A General-Purpose Illuminated Temperature Gradient Plate

Smiih, J. Drew; Reiter, Wolfgang

doi:10.4141/cjps74-153

Cited by 7 publications

(3 citation statements)

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“…In dogs treated with lethal doses, radiographie findings are consistent with a interstitial pneumonitis including severe acute inflammation with neutrophil and monocytic infiltration of alveoli and bronchioles, a proteinaceous alveolar exÃº date, capillary congestion, and alveolar cell necrosis (5,(25)(26)(27). In lower mammals the slope of the dose-toxicity curves are steep, with small differences between doses associated with reversible pulmonary toxicity and death ( 12,25,26).…”

Section: Ipo3 (mentioning

confidence: 86%

“…IPO binds immediately to nucleophilic macromolecules at the site of activation (4), leading to bron chiolar epithelial necrosis preferentially involving the Clara cells (4,25,26). Maximal expression of lung toxicity occurs between days 1 and 5 after treatment (12,25,26). In dogs treated with lethal doses, radiographie findings are consistent with a interstitial pneumonitis including severe acute inflammation with neutrophil and monocytic infiltration of alveoli and bronchioles, a proteinaceous alveolar exÃº date, capillary congestion, and alveolar cell necrosis (5,(25)(26)(27).…”

Section: Ipo3 (mentioning

confidence: 99%

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Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: Hepatotoxicity is dose limiting in humans

Rowinsky¹,

Noe

Ettinger

et al. 1994

Lung Cancer

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ABSTRACT4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemicalbiological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that met abolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity pref erentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development.Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predomi nately alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two-compartment first order elimination model, the rela tionship between IPO dose and area under the disposition curve was curvilinear, suggesting saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (Al and A2) were 6.7 and 114.5 min, respectively. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antitumor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients.The preponderance of clinical toxicity observed in liver rather than lung suggests that IPO may be preferentially activated and bound in liver rather than lung or other tissues in humans or that human lung tissue is more effective at detoxifying and/or is more tolerant to activated IPO than other species. In any event, these observations suggest further that the ra...

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Section: Ipo3 (mentioning

confidence: 86%

Section: Ipo3 (mentioning

confidence: 99%

Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: Hepatotoxicity is dose limiting in humans

Rowinsky¹,

Noe

Ettinger

et al. 1994

Lung Cancer

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show abstract

“…In studies on the effect of temperature on temporal progression of disease, inoculated leaves were incubated at 3,9,12,15,18,21,24,27,29, and 32°C. Each treatment consisted of five plates, each containing four inoculated leaves.…”

Section: Methodsmentioning

confidence: 99%