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T Hamilton

Publications and source records attributed to T Hamilton.

17 recordsLinked to original sources
PubMed1992

Preclinical and phase I studies with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme.

BACKGROUND: Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor xenografts and has activity against a number of vincristine-resistant tumors in vitro and in vivo. PURPOSE: This study describes the preclinical and clinical pharmacology of rhizoxin to apply a pharmacokinetically guided dose-escalation (PGDE) strategy during the phase I trial. METHODS: Rhizoxin was administered by a single intravenous bolus injection to female BALB/c mice over the dose range 7.5-18 mg/m2 from which we derived the dose that was lethal to 10% and 50% of the mice (i.e., LD10 and LD50, respectively). The LD10 was 11.7 +/- 0.7 mg/m2 (mean +/- SD), and the LD50 was 14.7 +/- 0.6 mg/m2. Pharmacokinetic studies were integrated with the toxicity study in female BALB/c mice at one-tenth the LD10, one-half the LD10, and the LD10 (i.e., 1.2, 6, and 12 mg/m2, respectively). From these data, a target area under the plasma drug concentration versus time curve (AUC) (i.e., 40% of the LD10 AUC) was calculated for clinical studies. Phase I studies were initiated at 0.8 mg/m2 (one-tenth the equivalent LD10 in male CD1 mice), with the intent of escalating the dose by an extended factor-of-two method until the target AUC and/or maximum tolerated dose (MTD) was reached. RESULTS: The major drug toxic effects in mice were body weight loss, sluggishness, ataxia, transient changes in hematological parameters, and hematuria. Diarrhea was universal at doses greater than 9 mg/m2, and hind limb paralysis was observed in one of 10 mice, but only at supralethal doses (18 mg/m2). Rhizoxin pharmacokinetics were best described by a two-compartment open model (half-life [t 1/2] alpha = 4.4 minutes +/- 0.9 minute [mean +/- SD], and t 1/2 beta = 84 minutes +/- 20 minutes at 12 mg/m2) and found to be nonlinear with respect to dose. At doses of 1.2, 6, and 12 mg/m2, the respective AUC values were 1.3, 22.4, and 70.6 microM x minute. From these data, a target AUC value of 28 microM x minute (40% of the LD10 AUC) was derived. Rhizoxin was not detectable in patient plasma (less than 5 ng/mL at 0.8 and 1.6 mg/m2), and doses had to be escalated by conventional methods. Myelosuppression was dose limiting in patients: Seven of eight treated at 2.6 mg/m2 experienced World Health Organization grade 3-4 neutropenia, and five of eight developed mucositis. The AUC values at the human MTD (2.6 mg/m2) were in the range of 0.41-1.01 microM x minute, considerably lower than the target AUC of 28 microM x minute. CONCLUSION AND IMPLICATIONS: Although PGDE schemes have been successfully employed for other antitumor agents, this methodology could not be applied during the phase I trial of rhizoxin. PGDE studies in the future may incorporate comparative murine versus human metabolism studies in vitro with phenotyped liver microsomes. It may also be useful to assess the comparative myelotoxicity of a new drug by performing in vitro cytotoxicity studies on mouse and human bone marrow stem cells.

Adolescent↗
PubMed1992

Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity.

The production of 14CO2 in the breath from an intravenous dose of [14C-N-methyl]-erythromycin (the erythromycin breath test [ERMBT]) and the measurement of the ratio of 6-beta-cortisol to free cortisol (6-beta-F/FF) in the urine have each been proposed as means of measuring hepatic P450IIIA catalytic activity in patients. We found that there was a significant correlation between the results of each test (r = 0.59, p less than 0.001) in 47 patients who were without liver disease and who were not taking medications believed to influence P450IIIA catalytic activity. In the 24 of these patients who were subsequently treated with the P450IIIA substrate cyclosporine, the ERMBT result was highly correlated with the mean trough cyclosporine blood level observed; however, there was no correlation between urinary 6-beta-F/FF and the cyclosporine blood levels. In a separate study of a patient during the anhepatic phase of liver transplantation surgery, the ERMBT result decreased by greater than 85%, whereas urinary 6-beta-F/FF decreased by just 50%. We conclude that the ERMBT and urinary 6-beta-F/FF do not always provide similar information about P450IIIA catalytic activity in patients, possibly because of extrahepatic production of 6-beta-F. Of the two tests, the ERMBT appears to provide the most relevant information for cyclosporine administration.

Aryl Hydrocarbon Hydroxylases↗
PubMed1992

Construction and characterization of a high-affinity chimeric anti-colorectal carcinoma antibody ccM4.

We have produced a high-affinity chimeric anti-colorectal carcinoma antibody, ccM4, chimerized in both heavy and light chains by the construction of two expression vectors, the chimeric heavy-chain expression vector mpSV2neo-EP1-Vm4Cr1 and chimeric light-chain vector mpSV2gpt-EP1-VKCK. These vectors contained the neo or gpt gene as a selection marker, the murine immunoglobulin promoter and enhancer (EP1), the genomic DNA fragments of human immunoglobulin constant region (CK and C gamma 1), and murine cDNA fragments of VH and VK region amplified and cloned directly from the B72.3 hybridoma RNA by the polymer chain reaction technique. These two vector DNAs were sequentially transfected into the SP2/0Ag14 cell line. Transfectants were selected in media containing both G418 and mycophenolic acid. The ccM4 antibody was purified from transfectant supernatants with positive binding reactivity for the TAG72 antigen on a protein A column. We demonstrated that ccM4 antibody retained the same high binding reactivity for the TAG72 antigen as its counterpart, the high-affinity chimeric heavy-chain cB72.3m4 antibody. The ccM4 antibody bound specifically to human colon cancer cells, displayed biodistribution patterns similar to cB72.3m4 antibody, and mediated effective antibody-dependent cellular cytotoxicity to human OVCAR3 tumor cells. Therefore, the high-affinity chimeric ccM4 antibody should be useful in cancer immunotherapy.

Animals↗
PubMed1992

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation. A study of left ventricular pressure-volume relationship.

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1990

Changes in photo-aged human skin following topical application of all-trans retinoic acid.

Although topical applications of retinoids on rodents and humans have been shown to cause epidermal hyperplasia, a detailed study of the influence of retinoids on epidermal differentiation in vivo has not been performed. In order to assess the pharmacologic effects of chronic topical tretinoin application used to improve the appearance of patients with photoaged skin, cutaneous biopsies from 25 patients in a controlled clinical study were examined histologically and immunocytochemically. Chronic application of tretinoin causes epidermal thickening (25 of 25 samples), stratum granulosum thickening (15 of 25), parakeratosis (13 of 25), a marked increase in the number of cell layers expressing epidermal transglutaminase (13 of 25), and focal expression of two keratins, K6 (12 of 25) and K13 (8 of 25), not normally expressed in the epidermis. The morphologic changes correlated with immunohistochemical abnormalities; neither of these correlated with the subjective cosmetic response. Three major epidermal differentiation products, keratins K1, K10, and K14 were not altered, within the limits of the methods used. Thus, chronic topical tretinoin reprograms some, but not all, aspects of human epidermal differentiation in vivo.

Administration, Topical↗
PubMed1979

Prolonged and continuous percutaneous intra-arterial hepatic infusion chemotherapy in advanced metastatic liver adenocarcinoma from colorectal primary.

Sixty patients with advanced metastatic adenocarcinoma of the liver from a colorectal primary were treated by prolonged and continuous intra-arterial hepatic arterial infusion chemotherapy over a period of time from December 1969 through July 1976. A 10-day course of 5-FU was administered in the hospital, and patients were discharged receiving 5-FUDR by continuous arterial infusion through a chronometric infusion pump. Objective responses of 100% were obtained in 15% of patients, 50% response in 39% of patients, and 25% response in 21% of patients. The median survival from onset of treatment was 8.5 months, 6.9 months, and 7 months, respectively, for 100%, 50%, and 25% responders versus 3.6 months for nonresponders. Survivals from onset of treatment were generally less in those with no disease-free interval. No relationship of response to sex and age was found. Patients previously treated with 5-FU intravenously responded to intra-arterial chemotherapy; 13% had a 100% response, and 54% had a 50% response. No relationship of drug dose to response was observed. Drug toxicity was frequently systemic and mild to moderate. Numerous complications occurred due to the catheter, complete or partial thrombosis occurring in 18.6% and 20.8%, respectively, and 30% of patients had displacement of the catheter. The role of partial arterial occlusion in terms of response and survival may be significant. Future studies should involve comparison of direct surgical placement versus percutaneous placement of catheters.

Adenocarcinoma↗
PubMed1978

Urinary etiocholanolone and prognosis in early carcinoma of the breast.

Etiocholanolone levels have been measured in both premastectomy and postoperative urines from 86 women with early breast cancer. Levels did not differ between patients subsequently surviving five years following mastectomy and those dying from recurrent disease within this period.

Breast Neoplasms↗
PubMed1976

Detection of breast disease in a family planning association clinic.

The incidence and prevalence of disorders of the breast have been assessed in 13,456 women examined annually at a family planning clinic over 5 years. Screening for disorders of the breast was by clinical examination alone and abnormalities were detected in 1 of every 58 women attending the clinic and these were referred for hospital opinion: biopsy was required in 1 in 114. Only 12 cancers of the breast were detected and all of these in women over 35 years. It is suggested that the usual policy of examining the breasts of women taking oral contraceptive preparations should be restricted to those over 40 years.

Adolescent↗
PubMed1975

Urinary aetiocholanolone in patients with early breast cancer from South East Scotland and South Wales.

Urinary aetiocholanolone levels have been measured in 417 women aged between 20 and 70 years. The women were drawn from South East Scotland and South Wales and consisted of patients with either benign or malignant disease of the breast and control patients suffering from no detectable breast disorder. The pattern of aetiocholanolone excretion with respect to age and menopausal status has been defined in each group of patients. No significant differences in urinary levels have been detected between patients with breast disease, whether benign or malignant, and control patients. More detailed examination of the 201 women with early cancer of the breast has also shown that there is no consistent correlation between pre-operative aetiocholanolone levels and factors of prognostic significance detectable at the time of primary treatment-tumour size, grade, round cell infiltration, histological involvement of nodes by tumour and the clinical palpability of lymph nodes. It would seem, therefore, that the prognostic value of pre-operative aetiocholanolone measurements is somewhat limited in patients with early breast cancer. It is noted, however, that low levels of aetiocholanolone are associated with post-menopausal patients, a group in which the prognosis is generally poorer than that in pre-menopausal women.

Adenofibroma↗
PubMedDate not supplied

Admissions for suspected snake bite to the Perth adult teaching hospitals, 1979 to 1988.

OBJECTIVE: To describe the epidemiology of snake bite in Perth, and the likelihood of envenomation. DESIGN: Information from case notes was retrospectively analysed. SETTING: Emergency medicine, teaching hospitals. PATIENTS: All patients admitted to the three adult teaching hospitals in Perth for suspected snake bite from 1979 to 1988. MAIN OUTCOME MEASURE: Systemic envenomation, was accepted as present if there were definite symptoms, signs or laboratory evidence (vomiting, abdominal pain, ptosis, convulsions, difficulty with breathing or swallowing, coagulopathy, haemolysis, rhabdomyolysis or renal failure). RESULTS: Ninety-nine patients were definitely bitten, with 53 envenomed, including three snake handlers. Thirty others may have been envenomed. Nearly half (44%) of the 82 patients with witnessed snake bite were envenomed. The dugite (Pseudonaja affinis) caused most cases of envenomation, most often producing coagulopathy only. The remainder were probably due to bites by the tiger snake (Notechis after occidentalis) and gwardar (Pseudonaja nuchalis), with one by a sea snake. The Commonwealth Serum Laboratories Snake Venom Detection Kit (VDK) enabled identification of the genus in 36% of definite cases of snake bite, and in 51% of cases of envenomation. It may occasionally produce false-positive results. The VDK is of greatest value in establishing the genus of snake in envenomed patients. CONCLUSIONS: It is suggested that a mixture of brown and tiger snake antivenom be used to treat patients envenomed by an unidentified snake in the Perth metropolitan area. This does not apply to patients bitten elsewhere in Western Australia or transferred to Perth from country regions where other snakes are more prevalent.

Adolescent↗
PubMedDate not supplied

Optimal storage period for extended heart preservation with the University of Wisconsin Solution. A study of the left ventricular pressure-volume relationship.

To define the optimal and safe storage period in the use of the University of Wisconsin Solution (UWS) for extended heart preservation, 34 adult canine hearts were preserved under static and hypothermic conditions for 6, 12, 18, and 24 hours. A group of 10 hearts were used as a control of the preparation used in the study. Left ventricular functions were assessed in an isolated heart preparation equipped with a computerized servo-pump to measure the pressure-volume relationship. The systolic, diastolic and total ventricular performance were derived from the end-systolic pressure-volume relationship, end diastolic pressure-volume pressure relationship, and the stroke work-end diastolic volume relationship, respectively. Myocardial water content and coronary resistance during reperfusion were also analyzed. The study revealed that UWS was able to maintain normal levels of systolic and diastolic functions, and consequently normal level of total ventricular performance after 6 hours of storage. There was a reduction of diastolic function while the systolic function was still well maintained after 12 hours of preservation. The results after 12 hours were poor. There was no increase in the myocardial water content for up to 24 hours of storage; however, the coronary resistance during reperfusion significantly increased in the 18-hour group and the 24-hour group. The findings suggest that UWS may extend the safe period of myocardial preservation beyond the traditional 4 hours of storage closer to 12 hours of storage.

Adenosine↗