Kinetics of α-difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase

Haegele, K. D.; Alken, R. G.; Grove, Jeffrey; Schechter, Paul J.; Koch‐Weser, Jan

doi:10.1038/clpt.1981.150

Cited by 65 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eflornithine is primarily eliminated by renal excretion (fraction excreted, Ͼ80%); no metabolites have been found, and the drug does not bind to plasma proteins (36). Its intravenous clearance is low (1.2 to 2 ml/min/kg) and is similar to the glomerular filtration rate (14,36,37). It is believed that these observed relationships, although not significant, might be a consequence of the influence of gender and body weight on the glomerular filtration rate (38).…”

Section: Discussionmentioning

confidence: 79%

Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness

Jansson‐Löfmark

Na‐Bangchang

Björkman

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma drug exposure, although it was not more pronounced for the L-enantiomer than for that of total eflornithine. This study may explain why oral treatment for late-stage human African trypanosomiasis (HAT) patients with racemic eflornithine has previously failed; the more potent L-enantiomer is present at much lower concentrations in both plasma and CSF than those of the D-enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further. Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic disease transmitted by the tsetse fly and has a mortality rate of nearly 100% if left untreated (1, 2). The disease is prevalent in 36 sub-Saharan African countries, with 60 million people at risk of being infected (3). It has been ranked as the world's third most important parasitic disease when adjusted for life years lost (1). In 1997, an estimated 450,000 individuals were infected (4). Although this number has decreased in recent years, thanks to coordinated campaigns, it remains a neglected disease, with numerous patients not having access to treatment (5).There are two parasitic subspecies that cause HAT, Trypanosoma brucei rhodsiense and T. brucei gambiense. The majority of the reported cases (Ͼ90%) are caused by the T. brucei gambiense subspecies (6). The disease is divided into two stages, an early hemolymphatic stage and a late encephalitic stage (1). For the late stage, there are few treatment options, i.e., melarsoprol and eflornithine. Eflornithine is administered either as monotherapy or in combination with orally administered nifurtimox (1, 2, 7). The arsenical drug melarsoprol, administered intravenously, causes severe side effects and shows signs of resistance (8, 9). As a result, eflornithine, which is effective mainly against the T. brucei gambiense subspecies, is more frequently recommended as a first-line treatment (2, 10-11). The main problem with eflornithine is the complicated mode of administration (intravenous infusion of 100 to 150 mg/kg of body weight every 6 h [QID] for 10 to 14 days), which leaves numerous patients untreated (11,12). Although the introduction of nifurtimox-eflornithine combination treatment (NECT) has allowed the eflornithine dosage regimen to be reduced to intravenous infusions of 200 mg/kg of body weight every 12 h (BID) for 7 days while retaining efficacy, this dosage regimen still requires specialized health facilities and personnel. An oral eflornithine-based treatment would greatly reduce the burden on health care personnel and allow more patients to have access to treatment. However, previous attempts to develop an oral monotherapy treatment with eflornithine have failed (12).Eflornithine elicits its trypanostatic effect on paras...

show abstract

Section: Discussionmentioning

confidence: 79%

Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness

Jansson‐Löfmark

Na‐Bangchang

Björkman

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Pharmacokinetic studies in humans have indicated that DFMO reaches levels of 0.5 to 0.6 mM in serum (1,13); with the much higher dosage regimens currently used in the treatment of pneumocystosis, inhibitory effects of DFMO against the organism should be well within achievable concentrations in serum.…”

Section: Discussionmentioning

confidence: 99%

Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro

Cushion¹,

Stanforth²,

Linke³

et al. 1985

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Rat Pneumocystis carinii grown on lung-derived cell lines in tissue culture flasks and multiwell plates was tested for susceptibility to four antimicrobial agents currently being used in the treatment of human pneumocystosis. Standard criteria for organism quantitation, replication, viability, and inoculum size were established. Trimethoprim-sulfamethoxazole inhibited P. carinii growth at a concentration ratio of 1:19 ,ug/ml, and pentamidine isethionate was active at 0.1 ,ug/ml. a-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, inhibited P. carinii at a concentration of 1 mM once erythrocytes (which are high in polyamine content) were removed from the inoculum; this effect could be overcome by the polyamine putrescine. Dapsone suppressed P. carinii replication at a dose of 0.1 ,ug/ml, but this effect was lost after 72 h in culture. Overall, the reduction in P. carinii numbers with these drugs was relatively modest (45 to 84%), which is consistent with their lack of lethal effects on the organism in vivo. Thus, the system presented here should be helpful in developing new anti-P. carinii agents and in elucidating their mechanism of action.Over the past two decades, Pneumocystis carinii has been recognized as a leading cause of pneumonia in immunosuppressed patients. With the emergence of the acquired immune deficiency syndrome (AIDS), the number of cases of pneumocystosis has greatly increased (5). Not only is AIDS the major predisposing host factor in the development of pneumocystosis, but P. carinii is also the most frequent opportunistic infection and a leading cause of death in AIDS. Trimethoprim-sulfamethoxazole (TMP-SMX) and pentamidine isethionate have been the principal drugs used in the therapy of pneumocystosis (17,34,39). The high recurrence rate of pneumocystosis and high frequency of adverse reactions to TMP-SMX in patients with AIDS emphasize the need to develop new forms of treatment (12, 14, 21, 30).The search for new drugs active against P. carinii in humans has rested primarily on naturally infected rodents. Rats administered corticosteroids for 8 weeks spontaneously develop pneumocystosis with histopathologic features identical to those in humans (9,35). Although the system is time consuming and has permitted the testing of relatively few antimicrobial agents, there has been a high correlation between drug efficacies in rats and humans (9,18,20). The most recent application of this form of drug development is dapsone (19), which is currently undergoing clinical trials. An exception seems to be a-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis; this agent has been ineffective in the rat model (19) but has shown promising activity in small numbers of P. carinii patients (11, 31). Thus, there is a need for alternative methods of drug evaluation.One approach to this problem has involved in vitro systems. Several different techniques of cell culture have been used for the cultivation of P. carinii, but these studies have been limited by a lack of reproducibili...

show abstract

“…It is also clear that the pharmacologic and toxicologic consequences of DFMO administration are directly related to depletion of polyamines engendered by the parent molecule. The oral bioavailability of 10 and 20 mg/kg doses in humans is 58% and 54% respectively (Haegele et al, 1981). Of the orally absorbed dose, 86% is recovered in the urine as unmetabolized drug; 81% of intravenously administered drug is also recovered as intact molecule in urine (Haegele et al, 1981).…”

Section: Metabolism Of Dfmomentioning

confidence: 99%

Metabolism and action of amino acid analog anti-cancer agents

Ahluwalia

Grem

Zhang

et al. 1990

Pharmacology & Therapeutics

220

173

View full text Add to dashboard Cite

Abstract--The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents. CONTENTS

show abstract

Kinetics of α-difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase

Cited by 65 publications

References 0 publications

Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness

Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness

Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro

Metabolism and action of amino acid analog anti-cancer agents

Contact Info

Product

Resources

About