1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

Lobl, Thomas J.

doi:10.3109/01485017908987337

Cited by 22 publications

(10 citation statements)

References 7 publications

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“…Lonidamine (AF 1890) or diclondazolic acid -I-[(2,4-dichlorophenyl)mcthyl]-lH-indazole-3-carboxylic acid) -has been found to have antispermatogenic [1][2][3][4], embryotoxic [5], and interesting anticancer activities [6][7][8]. The pharmacokinetics of lonidamine have been described in rats, rabbits, and monkeys by Segre and Catanese [9].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Lonidamine after Oral Administration in Cancer Patients

Besner¹,

Leclaire²,

Band³

et al. 1984

Oncology

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The pharmacokinetics of lonidamine has been studied in cancer patients after single and chronic oral administrations. After single administration the plasma kinetics are highly variable, while the dose eliminated in the urine is over 70% in all subjects. This suggests an active but interindividually variable first-pass effect. After repeated administrations, both the residual plasma concentration before administration () and that obtained after drug intake () have been studied. The values range from 4.5 to 25 µg/ml and values from 0.4 to 7 µg/ml. In patients where a therapeutic response was noted, a mean value of 2.98 Hg/ml for C^?n was measured. In patients unresponsive to drug therapy the mean was 1.5 µg/ml.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Lonidamine after Oral Administration in Cancer Patients

Besner¹,

Leclaire²,

Band³

et al. 1984

Oncology

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“…The reciprocal rise in LH indicates that Lonidamine suppresses Leyding cell function. The rise in FSH seen in 3 cases is probably explained by the cytotoxic effect of Lonid amine on germinal cells, analogous to the effects seen in various animal species [4][5][6][7].…”

Section: Discussionmentioning

confidence: 99%

“…apparently as the result of a specific effect on mitochondrial function. Laboratory studies have demonstrated that Lonidamine has anlispermatogenic and embryotoxic properties [4][5][6][7][8]. In experimental tumour model systems, Lonidamine has an anti tumour effect against Lewis lung and sarcoma 180 tumours [9,10].…”

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confidence: 99%

Phase II Evaluation of Lonidamine in Patients with Advanced Malignancy

Evans¹,

Shepherd²,

Mullis³

1984

Oncology

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Lonidamine, a substituted indazole carboxylic acid with unique effects on cellular respiration, was studied in 27 patients with advanced malignancies. Of the 18 evaluable patients, 5 had small-cell lung cancer, had non-small-cell lung cancer, 3 sarcoma, 2 breast cancer, and 5 other tumour types. All but 1 had had extensive prior treatment. A partial response was seen in 1 patient with metastatic synovial sarcoma, and tumour growth inhibition was demonstrated in 2 other cases. The major toxicity encountered was myalgia (66.6%) which was incompletely ameliorated by prednisone and required dose reduction in 2 patients and cessation of drug in 3. Other toxicities included auditory changes, anorexia, nausea and vomiting, diarrhoea, skin sensitivity, and conjunctivitis. No added toxicity was seen, when Lonidamine was combined with other chemotherapeutic agents. No correlation between Lonidamine dose and serum lactate levels was seen, although patients showed a progressive increase in lactate levels over time, thought to be related to their increasing tumour burden. 5 patients demonstrated a dramatic fall in serum testosterone levels 4–8 weeks after starting Lonidamine which was accompanied by an increase in luteinizing hormone levels in 3 patients. In summary, modest antitumour activity was demonstrated in 3 patients; moderate toxicity was seen in most patients, but was usually tolerable. Further studies of Lonidamine are warranted in less heavily treated patients, alone or in combination with other chemotherapeutic agents.

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“…However, more potent but relatively less toxic analogs were synthesized and studied extensively [122]. In rats effects are observed very quickly, even following a single oral dose of 50 mg/kg [120,[123][124][125]. Histologically, alterations of Sertoli cells are first noted within 12 h and reach a maximum in 5-10 days causing germ cell exfoliation into the lumina of the seminiferous tubules.…”

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confidence: 99%

Non-steroidal interference with male fertility

Vickery¹

1986

Adv Contracept

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IntroductionThe male gamete has long been thought to be the most vulnerable point at which to interfere with fertility, particularly when this could be accomplished noninvasively at the time of transfer from male to female reproductive tracts. Thus the earliest attempts to interfere with male fertility date back to Roman times [1]. They were mechanical in nature and depended upon prevention of intromission (infibulation) or use of a barrier (condom). Also from the beginnings of recorded history, materials have been inserted into the vagina which interact with spermatozoa to prevent fertilization. Early materials were employed empirically and consisted of acidic or sticky materials [2,3]. Early frank spermicidal materials included quinine and mercurials [4,5].A milestone in the development of spermicides was the discovery in the early 1950s of the efficacy of the detergents typified by nonoxynol-9 [6]. More potent surfactants have been identified from time to time [7]. In the carefully monitored, well-motivated small-scale clinical trials these vaginal spermicides can achieve failure rates as low as 0.3 per 100 women years, essentially equivalent to the oral contraceptives for women [8][9][10][11]. Unfortunately, in widespread use, failure rates are much higher and retrospective surveys have shown up to 40% of users to become pregnant within 1 year [12][13][14][15]. With the exception of the animal studies reported on an imidazole with some additional loci of action [16--18] and some acrosin and hyaluronidase inhibitors [19--21], no noteworthy research has appeared in this area recently.It is probable that attempting to nullify very large numbers of normal motile spermatozoa within the female tract and within the anatomical and time constraints involved is doomed to failure. A better approach to male contraception with lesser constraints would likely be through administration of agents directly to the male. The present review addresses the varied history of this approach as it applies to non-steroidal materials. Advances in (i) Pituitary inhibitionHormonally active agents The earliest recorded studies on control of male fertility by chemical means administered to the male capitalized upon the observation that administration of low doses of testosterone to male rats was antispermatogenic [22]. As we now know, this reflected sufficient circulating androgen to cause feedback inhibition of gonadotropin release but insufficient intratesticular androgen levels to maintain spermatogenesis directly [23][24][25]. Studies in men with testosterone or its esters, however, never consistently achieved azoospermia or protection from pregnancy, except at dose levels expected to change lipoprotein formation and/or blood cell formation [26--28]. The long history of attempts to use steroids as indirect regulators of spermatogenesis is outside the scope of this review and is described by Dr Nieschlag in his review paper [29].From time to time non-steroidal structures with hormonal activity have been described ( Figure 1) and used ...

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1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

Cited by 22 publications

References 7 publications

Pharmacokinetics of Lonidamine after Oral Administration in Cancer Patients

Pharmacokinetics of Lonidamine after Oral Administration in Cancer Patients

Phase II Evaluation of Lonidamine in Patients with Advanced Malignancy

Non-steroidal interference with male fertility

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