Biomedical subjects

R L Page

Publications and source records attributed to R L Page.

196 records · Page 11Linked to original sources

PubMedDate not supplied

Manipulation of intra- and extracellular pH in spontaneous canine tumours by use of hyperglycaemia.

We evaluated the use of hyperglycaemia to reduce tumour pH in dog with spontaneous tumours. Dogs were randomized to two groups: control and glucose. Intravenous administration of 20% glucose was used to induce and maintain hyperglycaemia. Extra- and intracellular tumour pH were measured using interstitial pH microelectrodes and 31P-MRS, respectively. During the administration of glucose, the mean (+/- SEM) blood glucose concentration was 419.8 (+/- 32.8) and 121.1 (+/- 8.0) mg/dl for the glucose and control groups, respectively. The mean extracellular tumour pH before and following 90 min of hyperglycaemia was 7.15 (+/- 0.08) and 7.15 (+/- 0.09). During consecutive measurements, intracellular tumour pH did not change significantly for the control group or the group subjected to hyperglycaemic manipulation. In contradistinction to previous rodent studies, our results demonstrate that hyperglycaemia alone is not sufficient to manipulate either intra- (pHi) or extracellular (pHe) hydrogen ion concentration in spontaneous canine soft tissue tumours.

Animals↗

PubMedDate not supplied

Effect of hyperthermia on cisplatin and carboplatin disposition in the isolated, perfused tumour and skin flap.

The effect of hyperthermia on the disposition of platinum (Pt) from cisplatin (CDDP) and carboplatin (CBDCA) in the isolated, perfused tumour and skin flap (IPTSF) was evaluated. Flaps (n = 4/treatment) were perfused with 3.0 micrograms CDDP or 15 micrograms CBDCA/ml perfusion medium at a rate of 1 ml/min for 3 h. Two-hour (CDDP experiments) or 3 h (CBDCA experiments) washout phases were then performed. The disposition kinetics of free Pt were characterized using a four-compartment, physiologically relevant, pharmacokinetic model. Hyperthermia (HT) may have enhanced the mobility of Pt but it did not increase total Pt mass in the tissue compartments in CDDP experiments. Conversely, HT significantly increased Pt mass in the fixed, non-tumour tissue compartment (p < 0.05) in CBDCA experiments. While a similar trend was noted in the fixed, tumour tissue compartment of CBDCA-treated flaps, the difference was not significant (p = 0.17). Total tissue Pt mass was significantly greater in CDDP compared with CBDCA experiments (p < 0.05). In conclusion, HT alters the disposition of Pt from CDDP and CBDCA under conditions of constant rate infusion. Further characterization of factors influencing drug disposition to non-tumour and tumour tissues can be systematically accomplished using the IPTSF.

Animals↗

PubMedDate not supplied

Effect of whole body hyperthermia on carboplatin disposition and toxicity in dogs.

Fifty dogs with refractory or disseminated spontaneous tumours were evaluated in two independent phase I studies using either carboplatin (CBDCA) alone or CBDCA plus whole body hyperthermia (WBH). CBDCA was administered as a 30 min infusion at the onset of the plateau phase of WBH in dogs receiving combined treatment. Serum samples were collected and drug disposition was determined in both treatment groups. The dose-effect relationship was mathematically described with a logistic regression model developed from categorical toxicity data accumulated throughout the first two treatment courses in all dogs. The maximum tolerated dose (MTD) was defined as that dose which resulted in a 50% probability of achieving moderate or severe toxicity. The only toxicities observed were neutropenia and thrombocytopenia, which were dose-dependent. The nadir occurred between 7 and 14 days following treatment. A significant decrease in the area under the serum CBDCA versus time curve for dogs undergoing WBH was consistent with increased tissue binding of the drug as well as increased urinary eliminations. Serum AUC values determined following the first course of treatment were predictive of subsequent toxicity in both treatment groups. The MTD (95%CI) for CBDCA and CBDCA/WBH were estimated to be 318(44) and 239(51) mg/M2 respectively (p = 0.08). A randomized phase II evaluation should be initiated to determine if a therapeutic gain can be achieved using combined CBDCA and WBH. Further refinement of the CBDCA dose in such a trial should be based on both pharmacokinetic parameters and normal tissue response.

Animals↗

PubMedDate not supplied

Inspired anaesthetic gas humidification improves thermal uniformity during canine whole body hyperthermia.

Supplying warmed saturated water vapour in anaesthetic gases during whole body hyperthermia (WBH) could potentially improve thermal uniformity in the trachea and esophagus. Four normal dogs were anaesthetized for WBH at 42 degrees C. A Puritan Bennett Cascade humidifier was used to supply anaesthetic gases saturated with water vapour at an average airway temperature of either 42 degrees C or 38 degrees C. Esophageal temperature was monitored at the thoracic inlet and 5 cm cephalad. Thermal dose was estimated by calculating equivalent minutes for an isoeffect at 43 degrees C (CEM 43 degrees Tx, where Tx is the site of temperature measurement). Endotracheal mucociliary transport velocity (MCTV) was determined before and 48 h following WBH by 99mTc-MAA scintigraphy. Compared to the 38 degrees C humidified gas group, dogs receiving 42 degrees C humidified gas reached 42 degrees C faster (p = 0.02) and had CEM 43 degrees T(esophageal) values equivalent to the target CEM 43 degrees T(rectal). Endotracheal MCTV with 42 degrees C humidified gas, however, was reduced 53% from baseline 48 h following WBH (p = 0.02). With 38 degrees C humidified gas, endotracheal mucociliary transport velocity was unchanged from baseline 48 h post WBH. Tracheal histology was examined using light and electron microscopy in four additional dogs euthanatized following 90 min of 42 degrees C humidified gas combined with WBH. There was no histological evidence of tracheal or lung thermal damage with 42 degrees C humidified gas in these four dogs. However, a moderate increase in tracheal goblet cell secretory granule staining was observed. This change could imply temporary heat-induced ciliary microtubule dysfunction, rather than decreased mucus production, as the likely mechanism of reduced mucociliary transport velocity 48 h following WBH. Administration of 42 degrees C humidified anaesthetic gases with WBH improves heating rate and esophageal thermal uniformity but temporarily depresses tracheal mucociliary transport velocity.

Anesthetics, Inhalation↗

PubMedDate not supplied

Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs.

The pharmacokinetics and toxicity of intravenous lonidamine were investigated in dogs receiving four cycles of lonidamine (400 or 800 mg/m2) +/- whole-body hyperthermia (WBH). Clearance and volume of distribution in dogs receiving lonidamine during WBH increased 1.6-2.3 and 1.9-3.5-fold respectively, relative to dogs receiving lonidamine under euthermic conditions (p < 0.02). In dogs receiving lonidamine under euthermic conditions or 400 mg/m2 + WBH, the area under the lonidamine concentration versus time curve (AUC) measured during the fourth treatment was 21-58% lower than the first treatment AUC. However, in dogs receiving 800 mg/m2 + WBH, the fourth treatment AUC was four-fold higher than the first treatment AUC (p < 0.02). This suggests repeated exposure to 800 mg/m2 lonidamine and WBH impairs lonidamine metabolism. Weakness, hypoglycaemia, and elevations in amylase, alanine aminotransferase, alkaline phosphatase and bilirubin were more severe or occurred exclusively in dogs receiving 800 mg/m2 + WBH. Since these changes were attributable to marked AUC increases, which occurred secondary to repeated exposure to 800 mg/m2 lonidamine during WBH, 400 mg/m2 was identified as the maximum tolerable dose to be administered intravenously to dogs during WBH.

Alanine Transaminase↗

PubMedDate not supplied

Effect of whole-body hyperthermia on lonidamine and doxorubicin pharmacokinetics and toxicity in dogs.

Six cycles of the maximum tolerable intravenous doses of lonidamine (400 mg/m2) and doxorubicin (30 mg/m2) were administered to three normothermic dogs and three dogs undergoing whole-body hyperthermia (WBH) (42 degrees C X 90 min), at 3-week intervals. Lonidamine pharmacokinetics was unaltered by WBH. WBH increased doxorubicin clearance 1.6-fold, however this trend was not statistically significant. WBH resulted in a 2.4-fold increase in the volume of distribution (Vdss) of doxorubicin relative to dogs treated under euthermic conditions (p < 0.001). This finding suggests tissue extraction of doxorubicin was increased by WBH. The specific tissues in which this occurred is unknown, but myelosuppression and cardiotoxicity were only minimally increased. Therefore, doxorubicin uptake in critical normal tissues was probably unaffected. The biochemical and haematologic toxicities observed 6 h and 1 week after each treatment did not appear to differ in character or severity from that reported in dogs receiving lonidamine +/- WBH or doxorubicin +/- WBH. These results suggest WBH did not decrease the maximum tolerable dose of doxorubicin when given with lonidamine, and that the antitumour activity of this combination should be assessed.

Animals↗

PubMedDate not supplied

Phase I evaluation of mitoxantrone alone and combined with whole body hyperthermia in dogs with lymphoma.

The maximum tolerated dose of mitoxantrone (MX) administered alone or combined with whole body hyperthermia (WBH) was determined in this nonrandomized, prospective study in dogs with lymphoma. MX was administered to 53 dogs every three weeks for a total of six treatments unless progressive disease or persistent, severe toxicity developed. Fifty dogs were evaluable (MX alone n = 30, MX/WBH n = 20). MX was administered as a 1 h infusion at the onset of the plateau phase of WBH in dogs treated with combined therapy. Dogs were evaluated weekly between treatments for the first four treatments with physical examination and complete blood counts to define acute and cumulative toxicity. Dogs were evaluated every three weeks for tumour response until relapse. The maximum tolerated dose (MTD) was defined as that dose in each group that resulted in a 50% incidence of moderate or severe toxicity as estimated from logistic regression analysis of the toxicity data. Myelosuppression was the only toxicity observed. Neutropenia was equal in frequency and severity between treatment groups. Thrombocytopenia was not observed in any dog receiving MX/WBH but occurred in 13% of dogs treated with MX alone. The MTD for MX +/- WBH was 6.1 +/- 0.6 and 6.5 +/- 0.8mg/M2 respectively. A steeper dose response relationship was observed in dogs receiving combined therapy compared to dogs treated with MX alone suggesting WBH may improve the uniformity of patient response to chemotherapy. We concluded that MX may be administered without dose reduction to dogs undergoing WBH and that MX should be evaluated more thoroughly in future thermochemotherapy studies.

Animals↗

PubMedDate not supplied

Potential complications associated with normothermic lonidamine infusion and with systemic acidosis in dogs receiving lonidamine during whole body hyperthermia (WBH).

The vascular toxicosis of lonidamine (40 mg/h) or vehicle infusion was investigated in six dogs. Vasculitis and thrombosis were observed in veins infused with lonidamine but not in veins infused with vehicle. This finding suggests that it may not be possible to use lonidamine infusion to circumvent therapeutic limitations associated with the oral lonidamine formulation currently used in patients. We also investigated the systemic toxicosis of lonidamine (400 mg/m2; rapid intravenous bolus) or vehicle in six other dogs that developed systemic acidosis (pH < or = 7.0) during whole body hyperthermia (42 degrees C x 90 min). Gross and histologic haemorrhage was observed in all dogs; however, haemorrhagic lesions in acidotic dogs receiving lonidamine + WBH were more severe than changes observed in acidotic dogs receiving vehicle + WBH. These observations confirm the results of in vitro studies which suggest that the combined effect of lonidamine and hyperthermia is enhanced under acidic conditions. Furthermore, these findings indicate that acid-base status of patients receiving lonidamine during WBH must be monitored carefully to avoid serious complications.

Acidosis↗

PubMedDate not supplied

Primary rib tumors in 54 dogs.

Fifty-four dogs with primary tumors of the rib were evaluated. Thirty-four dogs had osteosarcomas, 15 dogs had chondrosarcomas, three dogs had hemangiosarcomas, and two dogs had fibrosarcomas. Forty-nine dogs had en bloc excision. Within the osteosarcoma group, nine animals received postoperative adjuvant chemotherapy. These animals had significantly longer median disease-free intervals (225 days) and median survival times (240 days) than dogs with osteosarcoma treated by surgery alone (median disease-free interval, 60 days; median survival, 90 days). Chondrosarcoma had a better prognosis (median disease-free interval, 1,080 days; median survival, 1,080 days) than osteosarcoma, hemangiosarcoma, or fibrosarcoma of the rib. Age, weight, sex, number of ribs resected, tumor volume, and total cisplatin dose did not influence survival nor disease-free interval.

Animals↗

PubMedDate not supplied

Modulation of P-glycoprotein-mediated doxorubicin resistance in canine cell lines.

OBJECTIVE: To characterize the chemosensitivity of wild type and multidrug resistant canine cell lines and determine the relative potency of the P-glycoprotein (Pgp) modulators verapamil, tamoxifen and a cyclosporin-A analog (PSC833). METHODS: The dose required to reduce cell proliferation to 50% of control (ED50) for doxorubicin (DOX) and cisplatin was determined for canine cell lines 4TG11-50c, OS2.4wt, OS2.4DX and the human cell line MCF7/DX. The effect of Pgp chemomodulators on cytotoxicity was quantified by determining the dose modifying factor [DMF = (ED50 of Dox alone)/(ED50 of Dox + Modulator)]. Relative potency of modulators was defined as DMFMOD1/DMFMOD2. Pgp function was assessed by DiOC2 dye retention and by accumulation of DOX after chemomodulator addition. RESULTS: All cell lines were equally cisplatin sensitive but varied in doxorubicin resistance. PSC833 was 12X, 5X and 2X more potent than tamoxifen in 4TG11-50c, OS2.4WT and OS2.4DX, respectively. Dye retention was a better indicator of chemomodulator-enhanced cytotoxicity than was DOX accumulation. CONCLUSIONS: Pgp inhibition is cell line, modulator and concentration dependent but the cytotoxic potency of a modulator may be predicted by the extent of dye retention in canine drug resistant cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.

BACKGROUND: Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. METHODS: Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. RESULTS: The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. CONCLUSIONS: We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.

Acute Disease↗

PubMedDate not supplied

Setting up interdepartmental peer review. The British Thoracic Society's scheme.

In 1992 the British Thoracic Society arranged a series of voluntary interdepartmental peer reviews. Their prime objective was to help to improve services by enabling clinicians to share experiences and ideas on the organisational aspects of the service and training provided. This paper outlines the planning and implementation of the scheme and some of the key results, and discusses the benefits and difficulties of such 'peer reviews'. Much of the benefit comes from the free exchange of ideas at the time of the reviews and 82% of the participants felt that they had picked up new ideas during the review. In their reports, reviewers outlined the strengths and weaknesses of the units and put forward a list of their key recommendations for change. Importantly, in half of the reviews the reviewers identified factors requiring change that had not been anticipated by the reviewed units. In most cases, the reports were subsequently shown to the managers concerned. One year after the review, 53% of 144 major recommendations had been achieved or were imminent. This form of voluntary peer review benefits both the reviewers and the reviewed and could well be adopted by other specialties.

Humans↗

PubMedDate not supplied

Therapeutic hyperthermia: contribution from clinical studies in dogs with spontaneous neoplasia.

Dogs with spontaneously arising tumors have contributed greatly to the field of therapeutic hyperthermia. Pharmacologic, physiologic and immunologic characterization of the response to hyperthermia combined with radiation and chemotherapy in dogs has helped in development of new heating methods, warned of significant toxicity prior to human testing, and defined the effect of heat on drug distribution and relative potency. Clinical trials have been conducted in dogs with spontaneously arising cancer to refine treatment protocols prior to human clinical testing and have demonstrated the tumor control advantage of combined radiation/hyperthermia compared to radiation only in numerous prospective, phase III trials. These studies can be conducted less expensively and more rapidly than comparable studies in humans. This paradigm demonstrates the value of an intermediate, clinically relevant model in the study of novel treatment strategies and should continue to be used to investigate important issues for the benefit of both humans and animals with cancer.

Animals↗

PubMedDate not supplied

Immunophenotypic characterization of canine lymphoproliferative disorders.

One hundred ninety six dogs with spontaneously occurring lymphoproliferative disorders were immunophenotyped. Dogs with lymphoma (175) were determined to be derived from B-cells in 134/175 (76%), T-cells in 38/175 (22%) and 3/175 (2%) were null cells (non-reactive with any canine-specific lymphocyte antibody). Dogs with T-cell lymphomas were at significantly higher risk of relapse and early death compared with B-cell lineage lymphoma following therapy (52 vs. 160 days; p < 0.001 and 153 vs. 330 days; p < 0.001, respectively). Hypercalcemia was associated only with CD4+ lymphomas. A nonimmunoglobulin B-cell marker (B5), expressed in 95% of nonneoplastic lymphocytes, was expressed at a reduced level in 63% (64/104) of dogs with B-cell lymphoma. Dogs with lymphoma in which the B5 antigen was expressed below normal levels experienced shorter progression free survival (125 vs. 202 days; p < 0.05) and overall survival times (203 vs. 385 days; p < 0.05) than dogs with B-cell lymphoma in which the B5 antigen was expressed normally. Chronic lymphocytic leukemia in dogs was primarily associated with a CD8+ phenotype (8/12) and acute lymphoblastic leukemia was determined to be of either null cell (4/9) or T-cell (3/9) phenotype. Although canine and human non-Hodgkin's lymphoma are phenotypically similar, canine leukemia is phenotypically distinct from human leukemia. The development of canine-specific probes has facilitated a priori assessment of treatment outcome in dogs with lymphoma and may in the future contribute to the comparative understanding of leukemo- and lymphoma-genesis in these species.

Animals↗

PubMedDate not supplied

Fatal toxic epidermal necrolysis related to lamotrigine administration.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe life-threatening dermatologic conditions. To date, eight cases of TEN and one of SJS related to lamotrigine administration have been reported in the literature. Most patients were also taking concomitant valproic acid. It was hypothesized that valproic acid may interfere with glucuronidation of lamotrigine, leading to increased serum lamotrigine levels, or perhaps alter the drug's metabolism, resulting in accumulation of a toxic intermediate metabolite. Ultimately, this may possibly predispose a patient to increased dermatologic reactions, including TEN. A 54-year-old man developed TEN 4 weeks after beginning lamotrigine for complex partial seizures related to a glioblastoma multiforme brain tumor. The patient had also been taking concomitant allopurinol and captopril for more than 4 years with no complications, and valproic acid 3 months before the cutaneous event. Despite aggressive intensive care management, the patient died 17 days from the onset of symptoms due to multiple organ failure. Administration of lamotrigine, especially in combination with valproic acid, may lead to the development of TEN.

Anticonvulsants↗

PubMedDate not supplied

Characterization of canine MDR1 mRNA: its abundance in drug resistant cell lines and in vivo.

BACKGROUND: Overexpression of the MDR1 gene often contributes to antineoplastic drug resistance. The purpose of this study was to characterize the canine MDR1 mRNA homologue and evaluate its expression in both canine cell lines and lymphomas. MATERIALS AND METHODS: The abundance of the canine MDR1 transcript was assessed in three resistant cell lines and in pretreatment canine lymphoma using semi-quantitative RT/PCR. RESULTS: Canine transcript was 4.5 Kb with 93% sequence homology to human MDR1, and 90% homology to mouse and hamster equivalent genes. Increase in MDR1 transcript levels was observed in three progressively resistant canine cell lines. De novo MDR1 transcript expression was independent of response to therapy in dogs with lymphoma. CONCLUSIONS: We conclude that the canine MDR1 mRNA homologue is structurally similar to the human transcript. Expression of MDR1 mRNA correlates with in vitro drug sensitivity but does not correlate with in vivo doxorubicin sensitivity in canine lymphoma.

Adrenal Glands↗