Leishmania donovani in hamsters: Stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy

Summary Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters againstL. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described.MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1×10⁷ amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.     

Leishmania donovani in hamsters: stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy

Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters against L. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described. MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1 x 10(7) amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.     

3,5-Dibromo-2′-chloro-4′-isothiocyanatosalicylanilide,a potent anthelminitic

Summary The compound, 3,5-dibromo-2-chloro-4-isothiocyanatosalicylanilide, has been tested against various nematode and cestode parasites in experimental and domestric animals. It shoved 100% activity againstAncylostoma ceylanicum, A. tubaeformis, Syphacia obvelata, Ascaridia galli, Toxocara spp.,Toxascaris sp.,Gnathostoma spinigerum, Hymenolepis nana, Raillietina spp. andTaenia spp. in doses 25–70 mg/kg given in single or multiple administrations.Acknowledgments. We express sincere thanks to Dr Nitya Nand, F.N.A., CDRI, Lucknow, for his keen interest in the work, to Dr B. N. Dhawan, F.N.A. for providing informations about general pharmacology of the compound, and to Dr R. K. Chatterjee and Dr P. K. Murthy for carrying out antifilarial sreening. Technical assistance of Mr S. C. Bhar and Mr S. Ram is acknowledged.     

Monoaminoguanidine prevents sorbitol accumulation,nonenzymatic protein glycosylation and development of kidney lesions in diabetic rats

Summary Monoaminoguanidine administration (25 mg/kg b.wt, i.p. for 14 weeks) to alloxan diabetic rats (blood glucose 250 mg/dl) decreased the nonenzymatic protein glycosylation and sorbitol levels. It prevented development of Armanni-Ebstein tubular lesions, pathological changes in the glomerular capillary tufts and glomerular basement membrane thickening in the kidney.CDRI Communication no. 4694.     

Intergeneric interactions betweenEimeria separata (Apicomplexa) andNippostrongylus brasiliensis (Nematoda) in the rat

Summary Ova production inNippostrongylus brasiliensis infected rats was significantly greater than in rats singly infected with the helminth whenEimeria separata infections were introduced 4, 6 and 11 days postinoculation withN. brasiliensis. Patent periods were unaltered during concurrent infections. These results suggest that the presence ofE. separata affects helminth fecundity but does not increaseN. brasiliensis longevity as has been shown withE. nieschulzi.This study was supported by NIH MB RS Grant RRO8012-8.     

Note sur l'activité du nitrothiamidazole dans l'anguillulose

Summary Report of the results of 12 patients suffering from an obstinate enteritis withStrongyloïdes stercoralis, who were treated with nitrothiamidazole (CIBA 32.644-Ba) Ambilhar^® by the oral duct in 2 doses of 25–30 mg/kg/day for 4, 5 or 7 consecutive days. The clinical and parasitological recovery seems to be constant, quick, and lasting for those who escape a re-infestation.

---

---

CIBA 32.644-Ba commercialisé sous le nom d'Ambilhar^®, rapport CIBA 1965, Bâle, Suisse.     

Sanguinarine: its potential,as a liver toxic alkaloid present in the seeds ofArgemone mexicana

Summary The alkaloid sanguinarine reported to be responsible for several outbreaks of epidemic dropsy in the tropics was examined for its hepatotoxic potential in rats. The studies showed that a single i.p. dose (10 mg/kg) of sanguinarine not only increased the activity of SGPT and SGOT substantially but also caused a significant loss of microsomal cytochrome P-450 and benzphetamine N-demethylase activity. Furthermore, the treated rats exhibited considerable loss of body and liver weight, peritoneal edema and slightly enlarged livers with fibrinous material. Microscopic examination of the liver tissue showed progressive cellular degeneration and necrosis further substantiating that sanguinarine is a potential hepatotoxic alkaloid.     

Effect of praseodymium on drug metabolism in rat liver smooth and rough endoplasmic reticulum

Summary A small i.v. dose (3 mg/kg) of a light lanthanon, praseodymium, impairs the drug metabolizing capacity of both the smooth and rough fractions of rat liver endoplasmic reticulum. This decrease in the activity of drug metabolizing enzymes and in the amount of cytochromes P-450 and b₅ is more pronounced in the rough endoplasmic reticulum fraction.     

Influence of phosphorus supply and light intensity on mycorrhizal response inPisum-Rhizobium-Glomus symbiosis

The influence of mycorrhizal colonization withGlomus mosseae on parameters of N₂ fixation and plant growth was studied in pot experiments with pea plants (Pisum sativum L.) infected withRhizobium leguminosarum and supplied with varied levels of phosphorus (P) and nitrogen (N). Reduced light intensities were used to evaluate the dependence of the microsymbionts on assimilate supply. In plants grown with low P supply, mycorrhization increased the concentration of P in shoots, and thus N₂ fixation. Reduced light intensity significantly depressed mycorrhizal colonization and nodule growth in low-P plants. When P supply did not limit plant growth and N₂ fixation, however, the percentage of mycorrhizal colonization was reduced due to the higher P status, and the microsymbionts were not impaired by low light intensities. To maximize carbohydrate supply, another experiment was carried out at high light intensity of 900 mol m^–2s^–1 and with non-limiting P supply. Nitrogen fertilization, given as starter N, enhanced plant growth, but delayed nodule formation. Towards flowering, nodulation rapidly increased, but less so inGlomus inoculated plants. After 28 days mycorrhizal plants were lower in shoot dry weight, nodule dry weight and nitrogenase activity. The results suggest that under many, but not all, environmental conditions the host plant is able to restrict mycorrhizal colonization and, thus, to prevent impairment ofRhizobium symbiosis.deceased in May 1994     

Protective effect of Shigyaku-to,a traditional Chinese herbal medicine,on the infection of herpes simplex virus type 1 (HSV-1) in mice

The antiviral activity of Shigyaku-to (TJS-109), a traditional Chinese herbal medicine, was investigated in mice infected with herpes simplex virus type 1 (HSV-1). TJS-109 is a combination of the medicinal plant extracts fromZingiberis siccatum rhizoma,Aconiti tuber andGlycyrrhizae radix in a specific proportion. Mice infected with a 10 LD₅₀ dose of HSV-1 were treated with TJS-109 orally at doses of 1.25 to 20 mg/kg 2 days before, and 1 and 4 days after the infection. The treated groups had 80% (1.25 mg/kg), 40% (5 mg/kg) and 23% (20 mg/kg) mortality rates 25 days after the infection as compared with a 100% mortality rate in control mice treated with saline. When HSV-1 infected mice (recipients) received CD8⁺T cell fractions derived from spleens of mice treated with TJS-109 (donors), 70% of recipients survived, as compared with 0% survivors in the groups of mice treated with saline, B cell fractions, CD4⁺ T cell fractions or macrophage-enriched fractions prepared from the same donors. TJS-109 did not show any virucidal activities against HSV-1 or any virostatic activities on the growth of HSV-1 in Vero cells. These results suggest that TJS-109 protected mice exposed to lethal amounts of HSV-1 through the activation of CD8⁺ T cells.     

Resistance of in vivo-selected spontaneously transformed cells and Rous sarcoma virus-transformed cells to macrophage-mediated cytotoxicity

The cytotoxic activity (CTA) of activated peritoneal macrophages (MP) on variant lines of Syrian hamster embryo (HE) cells of differing malignant characteristics was studied. The target cells were a line of low-malignant cells resulting from spontaneous transformation of HE cells in vitro (STHE strain), and malignant variants selected from them in vivo (STHE-LM-4, STHE-LM-8, and STHE-75/18 strains). In addition, we used cells of the HET-SR-1 strain; these are HE cells transformed in vitro by a tumorigenic Rous sarcoma virus (Schmidt-Ruppin strain, RSV-SR), or the TU-SR strain induced by RSV-SR in vivo. Thioglycollate-elicited peritoneal MP from Syrian hamsters were activated in vitro with bacterial levan, LPS or MDP and used as effector cells. MP-mediated cytolysis was determined by means of a 42-h radioactivity release assay with³H-thymidine-labeled target cells. We found that only the parental STHE cells were susceptible towards fully-activated MP-mediated CTA. All three of the in vivo-selected malignant variants of the STHE cell sublines, as well as the tumorigenic RSV-SR transformants, were resistant to cytolysis by activated MP. Non-activated thioglycollate-elicited MP did not lyse any of the tumor cells studied.     

Competitiveness and communication for effective inoculation byRhizobium,Bradyrhizobium and vesicular-arbuscular mycorrhiza fungi

After a short summary on the ecology and rhizosphere biology of symbiotic bacteria and vesicular-arbuscular (VA) mycorrhiza fungi and their application as microbial inocula, results on competitiveness and communication are summarized. Stress factors such as high temperature, low soil pH, aluminium concentrations and phytoalexins produced by the host plants were studied withRhizobium leguminosarum bv.phaseoli andRhizobium tropici onPhaseolus beans. Quantitative data for competitiveness were obtained by usinggus ⁺ (glucoronidase) labelled strains, which produce blue-coloured nodules. ForPhaseolus-nodulating rhizobia, a group specific DNA probe was also developed, which did not hybridize with more than 20 other common soil and rhizosphere bacteria. Results from several laboratories contributing to knowledge of signal exchange and communication in theRhizobium/Bradyrhizobium legume system are summarized in a new scheme, including also defense reactions at the early stages of legume nodule initiation. Stimulating effects of flavonoids on germination and growth of VA mycorrhiza fungi were also found. A constitutive antifungal compound in pea roots, -isoxazolinonyl-alanine, was characterized.     

Effect of methyl ester of aristolic acid fromAristolochia indica Linn. on fertility of female mice

Summary Methyl ester of aristolic acid, a pure compound isolated from the roots ofAristolochia indica (Linn.), was found to exert 100% abortifacient activity at a single oral dose of 60 mg/kg b. wt when administered on 6th or 7th day of pregnancy; 20 and 25% abortifacient effect were observed at the same dose on day 10 and 12, respectively.The authors wish to thank Dr S.C. Pakrashi and his associate Mr P.P. Ghosh Dastidar for the compound. Thanks are also due to the Director General of Indian Council of Medical Research for granting a fellowship to one of them (C.S.).     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a¹⁴CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p<0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Trichinella spiralis: Acceleration and inhibition of cyst calcification in rats

Summary Daily administration of vitamin D₃ (75,000 IU/kg b.wt) for 7 days acceleratedTrichinella spiralis cyst calcification in rats with a 14-week-old infection. When disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) was administered (50 mg/kg b.wt) from 2 days before until 2 days after vitamin D₃ treatment, cyst calcification was inhibited. Thus, the ability to inhibitT. spiralis calcification has been demonstrated for the first time.Supported in part by EKU faculty research grant No. 03-05.Much appreciation goes to Dr Gordon S. Hassings and the Proctor and Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio USA for providing the EHDP used in this study.     

Phytoalexin response is elicited by a pathogen (Rhizoctonia solani) but not by a mycorrhizal fungus (Glomus mosseae) in soybean roots

Summary A container system was constructed to study the response of soybean roots to infection by mycorrhizal or pathogenic fungi. The system allows a rapid and synchronous inoculation byGlomus mosseae orRhizoctonia solani. The phytoalexin glyceollin was measured in roots of inoculated and uninoculated plants for a period of 30 days. A significantly increased content of phytoalexin was found inR. solani-infected roots as compared to uninfected control roots. However, there was no difference in the glyceollin contents of the mycorrhizal and the control roots for up to 23 days after inoculation. The accumulation of glyceollin inR. solani-infected roots was not influenced by a subsequent inoculation withG. mosseae. Moreover glyceollin accumulated in mycorrhizal plants to the same extent as in control plants when they were inoculated withR. solani. The two fungi did not mutually influence the course of infection when they were inoculated together.     

Comparison of circulating lipoprotein lipase activity in Zuckerfa/fa andFa/-rats

Summary Lipoprotein lipase activity was determined in Zucker rats by assaying VLDL radioactivity. Animals were i.v. injected with³H₂-oleic acid and¹⁴C-glycerol with or without Triton WR 1339. This enzymatic activity was higher infa/fa rats than in non-obeseFa/-rats.     

Splenic B-cell activation in lipopolysaccharide-non-responsive C3H/HeJ mice by lipopolysaccharide ofPorphyromonas gingivalis

Porphyromonas gingivalis 381 lipopolysaccharide (LPS) definitely exhibited mitogenic activity in purified B-cells, separated from spleens of LPS-responsive C3H/HeN mice and LPS-non-responsive C3H/HeJ mice by using a magnetic cell sorting system. The mitogenic activity induced byP. gingivalis LPS was incompletely inhibited by polymyxin B.P. gingivalis LPS also induced a higher production of interleukin-6 (IL-6) in splenic B-cells of C3H/HeN mice as compared withEscherichia coli LPS. Furthermore,P. gingivalis LPS, but notE. coli LPS, induced definite IL-6 production in C3H/HeJ mice.P. gingivalis LPS increased tyrosine, serine/threonine phosphorylation of proteins with various major induced bands in splenic B-cells of both C3H/HeN and C3H/HeJ mice. Additionally, radioiodinatedP. gingivalis LPS, similarly toE. coli LPS, bound to a 73-kDa protein on C3H/HeJ as well as C3H/HeN B-cells. ThusP. gingivalis LPS may activate B-cells of C3H/HeJ as well as C3H/HeN mice via the LPS-specific binding protein on the cells.     

Suppression of phytohemagglutinin induced splenocyte proliferation during concurrent infection withEimeria nieschulzi andNippostrongylus brasiliensis

Summary Results suggest that infection withEimeria nieschulzi (Protozoa) interferes with splenocyte proliferation induced by infection withNippostrongylus brasiliensis (Nematoda).This study was supported by NIH MBRS Grant RR08012-15.     

Oxygen consumption of the rat small intestine during infection with nematospiroides dubius

Summary Qo₂ of jejunal rings did not differ significantly between uninfected rats and rats infected for 7 days withNematospiroides dubius. Qo₂ of isolated jejunal mucosal epithelial cells was significantly greater 7 days after infection than in uninfected controls or at 29–36 days after infection.