Biomedical subjects

J D Nagel

Publications and source records attributed to J D Nagel.

9 recordsLinked to original sources

PubMed1992

Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration.

The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3-4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (elimination), 128 h (range, 28.3-171.0 h); Vdss (volume of distribution at steady state), 24.8 l (range, 17.0-232.5 l); delta'ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6-129.2 l/m2); and clearance, 0.25 l/h (range, 0.16-0.59 l/h). For plasma the median values were: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'ss, 1,345 l/m2 (range, 220-11,606 l/m2); and clearance, 117 l/h (range, 51-1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone.

Abdominal Neoplasms↗

PubMed1992

A new liver-tumor model in the rat.

A new tumor model for testing and comparing the effect of different forms of treatment on liver tumors is described. Single tumors were induced in the liver of rats by the implantation of small pieces taken from a subcutaneously growing tumor. Tumor growth was determined by measuring the weight of the implanted tumors after the animals had been killed. In this way, weight curves for treated and untreated tumors could be defined. The weight of untreated liver tumors increased exponentially with time (tumor weight in milligrams = 1 + e(t-0.31)/5). In addition, tumor growth defined as the geometric mean of three perpendicular diameters was determined. Tumor-diameter curves showed a linear increase with time in the untreated groups (tumor diameter in millimeters = 0.4 t + 1.90). The model was tested by assessing the effect of intraperitoneally injected cisplatin. The dose chosen produced a marked delay in tumor growth. On the basis of the weight gain shown by the treated animals and tumor growth delay, a therapeutic index can be defined, thus enabling to compare quantitatively different forms of treatment according to their antitumor effect and toxicity.

Adenocarcinoma↗

PubMed1991

Clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg.

The clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg were studied in five patients exhibiting solitary, localized malignant melanoma. Mitoxantrone was given as four 1-min infusions at 15-min intervals into the arterial line of the perfusion system at a total dose of up to 14 mg/m2. The mean half-lives for mitoxantrone in the blood circulation of the leg were: t1/2 alpha (distribution phase), 25.5 s, and t1/2 beta (elimination phase), 14.9 min. The mean volume of distribution at steady state in the leg was 25.6 1. In the arterial part of the perfusion, the mean AUC was 155.9 mg min l-1, and that in the corresponding venous part was 91.6 mg min l-1. Leakage of the drug from the leg into the systemic circulation amounted to 1.2% of the total delivered dose; 91% of the delivered dose remained in the leg after the perfusion had been completed. The mean elimination half-life of mitoxantrone in the systemic circulation was 123 min and the corresponding AUC for systemic concentrations was 8.59 mg min l-1. The present data revealed a high uptake of mitoxantrone into the leg and low systemic drug concentrations due to minor leakage, suggesting that mitoxantrone might be a good candidate for use in isolated, hyperthermic limb perfusion.

Adult↗

PubMed1990

A new intraperitoneal tumor model in the rat.

A new tumour model that is particularly suitable for testing intraperitoneal chemotherapy is described. Single tumours were induced to grow in the mesentery of rats by the implantation of small pieces taken from subcutaneous tumours. Tumour growth was monitored by repeated laparotomies at which the tumour size was measured with calipers. In this way, growth curves of treated and untreated tumours could be defined. The diameter of untreated intraperitoneal tumours increased linearly with time [diameter (mm) = 0.39 t (days) +2.4]. Tests using different numbers of laparotomies showed that the procedure itself had little influence on growth. Cell kinetic studies of 6-mm tumours showed a mean labelling index of 31% and a volume-doubling time of 3.9 days, resulting in cell-loss factors probably in excess of 70%. The model was tested by assessing the effect of the chemotherapeutic agent cisplatin. Regression and regrowth could be satisfactorily followed, leading to estimates of growth delay. This model therefore provides a quantitative way to assess the response of intraperitoneal tumours to chemotherapy.

Adenocarcinoma↗

PubMed1990

Anti-tumor effect of cisplatin, carboplatin, mitoxantrone, and doxorubicin on peritoneal tumor growth after intraperitoneal and intravenous chemotherapy: a comparative study.

Tumor growth was studied in a peritoneal tumor model in the rat after intravenous and intraperitoneal administration of doxorubicin (4 mg/kg), mitoxantrone (2.5 mg/kg) and cisplatin (4 mg/kg) and after intraperitoneal administration of carboplatin (20 mg/kg). All treatments delayed tumor growth and intraperitoneal treatment was more effective initially than intravenous treatment for all drugs tested. Regrowth occurred between 2 and 7 weeks after treatment and was less pronounced after intravenous treatment. Tumor sizes in cisplatin treated rats 7 weeks after treatment were comparable after intraperitoneal and intravenous treatments. Intraperitoneal carboplatin even with a dose 5 times higher than cisplatin resulted in a less tumor growth delay in all stages of the treatment, compared to cisplatin. All cytostatic drugs, except carboplatin, induced loss of body weight. Weight loss was similar for intraperitoneal and intravenous treatment with both cisplatin and mitoxantrone while for doxorubicin the weight loss was significantly higher after intravenous treatment than after intraperitoneal therapy. Considering the "therapeutic index", defined as the ratio of tumor growth delay to weight loss, cisplatin had the highest "therapeutic index", 1.5 (intraperitoneal) and 1.7 (intravenous) compared to 0.3 (intraperitoneal) and 0.6 (intravenous) for Mitoxantrone and 0.4 (intraperitoneal) and 0.5 (intravenous) for doxorubicin. This indicated that cisplatin was the most favorable drug to use in this peritoneal tumor model for both intraperitoneal and intravenous treatment. The tumor growth delay was initially more pronounced after intraperitoneal cisplatin compared with intravenous.

Animals↗

PubMed1989

A new method of sampling ascitic fluid from rats.

A new method of sampling ascitic fluid from rats over a period of at least 8 h in a reliable and easy way is described. The objective was to determine drug concentrations in ascitic fluid after intraperitoneal chemotherapy. Two silicon tubes were implanted into the abdominal cavity, one for drug administration and regulation of pressure, the other enabled ascitic fluid to be withdrawn.

Animals↗

PubMed1975

Haloperidol parenterally for treatment of vomiting and nausea from gastrointestinal disorders in a group of geriatric patients: double-blind, placebo-controlled study.

Twenty-eight geriatric residents of a nursing home participated in a double-blind study to compare the 12-hour therapeutic effectiveness of a single intramuscular injection (1.0 mg) of haloperidol with that of placebo for the relief of vomiting and nausea due to gastrointestinal disorders. Significantly fewer episodes of vomiting occurred in the haloperidol group than in the placebo group. Nausea also was less frequent in the haloperidol group. After four hours, symptoms recurred much more often in the placebo group. Global evaluations showed that a significantly greater number of haloperidol patients improved markedly than did those given placebo. There were no clinically significant changes in vital signs throughout the study in the haloperidol group. In 1 placebo patient the pulse rate was significantly increased; otherwise no adverse reactions were reported for this group. Thus, in a nursing-home population of geriatric patients who experienced vomiting and nausea due to gastrointestinal disorders, haloperidol administered parenterally proved to be a safe and highly effective antiemetic agent.

Age Factors↗

PubMedDate not supplied

New, simple model of mesenteric lymph node metastases in the rat.

Injection of 1 x 10(6) CC531 colonic carcinoma cells into the mesenteric lymph nodes of Wag/Rij rats resulted in the growth of tumors within the lymph nodes. These were apparent after 3 days, whereas lung and liver metastases were not observed until 5 weeks after inoculation. In vivo labeling with bromodeoxyuridine (BrdU) followed by immunostaining with an anti-BrdU monoclonal antibody showed a marked difference in the proportion of labeled cells of the metastases at different times after inoculation: after 3 days, many tumor cells but also many stromal cells were labeled; after 7 and 11 days, however, far less stromal cells were positive, most labeled cells being tumor cells.

Animals↗

PubMedDate not supplied

[Mitochondrial diseases].

Mitochondrial disease are a heterogeneous group, combining multiple symptoms resulting from defects in various organs. Thus identification of a particular mitochondrial disease due to clinical symptoms is not possible. However, simple biochemical tests can provide guiding and reliable results quickly. We present a classification of the mitochondrial diseases, describing important clinical symptoms and explaining a diagnostic plan to identify defects of biochemical mitochondrial pathways.

Abnormalities, Multiple↗