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1.
Martin A. Graham Suresh Senan Hernani Robin Jr. Nils Eckhardt Dennis Lendrem Jeffery Hincks Dennis Greenslade Roy Rampling Stanley B. Kaye Reinhard von Roemeling Paul Workman 《Cancer chemotherapy and pharmacology》1997,40(1):1-10
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug
free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination
with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were
investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold;
firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine,
and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic
studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every
3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration
of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a
PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic
ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t
1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of
36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally
bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold
increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the
two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose
enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism
observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between
species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have
been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at
tolerable doses.
Received: 27 May 1996 / Accepted: 30 September 1996 相似文献
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William E. Pelham Alan R. Lang Beverly Atkeson Debra A. Murphy Elizabeth M. Gnagy Andrew R. Greiner Mary Vodde-Hamilton Karen E. Greenslade 《The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions》1998,7(2):103-114
Distress and ad lib alcohol consumption after interactions with child confederates were investigated in parents of children with externalizing disorders—attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), or oppositional defiant disorder (ODD). Sixty subjects interacted with boys trained to act like either normal children or children with ADHD/CD/ODD. Interactions with deviant confederates resulted in feelings of inadequacy and produced negative affect but had no effect on alcohol consumption. Post hoc analyses showed that parents with a family history of alcohol problems (FH+) showed increased drinking after interaction with a deviant confederate, compared with FH+ parents who interacted with the normal confederate. FH- parents showed the opposite pattern of results. (Am J Addict 1998; 7:103–114) 相似文献
6.
Morale,stress and coping strategies of staff working in the emergency department: A comparison of two different‐sized departments
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7.
F C Greenslade A J Tobia S M Madison K M Krider K L Newquist 《Journal of molecular and cellular cardiology》1979,11(8):803-811
Labetalol was found to compete with [3H]dihydroergocryptine for specific alpha-adrenergic binding sites in rabbit uterine membrane preparations. Based on IC50 values from binding-competition curves, labetalol had 536 times lower affinity for alpha-sites than phentolamine. Labetalol competed with [3H]dihydroalprenolol for specific beta-adrenergic binding sites in guinea pig heart and lung membranes. The drug had 53 times lower affinity for the heart beta-sites than propranolol, and was significantly less potent than propranolol in inhibiting stimulation of cardiac adenylate cyclase by 10−5 m isoproterenol. Labetalol had 19 times greater binding affinity for beta binding sites in heart membranes than alpha binding sites in uterine membranes. In vivo studies in anesthetized dogs indicate that blockade of beta adrenergic responses predominates at lower dose of labetalol and that blockade of alpha responses was observed when the dose was increased by a factor of 10. These data are consistent with the hypothesis that labetalol antagonizes both alpha and beta adrenoceptors, and that labetalol is a more potent antagonist at beta than alpha-adrenergic sites. 相似文献
8.
Martin Than Louise Cullen Sally Aldous William A. Parsonage Christopher M. Reid Jaimi Greenslade Dylan Flaws Christopher J. Hammett Daren M. Beam Michael W. Ardagh Richard Troughton Anthony F.T. Brown Peter George Christopher M. Florkowski Jeffrey A. Kline W. Frank Peacock Alan S. Maisel Swee Han Lim Arvin Lamanna A. Mark Richards 《Journal of the American College of Cardiology》2012
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