCP by endoscopic calibration of the choledochal sphincter, delayed drainage of contrast material from the bile duct, or a dilated common duct with or without elevation of the serum alkaline phosphatase level. In 12 patients, stenosis was diagnosed during endoscopic manometry with the demonstration of elevated basal choledochal sphincter pressures. Stenosis was initially diagnosed during surgery in four patients. Common duct diameters were normal in all patients who had not had cholecystectomy. Choledochal sphincter stenosis was confirmed in all patients who subsequently underwent sphincteroplasty. The surgical approach to patients with pancreas divisum and intractable obstructive pain should include sphincteroplasty of both the major and minor sphincters rather than the minor sphincter alone.

Adolescent↗
PubMed1984

Phase I clinical investigation of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate (NSC 312887), a new purine antimetabolite.

9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-monophosphate (NSC 312887) is a new purine antimetabolite that has been evaluated in a Phase I clinical trial. The schedule of administration consisted of a single i.v. infusion over a period of 30 min once each day for 5 consecutive days, repeated at 4-week intervals. Thirteen patients received 30 courses of the drug in a dose range of 18 to 40 mg/sq m/day. Granulocytopenia and thrombocytopenia were dose limiting. Repeated courses produced similar degrees of granulocytopenia, but in 7 of 7 patients receiving 2 or more courses, the degree of thrombocytopenia was less severe during the first than during subsequent courses. Myelosuppression in humans was more severe than predicted from the mouse model. Lymphopenia was profound at all dose levels, but reversed within 3 weeks. Somnolence occurred during infusion in 8 of 13 patients, but quickly cleared after the infusion was completed. The infused drug was rapidly dephosphorylated in plasma and then cleared so there was no cumulation of drug in plasma when it was rapidly infused once each day in these doses. Phase II studies of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate are planned at a starting dose of 18 mg/ sq m/day for patients with prior chemotherapy or radiotherapy and 25 mg/sq m/day for those without prior therapy, as a single dose on each of 5 consecutive days repeated at 21- to 28-day intervals.

Adenocarcinoma↗
PubMed1983

Use of a human tumor cloning system to screen retinoids for antineoplastic activity.

Retinoid analogs are being actively evaluated as antitumor agents in man. A human tumor cloning system was used to assess the antineoplastic activity of all-trans-retinoic acid, all-trans-retinol and 13-cis-retinoic acid. The effect of retinoids on the formation of tumor colony forming units (T-CFU) was surveyed for 67 different human tumors. These analogs showed minor activity in a variety of neoplasms. The decrease in T-CFU varied between histologic tumor types and between tumor of the same type. No significant difference between retinoid analogs was noted.

Antineoplastic Agents↗
PubMed1983

Meptazinol in the treatment of severe post-operative pain: a comparison with morphine.

The efficacy of meptazinol (100 mg) was compared to morphine (15 mg) in the relief of post-operative orthopaedic pain. In a randomised double blind study, 35 patients received meptazinol and 28 morphine. The onset of maximum analgesia was quicker with meptazinol. The mean intervals between first and second intramuscular doses were 2.4 hours and 2.7 hours for meptazinol and morphine respectively. Four patients were withdrawn from the study after receiving meptazinol because analgesia was inadequate and morphine scored better than meptazinol in an assessment of overall quality of treatment. The effects on the cardiovascular system were similar for both drugs but meptazinol caused significantly less elevation of arterial PCO2 than morphine.

Adolescent↗
PubMed1982

Direct cloning of human breast cancer in soft agar culture.

A human tumor cloning system has been utilized to grow human breast carcinoma. A total of 225 specimens have been placed in culture. One hundred thirty-two were from primary chest cancer specimens and 93 were from metastatic lesions. Of these, 71% of the primary breast carcinomas and 75% of metastases formed greater than or equal to 5 colonies per 500,000 cells plated. Forty-five percent of the primary breast carcinomas and 52% of the metastases formed enough colonies (greater than or equal to 30 colonies per 500,000 cells plated) to perform meaningful in vitro drug testing. Estrogen receptor status did not influence the percentage of tumors which formed colonies in vitro. Histologic and nude mouse studies provided confirmatory evidence the colonies were composed of breast cancer cells. In 176 in vitro chemotherapeutic drug tests, the anticancer agents commonly used clinically for treatment of breast cancer, i.e., Adriamycin, 5-fluorouracil, etc., showed some in vitro activity. This activity was not as dramatic as is seen in the clinic with these conventional agents. Future work should concentrate on improving the number of colonies which form from breast cancer specimens and on prospective use of the system for screening for new agents for the treatment of human breast cancer.

Agar↗