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Biomedical subjects

L N Owen

Publications and source records attributed to L N Owen.

At least 19 recordsLinked to original sources
PubMed1984

Preclinical pharmacokinetics of benznidazole.

Benznidazole is a lipophilic analogue of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU. We have investigated the detailed pharmacokinetics of benznidazole in mice, dogs and sheep to provide a data base for the estimation of doses required for chemosensitization in man. Pharmacokinetic behaviour was linear except at high doses in mice. Absorption was fairly rapid and bioavailability was complete following both i.p. administration in mice and oral administration in dogs. Elimination t1/2 values were longer than for MISO, being 90 min in mice, 4-5 h in sheep and 9-11 h in dogs. At doses giving linear kinetics, peak whole plasma concentrations per administered mg kg-1 were 0.75 micrograms ml-1 for the i.p. route in mice and 1.8 micrograms ml-1 for the oral route in dogs. Though between 39 and 59% of plasma benznidazole was bound to protein, tissue penetration was generally good. Tissue/whole plasma ratios ranged from 59-99% for transplantable mouse tumours and from 14-70% for spontaneous dog neoplasms. Nervous tissue penetration was similar to that in tumours: brain/whole plasma ratios averaged between 61 and 76% in mice and 42% in dogs, while peripheral nerve/whole plasma ratios in dogs averaged 74%. Mean liver/whole plasma ratios were 42% and 71% in BALB/c and C3H/He mouse strains respectively. Only approximately 5% of the administered dose was excreted unchanged in the urine, indicating the likelihood of extensive metabolism. These data show that benznidazole should have suitable pharmacokinetic properties for clinical use as a chemosensitizer. Enhancement of CCNU response is likely to require circulating benznidazole concentrations of 10-30 micrograms ml-1 and we predict that these will be obtained with oral doses of 6-20 mg kg-1 in man.

Animals↗
PubMed1984

Preliminary report on the presence of RNA-dependent DNA polymerase in canine milk.

Milk from a variety of species has been shown to contain retroviruses, the causative agents of certain neoplastic diseases. A fundamental characteristic of the retrovirus is the presence of an RNA-dependent DNA polymerase (reverse transcriptase). Milk from 80 clinically normal beagle bitches was examined for this enzyme and significant activity was detected in milk from seven animals.

Animals↗
PubMed1983

Reverse transcriptase activity and particles of retroviral density in cultured canine lymphosarcoma supernatants.

Lymphoid tissue from 43 cases of canine lymphosarcoma and from 40 clinically normal dogs have been examined for markers of retrovirus infection. From 69-76% of culture supernatants from lymphosarcomas were shown to contain particles of retroviral density and to possess poly rC-oligo dG templated polymerase (reverse transcriptase) activity compared with 17-24% of culture supernatants from normal canine lymphoid cells. In 6 culture supernatants from cases of lymphosarcoma, high molecular weight 60-70S RNA was detected and shown to be found in association with this particulate reverse transcriptase activity. No such RNA was detected in 6 culture supernatants from normal canine lymphoid cells.

Animals↗
PubMed1983

Reverse transcriptase activity in a case of ovine lymphoblastic leukaemia.

Tissues taken post mortem from a sheep suffering from lymphoblastic leukaemia were examined for retroviral reverse transcriptase (RT) activity and for particles of retroviral density. Cultured bone marrow and lymph node cells were found to release into the medium particles of 1.16 and 1.21 g/ml density, and poly rC-oligo dG templated activity could be detected in cell-free supernatants. Tissues from two normal sheep were not found to exhibit these characteristics. Electron microscopic observation failed to reveal any retrovirus-like particles in the RT positive tissues. In vitro transmission studies indicated that the RT activity could not be transmitted to either sheep choroid plexus or lamb trachea cells, but was transmitted, at low efficiency, to both bovine kidney and mink lung cells.

Animals↗
PubMed1979

The penetration of misonidazole into spontaneous canine tumours.

The hypoxic cell-radiosensitizing drug misonidazole (1-(2-nitroimidazol-1-yl)-3-methoxypropan -2 -ol, Ro 07-0582, MIS) was administered at a dose of 150 mg/kg i.v. to 6 dogs bearing spontaneous tumours, and the resulting tumour concentrations were measured to HPLC analysis. In 4 dogs it was possible to obtain serial biopsy specimens up to 5 h. With the exception of a brain tumour, the tumour concentrations ranged between 47% and 95% of the plasma concentration, most of the values falling within the range 50--70%. Concentrations in the brain tumour were markedly lower. Barbiturate anaesthesia was necessary for the removal of the serial biopsy specimens, and the effects of sodium pentobarbitone anaesthesia on the pharmacokinetics of MIS were investigated in 2 dogs. After barbiturate anaesthesia peak plasma concontrations were raised and the availability of MIS was increased, although the biological half-life remained unaltered. The metabolism of MIS to the O-demethylated metabolite, Ro 05-9963, was delayed initially. The concentrations of MIS AND Ro 05-9963 in cerebrospinal fluid were also recorded in these dogs; MIS concentrations were found to approach those of the plasma, whereas the metabolite concentrations were considerably lower (0--58% of the plasma concentration).

Adenocarcinoma↗
PubMed1978

Leukocyte migration inhibition responses in canine lymphosarcoma.

The leukocyte migration inhibition (LMI) responses of 16 cases of canine lymphosarcoma were assessed at several stages of a combined chemotherapy immunotherapy regime. Pooled allogeneic lymphosarcoma cells used in treatment together with other allogeneic lymphosarcoma cells and autochthonous tumour cells were employed as antigens. Positive inhibitions were detected at all stages of treatment when medium controls were used but were not detected in five normal dogs with the same control. There was no association between relapse and remission and LMI response. When a normal lymph-node cell control was used only four dogs produced positive responses, all of which occurred after allogeneic cell administration. These positive responses could not be completely accounted for by sensitization to histocompatibility antigens but as they occurred both in remission and in relapse, including very advanced cases necessitating euthanasia, they were of no value in determining prognoses.

Animals↗
PubMed1976

Allogeneic grafts of spontaneous canine melanomas and their cell culture strains in neonatal immunosuppressed dogs.

Canine melanoma has been transplanted to allogeneic neonatal recipients receiving continuous immunosuppression with anti-lymphocyte serum. One spontaneous melanoma was directly transplanted into 8 recipients, 6 of which developed tumours. 5/5 melanoma cell cultures were transplantable, with 19 tumour takes in 31 allogeneic recipients. Serial passage was performed in the case of two melanomas. Tumour development required continuous immunosuppression and the site was dependent upon the route of inoculation and other factors. Transplanted cell cultures were all amelanotic in vitro and in vivo, except in the case of one melanoma which reverted to a melanotic morphology after in vivo growth.

Animals↗
PubMed1976

Contraceptive steroid toxicology in the Beagle dog and its relevance to human carcinogenicity.

Problems associated with the use of the Beagle dog in chronic toxicological studies of contraceptive steroids are described. A short review is presented on the occurrence of spontaneous tumours in dogs and in bitches of various breeds. The current status of knowledge of canine reproductive hormones and endocrinology is outlined, together with effects of contraceptive steroids. The pathology and histological classification of spontaneous and induced mammary neoplasia in the dog is discussed and compared with breast cancer in women. A series of recommendations are included for future research in this field which it is hoped may resolve some of the outstanding issues and lead to a more suitable toxicological model for contraceptive steroids.

Animals↗