Fansidar prophylaxis, therapy, and immune responses in rodent malaria (Plasmodium berghei)

In order to determine the effect of Fansidar on plasmodial infection in mice, outbred, adult, Swiss-Webster mice were treated with Fansidar (20 mg sulfadoxine and 1 mg pyrimethamine/kg body weight) at various intervals before and/or after inoculation with blood stages of Plasmodium berghei. Drug therapy resulted in cure if it was given before the parasitemia rose to 53%. Oral administration of Fansidar was more effective in reducing or preventing parasitemia than intramuscular injection. Fatal infections were prevented if mice were treated orally with one dose of Fansidar 2 days before inoculation with P. berghei, whereas only partial protection occurred in animals treated 4 or more days before inoculation. Fansidar administered on two consecutive days provided protection if the drug was given at 3 and 2 days before inoculation. Administration of Fansidar for three consecutive days protected all animals if given on days 8 to 6 before inoculation. After oral administration of Fansidar, the parasitemia dropped dramatically and was undetectable at 60 hr. At 12 hr after oral treatment, schizonts and trophozoites were numerous, but there were few merozoites. Schizonts were the predominant stage at 24 hr, whereas merozoites predominated at 36 hr. Swiss-Webster and C57BL/6 mice became immune to a lethal dose of P. berghei after 4 cycles of inoculation and drug cure. Protective immunity was still present at 472 days after the fifth parasite inoculation.     

The effect of salinomycin and lasalocid on laboratory cultures ofEnterococcus fœcium andStaphylococcus gallinarum strains

The growth ofEnterococus fœcium strains CCM 4231 and EF 26, andStaphylococcus gallinarum SG 31 was inhibited by salinomycin and lasalocid at concentrations of 25 and 50 mg/L.Staphylococcus gallinarum was more sensitive to the additives used than were enterococci. Maximum inhibition (90%) was measured after the growth with the SG 31 strain in the presence of both ionophores. Growth of organisms was more inhibited by salinomycin at 25 mg/L (67.5%) than at 50 mg/L (63%). The inhibitory effect in enterococcal strains reached after the addition of salinomycin and lasalocid (on average) 63 and 58%, respectively. The CCM 4231 strain was more inhibited by salinomycin as well as by lasalocid than was the EF 26 strain.     

The action of polyether ionophorous antibiotics (monensin, salinomycin, lasalocid) on developmental stages of Eimeria tenella (Coccidia, Sporozoa) in vivo and in vitro: study by light and electron microscopy

The effect of three polyether antibiotics (monensin, salinomycin, lasalocid) on developmental stages of Eimeria tenella (Coccidia, Sporozoa) was studied in vivo and in vitro by means of light and electron microscopy. It was found that these three drugs act against free merozoites, which are destroyed by bursting of the cell border (i.e. pellicle), endoplasmic reticulum and internal organelles even after very short exposure times (20 min) in media containing 1 ppm, 10 ppm or 100 ppm of these drugs. Sporozoites, however, survived these drug concentrations during an exposure time of 30 min (this would be sufficient to penetrate host cells and start development). Intracellular stages, which were situated in a parasitophorous vacuole within an intact host cell, were not attacked, apparently because these drugs are almost incapable of penetrating host cells. On the other hand, parasites (such as differentiated schizonts, gamonts) located within degenerating host cells showed slight disintegration, which did not necessarily led to their death. From these results it becomes clear why these polyether antibiotics have to be fed daily. Doses of 70 ppm salinomycin, 125 ppm monensin and 125 ppm lasalocid were found to bring about an equivalent protective effect against an infection with 40,000 Eimeria tenella oocysts.     

Antiplasmodial effects of the aqueous extract of Phyllantus amarus Schumach and Thonn against Plasmodium berghei in Swiss albino mice.

Phyllantus amarus Schumach and Thonn is a medicinal plant used commonly for the treatment of malaria-related symptoms by the general public in southeastern Nigeria. The present study determines the possible antiplasmodial effects of the aqueous extract of the leaves and stem of the plant against Plasmodium berghei infection using Swiss albino mice as models. The blood schizonticidal activity of the aqueous extract in early infection and in established Plasmodium berghei infection was assessed and compared to the activities of chloroquine and sulfadoxine/pyrimethamine. The repository activity of the extract was also assessed and compared to the activity of pyrimethamine. The LD50 of the aqueous extract of the leaves and stem of the plant was also determined using albino Wistar rats. The results show that the LD50 of the aqueous extract of Phyllantus amarus Schumach and Thonn was 650 mg/kg. In early infection, the extract at doses of 108.33 mg/kg, 165 mg/kg and 325 mg/kg was found to cause a significant dose-dependent suppression of P berghei parasites [P < P0.05] sulfadoxine/pyrimethamine caused a similar significant suppression of P berghei parasites [P < 0.05] while chloroquine at a dose of 5 mg/kg did not cause a significant effect on P berghei parasites. Similarly, the extract was found at all doses to cause a statistically significant [P < 0.05] suppression of P berghei parasites via a repository action. This effect was comparable to the effects of pyrimethamine a standard repository agent. In established infection, the extract at all doses administered, was found to significantly suppress P berghei parasites at 24 and 72-hour periods [P < 0.05]. Comparatively, sulfadoxine/pyrimethamine caused a similar statistical [P < 0.05] suppression of the parasites of P. berghei. However, the effects of sulfadoxine/pyrimethamine were more sustained over the 72-hour period. The present study therefore validates the local use of the extracts of Phyllantus amarus Schumach and Thonn as an antimalarial agent. Further studies are however recommended to identify and possibly characterize the potential antiplasmodial agents in the aqueous extract of the plant.     

In vivo antiplasmodial activity of 11(13)-dehydroivaxillin from Carpesium ceruum

The whole plants of Carpesium genus are used in traditional medicine as anti-pyretic, analgesic and vermifugic, including a topical application for sores and inflammation. A previous study on Carpesium genus suggested that the antiplasmodial activity against Plasmodium falciparum was due to the existence of 11(13)- dehydroivaxillin (DDV) from EtOAc extracts of C. ceruum (Compositae). Here, the antimalarial activity of DDV was evaluated against Plasmodium berghei in mice. The LD(50) of the compound was determined as 51.2 mg/kg, while doses of 124 mg/kg and above were found to be lethal to mice. DDV (2, 5, 10 mg/kg/day) exhibited a significant blood schizontocidal activity in 4-day early infection, repository evaluation and in an established infection with a significant mean survival time comparable to that of the standard drug, chloroquine, 5 mg/kg/day. DDV possesses a promising antiplasmodial activity, which can be exploited in malaria therapy.     

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).     

Gametocytocidal and sporontocidal effects of antimalarial drugs on malaria parasites. II. Action of the folic reductase inhibitors, chlorguanide, and pyrimethamine against Plasmodium cynomolgi

The antimalarial activity of the dihydrofolate reductase inhibitors, chlorguanide and pyrimethamine, against gametocytes and sporogony of the simian parasite, Plasmodium cynomolgi was tested. Plasmodium cynomolgi infected rhesus monkeys (Macaca mulatta) were treated orally with multiple doses of chlorguanide (5.6 or 11.3 mg base/kg/Day X5) or a single dose of pyrimethamine (3 mg base/kg). Batches of mosquitoes (Anopheles maculatus) were allowed to feed immediately prior to and at appropriate intervals after drug administration. The effects of the drugs on the developmental stages of the parasite were assessed within the mosquito host. The results indicated that sporogony was interrupted in mosquitoes fed 1 hr after initial dosing with chlorguanide. With pyrimethamine, a clear-cut sporontocidal action was shown as early as 15 min after the drug was given. Both compounds inhibited further development of young oocysts and successive batches of mosquitoes fed 1 hr or more after medication ware consistently negative for sporozoites. Administration of either compound in the indicated doses did not prevent exflagellation, zygote or ookinete formation. However, the behavior of the latter forms was apparently altered by the action of the drug. There was a marked retarding effect in the formation of ookinetes in mosquitoes fed 24 hr after initial medication and thereafter. The schizontocidal and gametocytocidal action of chlorguanide was more evident than it was in pyrimethamine.     

Initiation of embryo implantation and maintenance of early pregnancy in the rat by chlordecone (Kepone).

The effect of chlordecone (Kepone), an insecticide/fungicide with reproductive toxicity, on the early stages of pregnancy in the rat was studied. Intraperitoneal injection of chlordecone into adult virgin female Holtzman strain rats before mating, in doses as high as 80 mg/kg, did not prevent fertilization, early development of the embryo to the blastocyst stage, transport of the embryo through the oviduct, or its implantation into the uterus. However, a single dose of 60 or 80 mg/kg, but not 20 or 40 mg/kg, before mating significantly reduced the concentration of progesterone in the serum of rats undergoing normal embryo implantation 5 days later. A dose of 80 mg/kg of chlordecone reduced progesterone levels in the serum by more than 50% within 48 hr in ovariectomized rats with Silastic tubing implants containing crystalline progesterone. This dose of chlordecone induced deciduomata formation in progesterone-primed ovariectomized rats to the same extent as 1 microgram of estradiol benzoate. The minimal effective single dose of chlordecone to initiate implantation of blastocysts in the uteri of hypophysectomized progesterone-primed rats, and to maintain embryo development for at least 5 days, was 50 mg/kg. Daily doses of 20 mg/kg for 3 or 5 days were effective at initiating implantation but did not maintain pregnancy. The latter treatment, however, did not prevent initiation of implantation or embryo development induced by subsequent administration of estrone. The results are consistent with the view that chlordecone is a weak estrogen that has both nongenomic and genomic estrogenic actions.     

Plasmodium yoelii nigeriensis (MDR)-efficacy of oral pyronaridine against multidrug-resistant malaria in Swiss mice

A multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) showing a wide spectrum of resistance to chloroquine, amodiaquine, mepacrine, mefloquine, halofantrine, quinine, and quinidine was used in this study for in vivo evaluation of the blood schizontocidal activity of pyronaridine, a topoisomerase II inhibitor, in Swiss mice. The parasite produces 100% lethal infection in mice. The drug was administered orally once a day from day 0 onward. The initial studies showed that low doses of pyronaridine (0.625 to 5.0 mg base/kg x9 days) did not completely control blood-induced P. yoelii nigeriensis infection. Finally a series of doses of pyronaridine ranging from 1.25 to 30.0 mg/kg administered orally for 7 consecutive days were evaluated and in spite of high level of resistance to standard antimalarials, the parasite P. yoelii nigeriensis has shown complete susceptibility to pyronaridine (15 mg/kg dose x7 days). The present paper also compares the merits of a single MDR strain vs a battery of different resistant lines for quick antimalarials screening.     

The site of action of the anticoccidial salinomycin (Coxistac).

The anticoccidial salinomycin has a cidal effect against chicken coccidia. Restricted and unrestricted medication studies and histopathological examinations of chicks infected with Eimeria acervulina, E. maxima, or E. tenella showed that parasites were destroyed within host cells during asexual development. Most sporozoites failed to become trophozoites and were destroyed 30--72 hr after ingestion of oocysts. The drug also affected schizonts during initial nuclear replication by either destroying or significantly delaying their maturation. Parasites affected by the drug were distorted grossly. Drug action against gametogony was not observed histologically, but when medication was restricted to this period of the life cycle, subsequent oocyst shedding of all 3 species was reduced by 20--70% compared to unmedicated controls. When drug was provided during the entire parasite life cycle, activity against asexual stages was so complete that only a limited number of parasites survived to form gamonts, and oocyst shedding was reduced by 80--90% relative to controls. As with other ionophores, salinomycin had no effect upon rate of oocyst sporulation.     

Antihypertensive profile of the angiotensin-converting enzyme inhibitors CI-906 and CI-907

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.     

Effect of cyclosporin A and some derivatives in Litomosoides carinii-infected Mastomys natalensis

Litomosoides carinii-infected Mastomys natalensis were treated 85 days post infection with cyclosporin A (CyA) or 8 derivatives with different immunosuppressive capacities. CyA (oral doses of 5 X 25 mg/kg, 5 X 50 mg/kg, 5 X 80 mg/kg on consecutive days) reduced parasitaemia levels in a dose dependent way, beginning 3 weeks after first drug administration. Using 5 X 50 and 5 X 80 mg/kg animals were free from circulating microfilariae on the day of necropsy (day 56). Derivatives were administered in 5 daily oral doses of 50 mg/kg. Compounds B-5-49 and G-7-53 had similar effects as CyA. Compounds A-4-16 and E-6-44 caused mean microfilaraemia reductions of about 80% until day 56. Compounds C-5-34, D-6-45, F-7-62 and H-7-94 were only marginally effective (10-40%). None of the drugs affected the number or the motility of adult worms. However, in the case of efficacious compounds the number of intrauterine microfilariae was considerably reduced and most of the intrauterine stages were pathologically altered. The efficacy of the various derivatives was independent of their immunosuppressive activity in vivo and in vitro, their anti-inflammatory activity and their activity against Plasmodium berghei. Effects on intrauterine stages were first detectable 7 days after treatment with 5 X 80 mg CyA/kg when the number of intrauterine microfilariae had decreased and the proportion of pathologically altered stages had increased. Alterations increased with time after treatment. Additionally, the uteri contained relatively large amounts of highly active microfilariae which were still included in an ovoid sheath.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasmodium species: flow cytometry and microfluorometry assessments of DNA content and synthesis

Fluorescence intensities were established by flow cytometry of different erythrocytic stages of Plasmodium berghei after staining of their DNA with Hoechst-33258 or Hoechst-33342. Parasites were obtained from highly synchronized infections or in vitro cultures. Most fluorescence measurements were performed using a low cost, clinical flow cytometer, equipped with a mercury arc lamp. Cells infected with P. berghei could be readily distinguished from uninfected cells on the basis of Hoechst-DNA fluorescence and single, double, and triple ring infected cells were separated clearly. The relative fluorescence intensities of different developmental stages (merozoites, ringforms, trophozoites, schizonts, and gametocytes) corresponded closely to the relative DNA contents of these stages as measured by microfluorometry. Flow cytometry appeared to be a sensitive and rapid method to measure DNA synthesis during asexual development; a C50 value of 5 microM of aphidicolin, a specific inhibitor of DNA synthesis, was established. Vital staining of parasites in culture was possible with both Hoechst dyes. After removal of Hoechst-33258, normal in vitro development of the stained parasites was observed. After Hoechst staining, the haploid ringforms of P. vivax showed slightly less fluorescence (15%) than ringforms of P. berghei and P. falciparum. No differences in fluorescence intensity were observed, however, by direct microfluorometry after Feulgen-pararosaniline staining, indicating that all three species have the same DNA content.     

Behavioral effects of acute and chronic triazolam treatments in albino rats

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.     

Hypoglycemic effect of Sclerocarya birrea {(A. Rich.) Hochst.} [Anacardiaceae] stem-bark aqueous extract in rats

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 100-800 mg/kg p.o.) produced dose-dependent, significant reductions (P < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.     

Acute toxicity of combinations of sodium dichromate, sodium arsenate and copper sulphate in the rat

1. The intraperitoneal treatment of adult male Wistar rats with various combinations of low doses of sodium dichromate (5 mg/kg), sodium arsenate (25 mg/kg) and copper sulphate (5.9 mg/kg) tended to counteract the inherent acute toxicity of each compound. 2. The co-administration of low doses of one or more of the test compounds with a high dose of sodium dichromate (35 mg/kg), sodium arsenate (90 mg/kg) or copper sulphate (23.5 mg/kg) resulted in a significant increase in acute toxicity in comparison with that produced by the administration of high doses of dichromate, arsenate or Cu2+ alone.     

Cytogenetic and dominant lethal studies on captan.

Possible mutagenic activity of captan was investigated by in vitro and in vivo cytogenetic studies and by the dominant lethal study in mice. In vitro cytogenetic study with cultured human diploid cells revealed a significant increase in the frequency of cells showing stickiness and a severe mitotic inhibition at concentrations of 3.0 and 4.0 microgram of captan per ml. although no chromosomal aberrations were observed. In in vivo cytogenetic study, no chromosomal aberrations were induced in the bone marrow cells of rats treated orally with captan at a single dose of 500, 1000 or 2000 mg/kg or at five consecutive doses of 200, 400 or 800 mg/kg/day. Dominant lethal study also failed to show any mutation induction after treatment of male mice with daily oral dose of 200 or 600 mg of captan per kg bw for five days.     

Effect of indomethacin, tiaprofenic acid and dicrofenac on rat gastric mucosal damage and content of prostacyclin and prostaglandin E2

Gastric ulcerogenicity and depletion of endogenous prostaglandins (PGs) content induced by tiaprofenic acid, dicrofenac and indomethacin were examined using the same antiinflammatory effective doses. Male Wistar rats were given each of these drugs intragastrically 24, 18, and 3 hrs before sacrifice in the following doses (mg/kg): indomethacin (0.8, 4 and 20); tiaprofenic acid (1.2, 6 and 30); dicrofenac (0.8, 4 and 20). Endogenous prostacyclin (PGI2) and PGE2 in fundic mucosa were determined by radioimmunoassay. The three compounds produced fundic mucosal lesions in a dose-dependent manner. However, tiaprofenic acid and dicrofenac were both less potent than indomethacin in producing gastric mucosal lesions at similar antiinflammatory doses. Mucosal PGE2 content was abolished by the three compounds in the following doses (mg/kg): indomethacin (4 and 20); tiaprofenic acid (6 and 30); dicrofenac (20). Mucosal PGI2 was maintained around 50% of the control value in rats given tiaprofenic acid in a dose of 6 mg/kg or dicrofenac in a dose of 4 mg/kg, while indomethacin in a dose of 4 mg/kg markedly reduced mucosal PGI2 to 17% of the control value. In larger doses, tiaprofenic acid and dicrofenac were also significantly less potent in reducing mucosal PGI2 than indomethacin. These results suggest that the difference in ulcerogenicity between indomethacin and the other two compounds was closely related to their potency in decreasing PGI2 in the gastric (fundic) mucosa.     

Host cell specificity and schizogony of Plasmodium berghei under different in vitro conditions

Invasion and intra-erythrocytic growth of two strains of Plasmodium berghei (ANKA and K173) were studied under different in vitro conditions. Some important limiting factors for the mass cultivation of this rodent malaria parasite were reconsidered. Parasites of both strains developed normally from ringforms into mature schizonts in RPMI1640 supplemented with Fetal Calf Serum (FCS). At a temperature of 37 degrees C the duration of the schizogonic cycle was comparable to that of the same parasites developing under in vivo conditions. At 27 degrees C, however, the asexual cycle took 60-72 h. In medium supplemented with mouse serum instead of FCS the growth of the parasites was severely inhibited. Parasites of both strains showed a strict preference for reticulocytes. Red blood cells from rats, mice and hamsters were readily invaded by merozoites from both strains. Erythrocytes from rabbits and guinea pigs were resistant to invasion by P. berghei. It is concluded that host cell specificity technically limits the possibilities for mass cultivation of P. berghei. The validity of recent publications, describing alternative culture systems for this rodent parasite, is discussed.     

Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration

The pharmacokinetic profile of (+/-)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (+/-)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr-1. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg.hr/liter, respectively. The bioavailability of a single oral dose of (+/-)-gossypol in rats was 60%. The change in plasma (+/-)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (+/-)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (+/-)-gossypol was eliminated at a rate constant of 0.01 hr-1, corresponding to half-life of 64.76 hr. Subchronic oral administration of (+/-)-gossypol showed an apparent half-life of 101.91 hr-1, corresponding to a rate constant of 0.007 hr-1. The results indicate that multiple oral dosing of (+/-)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (+/-)-gossypol may play, at least in part, a role in the reproductive toxicity of subchronic but not single oral dosing.