Effect of some non-steroidal antifertility agents on biochemistry of the uterus and uterine fluid in rats

The effect of 3 postcoital antifertility agents (4 and 20 mg/kg DBF, 2 and 10 mg/kg NF, and .25 and 1.25 mg/kg Centchroman) on histology and biochemistry of the uterus and uterine fluid of mated rats was investigated. The low and high doses of all the compounds showed, in general, estrogenic type histologic changes. They generally caused an increase in uterine dry matter, protein, RNA, glycogen, and alkaline phosphatase, and a decrease in wet weight, nonprotein nitrogen, and acid phosphatase (p.01). In uterine fluid, alkaline phosphatase was markedly stimulated after high dosages of DBF and NF and low dosages of Centchroman (p.01). .25 mg Centchroman possessed estrogenic activity, whereas 1.25 mg showed antiestrogenicity. The compounds appeared to interfere with the action of both estrogen and progesterone in varying degrees.     

Clinical pharmacology studies with Centchroman.

A pharmacological evaluation of centchroman (3,4-trans-2,2,dimethyl-3-phenyl-4-p-(beta-pyrrolidino ethoxy)-phenyl-7-methoxychroman), a new postcoital contraceptive, in normal healthy human volunteers was performed to determine the maximum tolerated dose and to discover any abnormal toxic effects in humans. The study was carried out for both men and women as a double-blind noncrossover trial in 2 parts: 1) a single dose study (40 volunteers) and 2) a multiple dose study (28 females) for 30 days. Centchroman was well tolerated without significant side effects in single doses up to 320 mg, severalfold higher than the anticipated therapeutic dose. In the multiple dose schedule, the compound was found safe at doses of 60-120 mg/day. however, similar effects were observed in subjects receiving placebo and are not unexpected in a normal population over a 1-month period. Centchroman is presently undergoing clinical trials for postcoital contraceptive efficacy in humans.     

Antifertility activity and toxicity of alpha-chlorohydrin aromatic ketal analogues in male rats

The antifertility activity and toxicity of alpha-chlorohydrin and seven aromatic ketal derivatives were investigated in male rats. At a dose of 5 mg/kg injected intraperitoneally each day for 14 days, alpha-chlorohydrin and the methoxy benzaldehyde derivative (compound 2) produced complete infertility. The benzaldehyde derivative (compound 1) was 89% effective and the other five compounds 71-25% effective. All compounds except the least effective antifertility agent, the methylbenzaldehyde derivative (compound 3), reduced the motility of sperm recovered from the epididymis. None of the compounds caused a decrease in body or testes weight but some increased adrenal weight.     

Effects of centchroman, a synthetic estrogen antagonist on the fertility of female hamsters

Centchroman (3, 4-trans-2, 2-dimethyl-3-phenyl-4-p-beta-pyrrolidinoethoxy-phenyl-7-methoxy-chroman) , a non-steroidal, estrogen antagonist, injected subcutaneously (2 mg/kg body wt) on days 1, 2 and 3 post-coitum in hamsters, prevented implantation in 70% of the animals. A significant decrease in the circulating levels of estradiol and progesterone was observed on day 4 post-coitum as compared to control animals following the treatment of centchroman. The activities of various lysosomal enzymes were also found diminished in the treated animals. This study shows that centchroman may act as an anti-implantation agent in hamsters indicating that estrogen plays a key role during the process of ovum implantation in this species.     

Effect of parenterally injected benzimidazole compounds on Echinococcus multilocularis and Taenia crassiceps metacestodes in laboratory animals.

In mice infected with metacestodes of Taenia crassiceps, the following compounds were at least partially effective when injected intraperitoneally at the dosage indicated: cambendazole (500 mg/kg), mebendazole (6.25 mg/kg), oxibendazole (500 mg/kg), 5-benzamido-2(4-thiazolyl)benzimidazole (500 mg/kg), 2-carboethoxyamino benzimidazole (125 mg/kg), and 2-carbomethoxyamino benzimidazole (500 mg/kg). The following were inactive at the dosage indicated: parbendazole (500 mg/kg), thiabendazole (1,000 mg/kg), and fenbendazole (1,000 mg/kg). Mebendazole, which showed some activity at 6.25 mg/kg, was highly active as a single intraperitoneal dose at 25 mg/kg. When injected subcutaneously, mebendazole was much less active than when given intraperitoneally. In mice infected with metacestodes of Echinococcus multilocularis, intraperitoneal injection of mebendazole at 75 to 150 mg/kg, daily for 3 days, was highly effective (95 to 100% reduction in cyst mass). In contrast, oral administration at 1,000 mg/kg, daily for 3 days, was only partially effective. The drug was also effective when given intraperitoneally to infected cotton rats. A water-soluble benzimidazole, carboxymethyleneamino cambendazole, was approximately 50% effective in mice when injected daily for 3 days at a dosage of 75 or 150 mg/kg. The results suggest that, in metacestode infections of medical importance, it may be possible to kill the parasite by delivering a drug to its immediate vicinity, and so to reduce the required dosage with respect to the host.     

Structural requirements of some sulphonamides that possess an antifertility activity in male rats

Sulphonamides with different chemical structures were synthesized and these 13 compounds together with 7 commercially available sulpha drugs were tested for antifertility activity by natural mating in male rats. All compounds were given daily by gastric intubation at doses of 125, 150, 250 or 450 mg/kg for 6 weeks. Sulphapyridine caused a dose-related and reversible reduction in fertility at doses between 125 and 450 mg/kg. At the high dose, fertility was reduced to 25.9% of control at 5 weeks after treatment, and complete recovery occurred by 3 weeks after drug withdrawal. This activity was abolished when the pyridine ring was substituted by other heterocyclic rings, except sulphachloropyridazine which had only weak activity. Replacement of the pyridine ring by a hydrogen atom or short aliphatic chains preserved or even enhanced the potency. Thus, sulphanilamide, N1-methylsulphanilamide or N1-diethylsulphanilamide produced a marked but reversible reduction in fertility. Removal or substitution of the N4-amino group on the benzene ring of sulphapyridine with a methyl group destroyed the activity. However, the bromo or nitro analogue (at the para- but not the meta-position of the benzene ring) still possessed some activity. N4-Acetyl derivatives of sulphapyridine, sulphanilamide, and N1-diethylsulphanilamide were as potent as their parent compounds. These results suggest that the presence of pyridine or other heterocyclic rings is not necessary for the antifertility activity of sulphonamide compounds. However, the N4-amino group is indispensable. In addition, acetylation of this amino group does not change the potency. The prototype of the antifertility sulphonamides therefore seems to be sulphanilamide.     

Effect of Centchroman administration in normospermic & oligospermic individuals

The effect of Centchroman, 3,4-trans-2,2-dimethyl-3-phenyl-4-para-(beta -pyrrolidinoethocy)-phenyl-7-methorychroman, administration was investigated in normospermic and oligospermic subjects. 3 normal volunteers, aged 32-40 years, were treated with increasing doses (30, 60, and 120 mg/day, each dose for 2 weeks). The sperm count was decreased in 1 volunteer but the percentages of nonmotile and abnormal spermatozoa were increased in all 3. There was no change in plasma testosterone and urinary 17-ketosteroid (17-KS) levels but the 17-ketogenic steroids (17-KGSs) were decreased in all of them. 3 out of 5 oligospermic subjects, aged 24-35 years, who received 30 mg/day for 6 weeks revealed increased sperm counts. Plasma testosterone levels were decreased in 4, urinary 17-KGSs were decreased in 2, and 17-KSs were decreased in 1 subject. Acid phosphatase, fructose, sialic acid and glycerylphosphoryl choline levels in semen, and serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, and urea in blood were not markedly altered in either group.     

Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2''-hydroxy naphthalen-1''-yl)-1,5-diphenyl-2-pyrazolines

Five new 1,3,5-triphenyl-2-pyrazolines were synthesised by reacting 1,3-diphenyl-2-propene-1-one with phenyl hydrazine hydrochloride and another five new 3-(2'-hydroxy naphthalen-1'-yl)-1,5-diphenyl-2-pyrazolines were synthesised by reacting 1-(2'-hydroxynaphthyl)-3-phenyl-2-propene-1-one with phenyl hydrazine hydrochloride. The structures of the compounds were proved by means of their IR, (1)H NMR spectroscopic data, and microanalyses. The antidepressant activity of these compounds was evaluated by the 'Porsolt behavioural despair test' on Swiss-Webster mice.1-Phenyl-3-(2'-hydroxyphenyl)-5-(4'-dimethylaminophenyl)-2-pyrazoline, 5-(4'-dimethylaminophenyl)-1,3-diphenyl-2-pyrazoline, 1-phenyl-3-(2'-hydroxynaphthalen-1'-yl)-5-(3',4',5'-trimethoxyphenyl)-2-pyrazoline, 1-phenyl-3-(4'-methylphenyl)-5-(4'-dimethylaminophenyl)-2-pyrazoline and 1-phenyl-3-(4'-bromophenyl)-5-(4'-dimethyl amino phenyl)-2-pyrazoline reduced immobility times 25.63-59.25% at 100mg/kg dose level. In addition, it was found that the compounds possessing electron-releasing groups such as dimethyl amino, methoxy and hydroxyl substituents, on both the aromatic rings at positions 3 and 5 of pyrazolines, considerably enhanced the antidepressant activity when compared to the pyrazolines having no substituents on the phenyl rings.     

Antifertility mechanisms of gossypol acetic acid in female rats

Gossypol acetic acid was administered orally (30, 60, 90 and 120 mg/kg/day) on Days 1-5 post coitum to mature female rats. At autopsy on Day 10, pregnancy in most treated animals (6/7 and 6/8) was blocked at high doses (90 and 120 mg/kg/day respectively). As the daily dose decreased to 60 mg/kg/day half (4/8) were not pregnant. However, at a lower dose (30 mg/kg/day), or at a single dose of 200 mg/kg at Day 1 p.c., pregnancy was not blocked. The concentrations of progesterone in the serum of these females were significantly decreased except at the low dose. The numbers of implantation sites in the treated females that did remain pregnant were similar to those in control females except at the dose of 120 mg/kg/day. Gossypol did not retard the development of the preimplantation embryo or cavitation. The Pontamine Blue test revealed that the drug did not interfere with the initiation of implantation. We suggest that gossypol has an antifertility effect in the female rat because it is luteolytic and disrupts post-implantation development.     

Potent in vivo but not in vitro inhibition of monoamine oxidase by 3-chloro-alpha-phenylpyrazinemethanol.

3-Chloro-alpha-phenylpyrazinemethanol (3-CPM) inhibited monoamine oxidase (MAO) types A and B in vivo in mouse brain, heart and liver. The inhibition was dose-dependent at doses of 0.3-32 mg/kg i.p. and occurred within 1 h after the compound was injected. 3-CPM was a very weak inhibitor of mouse brain mitochondrial MAO activity in vitro, even when preincubated with the enzyme; MAO-A was inhibited only about 50% at a high concentration of 3-CPM (1 mM), and MAO-B was inhibited even less. After a 10 mg/kg i.p. dose of 3-CPM in mice, both MAO-A and MAO-B were inhibited at day 1, but activity had largely recovered within a few days in brain, liver and heart. 3-CPM at doses of 1, 3, 10 and 32 mg/kg i.p. caused dose-dependent antagonism of the depletion of striatal dopamine and of cortical norepinephrine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 3-CPM is therefore a potent inhibitor of MAO-A and of MAO-B in mice in vivo despite its weak effect on the enzyme in vitro. A metabolite of the drug may be involved in the in vivo effects.     

Ultrastructural, fertility, and spermicidal studies with isomers and derivatives of gossypol in male hamsters

The effects of fourteen new, orally administered synthetic analogs of gossypol on testicular ultrastructure and fertility in hamsters and the spermicidal properties of these compounds, as well as of the optical isomers of gossypol against hamster and human sperm in vitro, are reported in this study. Test compounds were administered to adult male hamsters by daily gavage for 9 weeks at doses ranging from 15 to 50 mg/kg. The results of this study have demonstrated that the fourteen new gossypol analogs evaluated herein are not effective as male antifertility agents and their in vitro activity or lack of activity as spermicides is unrelated to their in vivo contraceptive potential. In addition, the results of the study suggest that (1) the isopropyl moiety of the gossypol molecule, like the aldehyde group, is essential for its mechanism of action and (2) the pathognomonic defect in the mitochondrial sheath induced by gossypol appears to be related to its unique activity as a male antifertility agent. The significance of these findings is discussed.     

Inhibition of aromatase activity in the rat by aminoglutethimide and related compounds

Two compounds possessing aromatase inhibitory activity have been evaluated for their effects on oestradiol (E2) biosynthesis in the rat. These compounds, structurally related to aminoglutethimide (1), were administered intra-peritoneally at two dose levels to 10 week old female rats previously treated with pregnant mares' serum gonadotrophin (PMSG, 100 i.u. subcutaneously every other day for 9 days). Three hours after dosing, blood was collected and plasma oestradiol levels determined by RIA. Aminoglutethimide, 3-(4'-aminophenyl-3-ethylpyrrolidine-2,5-dione (2) and N-methyl-3-(4'-aminophenyl)-3-ethylpyrrolidine-2,5-dione (3) decreased E2 blood levels by 98, 97 and 82% of control levels respectively (n = 6) at a dose of 50 mg/kg. Similarly effective inhibition was also observed at a dose of 25 mg/kg (n = 4). Ovarian aromatase activity, assessed by incubating the homogenised ovaries of treated rats with tritium-labelled androstenedione (0.2 microM) or testosterone (1 microM), indicated that residual enzyme activity was reduced compared with controls. Aminoglutethimide, and the new pyrrolidinedione aromatase inhibitors 2 and 3, are therefore effective inhibitors of E2 biosynthesis in the rat with functioning ovarian activity.     

Induction of aneuploidy by mitotic arrestants in mouse bone marrow

Most human and animal carcinogens induce gene mutation, chromosome breakage or other types of DNA lesions. However, recent studies indicate that some carcinogens do not directly damage DNA, but may cause missegregation of chromosomes resulting in aneuploidy production. Aneuploidy-producing agents pose serious genetic hazards to the human population. Such agents may cause genomic imbalance not only in somatic cells which may result in cancer development, but also in germinal cells which may result in the production of abnormal offspring (e.g. Down's syndrome). To limit human exposure to potential aneuploidy-producing agents, such agents must first be identified in experimental animals. The present study demonstrates that vinblastine and colcemid are capable of inducing aneuploidy in bone marrow cells of treated mice. Both of these compounds are chemotherapeutic agents that arrest mitosis by interfering with the formation of spindle microtubules. Single intraperitoneal injections of vinblastine, at a dose of 9 mg/kg, were found to produce 1.5-5.2% of hyperdiploidy in all of the 10 treated mice sampled at 17-96 h after injection. Only the frequency of hyperdiploidy was determined because hypodiploid cells could result from artifactual chromosome loss during slide preparation. At 0.9 mg/kg, vinblastine was found to produce 0.5-3.5% of hyperdiploidy in 8 of the 10 treated animals. The frequency of hyperdiploid cells in animals treated with colcemid was low. A dose as high as 37 mg/kg was found to produce only 0.5-1% of hyperdiploidy in 3 of the 10 treated animals, and hyperdiploidy was observed only in animals sampled at 17-24 h. In 10 mice treated with saline alone, no hyperdiploid cells were observed. Unlike cell cultures where vinblastine and colcemid had been shown to be equally effective in producing aneuploidy, vinblastine was found in this study to be a much more potent aneuploidy inducer than colcemid in mice.     

Protective effect of extract of Acanthopanax senticosus Harms on dopaminergic neurons in Parkinson's disease mice

To study the neuroprotective effect of extract of Acanthopanax senticosus Harms against MPTP-induced mice model of Parkinson's disease and its mechanism. The Parkinson's disease mice model was induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Hydrochloride (MPTP-HCl, 30mg/kg daily for 5 days). High dose group and low dose group were medicated with extract of Acanthopanax senticosus Harms for 20 days, dose amounted to 182mg/kg and 45.5mg/kg daily respectively. The behavioral testing of mice was assessed using pole-climbing test. The levels of Dopamine (DA) and Homovanillic acid (HVA) in striatum were determined by Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC-ToF-MS). The levels of dopamine receptor 1 and 2 in striatum were assayed simultaneously with the help of immunohistochemical method. The level of Caspase-3 protein in substantia nigra was analyzed by Western Blot. From Day 5 during the administration of extract of Acanthopanax senticosus Harms, pole-climbing time in low and high dose group were significantly less than model group (p<0.05). Compared with model group, the DA level of striatum in low dose group was significantly higher (p<0.01), the number of dopamine receptor 1 and dopamine receptor 2-positive cells in low and high dose group were significantly less (p<0.05), the Caspase-3 protein level of substantia nigra in low and high dose group were significantly less (p<0.05). The neuroprotective effect of extract of Acanthopanax senticosus Harms may be able to protect C57BL/6 mice against MPTP-induced dopaminergic neuronal damage.     

Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat

The effects of toremifene, a new triphenylethylene derivative, on the uterus and DMBA-induced mammary tumors in rats were compared to tamoxifen. The ability of toremifene to compete with [3H]estradiol for cytoplasmic estrogen receptor from rat uterus was similar to tamoxifen, the IC50 being 26 and 23 microM respectively. In immature intact rats the two compounds, administered orally for three consecutive days, had similar intrinsic partial estrogenic efficacy, at 50 mg/kg, about 40% of that of estradiol benzoate (EB). However, at doses less than or equal to 10 mg/kg, the estrogenic effect of toremifene was seen at doses about 40 times higher than that of tamoxifen. The two compounds, administered together with a standard dose of EB, expressed the same maximal antiestrogenic efficacy (about 65% inhibition) at 50 mg/kg. However, the minimal effective antiestrogenic dose of toremifene was about 10 times that of tamoxifen and the ratio between antiestrogenic/estrogenic properties was favourable to toremifene. The duration of the antiestrogenic (antiuterotrophic) effect of a single oral dose (10 mg/kg) of the two compounds proved similar: at least 4 days in intact rats and 3 days in ovariectomized rats. In DMBA-induced tumor bearing rats toremifene was administered p.o., 6 times/week for 4 weeks at 0.08, 0.4, 2, 10 and 50 mg/kg. It was effective at the doses of 2, 10 and 50 mg/kg, inducing 39, 35 and 46% tumor regressions. The activity of toremifene at the minimal effective dose of 2 mg/kg was then compared with that of tamoxifen given at the same dose level. The compounds had comparable activity (47 vs 44% tumor regressions).     

Differential depressant effects of general anesthetics on the cardiovascular response to cocaine in mice.

In recent years, murine models have gained increasing importance for studies of cardiovascular physiology and pharmacology, largely due to the development of transgenic strains with specific alterations in phenotype. Differential effects of general anesthetic agents on the cardiovascular responses to cocaine have been reported in larger mammals; therefore, we studied the effects of commonly used anesthetics on heart function and on blood pressure responses to cocaine in Swiss Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid artery or left ventricle of mice anesthetized with equivalent anesthetic dose of either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg) or alpha-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1 mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus injection. In the KX group, the basal mean arterial pressure (MAP) and systolic left ventricular pressure (LVP) were 110 +/- 12 and 120 +/- 13 mmHg, respectively, close to conscious values. However, PEN and CU significantly decreased the basal parameters (P < 0.01 compared to the KX group). The lowest dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were obtained with a 1-mg/kg dose of cocaine (P < 0.01 compared to baseline). However, at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups. Compared to published conscious animal data, anesthetic agents attenuated the cardiovascular effects of cocaine. Taken together, our results indicate that minimally effective doses of general anesthetics may significantly alter the basal hemodynamic state and the responses to sympathomimetic agents in the murine model, as has been reported in larger mammalian species. We concluded that anesthesia with ketamine-xylazine provides baseline hemodynamic values close to reported values in conscious animals, but also attenuates the hemodynamic response to cocaine.     

<Emphasis Type="Italic">In vivo</Emphasis> studies with a <Emphasis Type="Italic">Candida tropicalis</Emphasis> isolate exhibiting paradoxical growth <Emphasis Type="Italic">in vitro</Emphasis> in the presence of high concentration of caspofungin

We investigated the activity of caspofungin against a Candida tropicalis clinical isolate showing paradoxical growth in vitro. BALB/c mice immunosuppressed by cyclophosphamide were infected intraperitoneally using 10⁷ CFU/mouse. Caspofungin was administered intraperitoneally once daily for 5 days or as a single dose using the following doses: 0.12, 0.25, 1, 2, 3, 5, and 15 mg/kg. The single dose of caspofungin was effective only at 5 and 15 mg/kg concentrations (100% survival). Five-day caspofungin treatment led to 100% survival at doses of 1 mg/kg or higher. Caspofungin treatment significantly decreased the number of viable yeasts in the peritoneal lavage samples as well as in the infected abscesses at doses 1, 3, 5, and 15 mg/kg caspofungin as compared to the untreated control (P<0.001 in all cases), and even to the group treated with 0.12 mg/kg caspofungin (P<0.05 in all cases). At 2 mg/kg caspofungin dose, sterilization of the internal organs was reproducibly incomplete, suggesting that the role of paradoxical growth in the late clinical failure cannot be excluded.     

The effects of alpha-chlorohydrin on the composition of rat and rabbit epididymal plasma: a possible explanation of species difference.

The relationship between the antifertility effect of alpha-chlorohydrin and changes in composition of luminal plasma from the cauda epididymidis of rats and rabbits has been investigated. At each dose regimen studied, the fertilizing capacity of rats treated with alpha-chlorohydrin was reduced to zero. The levels of sodium, potassium, glycerylphosphorylcholine (GPC), acid phosphatase and alkaline phosphatase in epididymal plasma were not markedly affected by drug treatment. The most noticeable change was a considerable increase in the concentration of lactic dehydrogenase (LDH) at all dose levels and of glutamic-oxaloacetic transaminase (GOT) after 7 days of treatment with 8 and 16 mg/kg. The effect of cold shock on the composition of epididymal plasma showed that LDH and GOT are, at least in part, derived from spermatozoa. In contrast, alpha-chlorohydrin did not have an antifertility action in the rabbit, and the only notable change in the compositon of epididymal plasma was an increase in the level of GPC. These results provide evidence that, in the rat, alpha-chlorohydrin or a metabolite primarily exerts its antifertility effect by a direct action on the spermatozoa, whilst in the rabbit a barrier may exist to the entrance of the drug into the lumen of the epididymal duct.     

Resistance of the mouse to the antifertility effects of LHRH agonists

In the mouse, the LH-releasing activity of the LHRH agonist, D-Trp⁶-N^α-Meleu⁷-DesGly¹⁰-Pro⁹-NHEt-LHRH (Wy-40, 972), was established by its ability both to induce ovulation when administered at 1600 hours on the second day of diestrus and to elevate serum LH in adult males. While Wy-40, 972 was only slightly less active in terms of these end points than it was in the rat, the predictive and possibly causal association between LH-releasing and antifertility activity established for this LHRH analog in the rat could not be clearly identified in the mouse. A total daily dose of 1000 μg Wy-40, 972/mouse was required to completely inhibit pregnancy during days 1–7 of pregnancy and produced only partial inhibition during days 7–12. This dose represents, on a body weight basis, 8250 times the 100 percent effective pregnancy-terminating dose for the rat during equivalent intervals. The resistance of the mouse to the antifertility activity of Wy-40, 972 was found not to be restricted to this particular LHRH analog or to the reproductive state. Administration of another potent LHRH analog, D-Ala⁶-DesGly¹⁰-Pro⁹-NHEt-LHRH (Wy-18,481), to adult male mice at a dose of 100 μg/mouse/day for up to 14 days had no inhibitory effect on the weights of the testes or sex accesory organs. This dose of Wy-18,481 is 7500 times that necessary for significant reduction of these reproductive organ weights in rats within 7 days of treatment. Investigations as to the nature of the mouse's apparently divergent response to the LHRH agonists may further elucidate the antifertility mechanism of such compounds in susceptible species.     

Electron microscope study of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, an exfoliative antispermatogenic agent, in the rat testis

We were interested in discovering whether the antifertility agent, DICA [1-(2,4-dichlorobenzyl)-1-H-indazole-3-carboxylic acid] induced Sertoli cell tight junction damage. Testis were fixed in 1% lanthanum nitrite cacodylate-buffered 2% gluteraldehyde at various times following a single oral 100 mg/kg dose of DICA. In control animals adluminal lanthanum was never seen. At one and ten days following DICA treatment adluminal lanthanum was seen. This suggests that the Sertoli cell tight junctions are more permeable to lanthanum following DICA treatment.