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Biomedical subjects

H Zahner

Publications and source records attributed to H Zahner.

At least 73 records · Page 4Linked to original sources
PubMed1990

Antifilarial activities of benzazole derivatives. 3. Effects of benzothiazoles on third stage larvae and preadult worms of Acanthocheilonema viteae, Brugia malayi and B. pahangi in Mastomys natalensis.

Ten structurally defined benzothiazoles (5-methyl and the analogous 5-methoxy derivatives) with known macrofilaricidal and microfilaricidal activities were tested for efficacy against third stage larvae and preadult worms in Acanthocheilonema viteae, Brugia malayi, and B. pahangi infected Mastomys natalensis. Drugs were administered in single oral doses of maximally 100 mg/kg. The benzothiazoles were active against the two stages of the three species. Generally the 5-methoxy derivatives displayed slightly higher activity than the 5-methyl compounds. 6-Isothiocyanates (CGP 21306, CGP 20308) and 6-dithiocarbamic-S-(2-carboxyethyl)esters (CGP 21835, CGP 20376) were more active than thiocarbonylamides (CGP 21833, CGP 20309, CGP 26702, CGP 24589). 6-Dithiocarbamic-S-(sulfomethylsodium)esters (CGP 26701, CGP 24588) showed intermediate efficacy. A. viteae was usually slightly more resistant than the Brugia spp. Minimum curative doses (greater than 95% reduction of worms) against the two stages of the various species were either identical or preadult worms were slightly more resistant than third stage larvae. When these curative doses were compared with curative adulticidal doses or effective doses against microfilariae the various doses were very similar and never differed from each other by more than the factor 2.

Animals↗
PubMed1989

Reactivity of IgE in human Schistosoma mansoni sera to S. mansoni antigens.

Sera from Schistosoma mansoni-infected human patients were tested for total IgE levels and specific IgE and IgG antibodies to S. mansoni adult worm, cercaria, and egg antigen by ELISA. Of 50 sera, 28 were investigated by enzyme-linked crossed immunoelectrophoresis (ELCIE) to detect IgE reactivity to individual adult worm extract components. All sera showed increased total IgE levels. Specific IgE antibody levels to the different antigens varied; they were significantly correlated with each other but independent from total IgE. No correlation was found between specific IgG and any of the IgE antibody levels. Testing of the 28 individual sera by ELCIE revealed heterogeneous patterns. Seven sera were found to be nonreactive: three reacted with one precipitate, and the others reacted with between two and nine precipitates. However, in no case were identical patterns recognized, although four antigens reacted with about 80% of the sera. The number of bands detected by the individual sera depended neither on the levels of total IgE nor on those of specific IgE.

Animals↗
PubMed1989

Altered immune response (humoral and delayed-type hypersensitivity reactions) to sheep red blood cells in the course of experimental filarial infections (Litomosoides carinii, Brugia malayi, Acanthocheilonema viteae) of Mastomys natalensis.

Litomosoides carinii-, Acanthocheilonema viteae- or Brugia malayi-infected Mastomys natalensis were sensitised against sheep red blood cells (SRBC) on various occasions after infection to determine the effect of filarial infections on the immune response to a non-filarial antigen. The phagocytic activity of the reticuloendothelial system (RES) was controlled in vivo by the elimination of 51Cr-labelled SRBC. Antibody titres against SRBC (agglutinating and lytic antibodies) were similar to those of uninfected controls in L. carinii- or B. malayi-infected Mastomys sensitised during prepatency or early patency up to 90 days post infection (p.i.) but were reduced in animals sensitised during patency. A significant inverse correlation existed between anti-SRBC antibody titres and microfilaraemia levels. In contrast, A. viteae-infected Mastomys showed reduced humoral anti-SRBC responses at the end of prepatency, whereas the response tended towards normal with increasing parasitaemia. Delayed-type hypersensitivity (DTH) against SRBC was measured as footpad swelling after sensitisation by the s.c. or i.v. route and intraplantar challenge. DTH reactions were reduced during prepatency in all infections after s.c. sensitisation. During patency, 24-h reactions were similar to those of age-matched controls but the swelling persisted 24 or 48 h longer than in the latter. In A. viteae infections, even enhanced 24-h reactions were found during patency. Histological investigations did not reveal differences in the type of cell infiltrations between infected and control animals. After i.v. sensitisation with SRBC, L. carinii- and A. viteae-infected animals showed weaker DTH reactions than the controls, independent of the period after infection. In the case of B. malayi infections, DTH reactions were similar to those of controls during early prepatency, whereas reduced DTH responses were observed later than 50 days p.i. As shown in L. carinii-infected animals, depressed DTH reactions after i.v. sensitisation did not depend on an altered expression phase but rather on an altered regulation during the inductive phase of the response: increases in the sensitising SRBC doses that caused decreasing DTH reactions in uninfected animals led to enhanced reactions in infected animals. Phagocytosis of i.v. injected 51Cr-labelled SRBC was enhanced during prepatency in L. carinii infection and during patency in all infections.

Animals↗
PubMed1989

Litomosoides carinii: mode of action in vitro of benzothiazole and amoscanate derivatives with antifilarial activity.

It is suggested that the recently developed benzothiazole and amoscanate derivatives with antifilarial activity exert their action in vitro by an inhibition of mitochondrial-derived respiration. It was confirmed that the drugs CGP 20376, 21835, 20308, 21306, and 6140 cause a rapid immobilization in vitro of the adult filarial worm, Litomosoides carinii, the time required being similar to rotenone at the same concentration. The other drugs investigated, CGPs 20309, 21833, 24589, 23518, and 13231, were also effective; however, they required much longer incubation times. Submitochondrial particles (SMP) were prepared from Ascaris muscle and rat liver. The concentration of drug causing 50% inhibition of respiration (IC50) was calculated. It was found that the drugs most rapidly inhibiting respiration have IC50s for NADH oxidase of less than 25 microM in both Ascaris and rat liver SMP. This effect on SMP respiration could be overcome by using succinate as a substrate, indicating the site of inhibition to be within complex I of the mitochondrial respiratory chain. Further experiments showed that whereas the respiratory chain's NADH:ferricyanide reductase was unaffected by these drugs, there were pronounced effects on both Ascaris and rat liver NADH:quinone reductase activity. This suggests that the inhibition within complex I occurs after the flavoprotein dehydrogenase, but before the site of the quinone reduction. The other compounds examined, which had a slower effect on motility, also showed inhibition of the NADH oxidase, but not to as great an extent as the aforementioned compounds. The compounds most active against motility were also most effective at inhibiting respiration in intact adult L. carinii. Analysis of the aerobic end products produced by L. carinii showed that acetate production was greatly reduced even in the presence of low concentrations of the drugs. There was also a slight decrease in lactate production. However, a direct effect on the glycolytic pathway was ruled out by two observations. One, that the production of lactate from cell-free extracts of L. carinii is unaffected by the presence of the drugs, and secondly, that a protozoan, Giardia lamblia, reliant on glycolysis for energy production, can survive for long periods of time in the presence of high concentrations of the drugs. A correlation can be observed between the time for immobilization of the filarial worm and the strength of inhibition of mitochondrial respiration. Therefore, it is suggested that, at least in vitro, the mechanism of toxicity of these antifilarials in L. carinii is due to the blocking of the respiratory chain at a site similar to that of rotenone.

Anaerobiosis↗
PubMed1989

19s and 7s antibody response of Mastomys natalensis in experimental filarial (Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi, B. pahangi) infections.

Specific total antibody (ab), 19s and 7s ab levels in the serum of M. natalensis were investigated after infection with L. carinii, A. viteae, B. malayi and B. pahangi for period of about 500 days p.i., using ELISA (homologous adult antigen) and indirect immunofluorescence tests (IIFT: homologous adult and microfilariae antigen). Total ab levels in L. carinii infected animals rose moderately during prepatency Maximum levels occurred during patency. The response during prepatency was stronger in A. viteae and Brugia spp. infected hosts. Lateron ab levels increased continuously in Brugia infections; in A. viteae infection they decreased with decreasing parasitaemia. 19s abs were stimulated during prepatency and at the beginning of patency, or were found at moderate levels throughout to period of investigation (Brugia infections). 7s abs predominated beginning at the period of late prepatency (IIFT) or at the beginning of patency (ELISA). The time courses of 7s abs corresponded to those of total abs. As obvious by IIFT (adult worm antigen) total and 19s titres were higher against cuticle antigens, egg shell antigens and intrauterine amorphous material than against antigens located in the hypodermis and musculature. 7s abs showed best reactivity with cuticle antigens. Using microfilarial antigens 19s abs reacted predominantly with cuticle antigens whereas 7s abs often showed higher titres against antigens which were localized within the larvae than against cuticle antigens.

Animals↗
PubMed1989

Antifilarial activities of synthetic and natural retinoids in vitro.

Fourteen synthetic retinoids with known and different binding affinities to retinol binding proteins of Dirofilaria immitis, retinol, and retinoic acid were tested in vitro against female Litomosoides carinii (drug levels 20, 10, 1 nM/ml) and against microfilariae of L. carinii, Brugia malayi, B. pahangi and Acanthocheilonema viteae (drug levels 100, 20, 10, 1 nM/ml). All compounds including retinol and retinoic acid had at least some effects on the filarial parasites. Except for 3 synthetic retinoids, continuous exposure of adult L. carinii to the drugs reduced the motility of the worms completely or remarkably by day 7 of incubation in a dose and time dependent fashion. Also, the release of microfilariae was completely or remarkably suppressed in a dose and time dependent manner by 20 and 10 nM/ml of all except 4 of the retinoids. Short term exposure to the drugs (up to 20 nM/ml) for 4 h followed by subsequent incubation in drug-free medium was ineffective except for one synthetic retinoid (13-cis-N-(2-hydroxyethyl)retinamide:13-cis-Her). Effects on microfilariae were also dose and time dependent. All compounds affected markedly the motility of L. carinii microfilariae within 20 h at dose levels of 1 nM/ml and above. Microfilariae of B. malayi, B. pahangi and especially of A. viteae were generally less sensitive. Eight of the synthetic retinoids, but not retinol and retinoic acid, were effective (10 nM/ml). There were generally no correlations between the various effects of individual compounds; i.e., activities varied within one species depending on the parameters used and depending on the parasite species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Antifilarial activities of benzazole derivatives. 2. Microfilaricidal effects against Litomosoides carinii, Acanthocheilonema. vitae, Brugia malayi and B. pahangi in Mastomys natalensis.

The spectrum of antimicrofilarial activities of eighteen 2-tertbutylbenzazole derivatives was evaluated comparatively in Mastomys natalensis infected with Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi or B. pahangi. The minimal effective dose (DEM) against microfilariae (greater than 95% reduction of microfilariae counts in the peripheral blood) was determined on day 3 (DEM-3), on day 7, 14, 21, 28 and 42 (DEM-7, DEM-14, DEM-21, DEM-28 and DEM-42) after the first treatment. All compounds were effective against the microfilariae of all 4 species. The benzoxazole derivatives were invariably less potent than the corresponding benzothiazole analogues. Upon repeated oral treatment (once daily [o.d.] for five days) the DEM-7 of the benzoxazoles varied depending on the species and on the chemical structure between 25 mg/kg o.d. x 5 and greater than 100mg/kg o.d. x 5 days. Within the benzothiazole series the DEM-7 varied between 6.25 mg/kg o.d. x 5 and 100 mg/kg x 5. In all but 5 of the 40 parasite-compound combinations of the benzothiazoles the 5-methoxy-derivates were more effective than the 5-methyl analogues. Similar differences were found with the eight benz-oxazoles tested. The lowest DEM-7 was observed with compound CGP 20308 which is 2-tert-butyl-5-methoxy-6-isothio-cyanatobenzothiazole and with compound CGP 20376 which is 3-(2-tert-butyl-5-methoxy-benzothiazol-6-yl] amino-thiocabo-nylthio) propionic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Antifilarial activities of benzazole derivatives. 1. Macrofilaricidal effects against Litomosoides carinii, Dipetalonema viteae, Brugia malayi, and B. pahangi in Mastomys natalensis.

Eighteen 2-tert-butyl-benzazole derivatives were evaluated comparatively as macrofilaricidal agents against L. carinii (L.c.), D. viteae (D.v.), B. malayi (B.m.) and B. pahangi (B.p.). Upon repeated treatment (once daily) for five consecutive days the eight benzoxazole derivatives were invariably less potent than the corresponding benzothiazole derivatives. The minimal curative dose (DCM) of the benzoxazoles varied depending on the species and on the chemical structure between 25 and 100 mg/kg p.o. once daily for five days. In the benzothiazole series the lowest DCMs were observed with compound CGP 20376 which is the 5-methoxy-6-dithiocarbamic-S-(2-carboxy-ethyl)ester derivative. This compound eliminated all macrofilariae of L.c., B.m. and Bp. at 6.25 mg/kg p.o. once a day for five days, whereas 12.5 mg/kg x 5 days were needed against D.v. For all other benzothiazole derivatives the DCMs varied between 6.25 mg/kg p.o. x 5 to 100 mg/kg x 5. Six of the most potent benzothiazoles were tested by single oral treatment. In general doses had to be increased 2-4 times to reach minimum curative effects. CGP 20376 was fully effective against B.m. and B.p. at 12.5 mg/kg p.o., against L.c. at 25 mg/kg p.o. and against D.v. at 50 mg/kg p.o.. This compound has been selected from this series of novel benzazoles as a first candidate for trials against human bancroftian filariasis.

Administration, Oral↗
PubMed1987

Intermediate host (Biomphalaria alexandrina) antigens partly protect against subcutaneous infections with cercariae of Schistosoma mansoni but are ineffective in infections by percutaneous invasion.

Mice were immunized against hepatopancreas homogenate of Biomphalaria alexandrina, using Al(OH)3 as adjuvant, and challenged by subcutaneous (s.c.) injection of Schistosoma mansoni cercariae, percutaneous invasion of cercariae and intravenous (i.v.) injection of mechanically prepared schistosomula of different ages. Significantly reduced (about 50%) numbers of adult S. mansoni were found 42 days after challenge in immunized animals infected by s.c. injection of cercariae. Protective effects were detectable as early as 4 days after infection when the numbers of schistosomules in the lungs were reduced in immunized animals. However, immunized animals lacked protective immunity against S. mansoni when infected via the percutaneous route with cercariae or by i.v. injection of schistosomules of different ages. Experiments show that immunization of hosts against intermediate host antigens does not protect against S. mansoni infection via the natural route.

Animals↗
PubMed1987

Lectin binding studies on adult filariae, intrauterine developing stages and microfilariae of Brugia malayi and Litomosoides carinii.

Sections of macrofilariae of Brugia malayi and Litomosoides carinii revealed binding of the gold-labelled lectins WGA, DBA and PNA. Specificity of binding was controlled by competitive inhibition with the respective sugars. N-acetyl-glucosamine, N-acetylgalactosamine and galactose residues seem to be present in the respective tissues. The lectins were bound preferentially to parts of the reproductive organs and to the fluid contents of their lumina. The results of the chitosan test and binding experiments with WGA-gold conjugate suggest the presence of chitin in the sheath of oocytes or zygotes. Binding of WGA could not be inhibited with 0.5 M N-acetylglucosamine, but only with 10 mM triacetyl chitotriose. In older stages, binding of WGA to the sheath could be inhibited by 0.5 M N-acetylglucosamine. In mature microfilariae, the outer surface of the sheath did not show affinity for WGA, but small amounts were bound to the inner surface. Therefore, the sheath of later developmental stages and microfilariae does not contain chitin but only N-acetylglucosamine residues. The degradation of the chitin content might enable the elongation and flexibility of the sheath of microfilariae.

Animals↗
PubMed1987

Formation by the uterus of a peripheral layer of the sheath in microfilariae of Litomosoides carinii and Brugia malayi.

The eggshells of young developmental stages in the uterus are rather thin and homogenous. In the brezel stage of Brugia malayi they are 35 nm thick and 20 nm in Litomosoides carinii. In young developmental stages up to brezel stages the eggshells bind the lectins WGA, DBA and PNA labelled with colloidal gold. This shows that GlcNAc, GalNAc and Gal residues are present at the surface of the sheath. In intrauterine microfilariae of B. malayi the original sheath is reduced to a thickness of 7 nm. It is reinforced by secretions from a specialized area of the epithelium of the uterus which do not appear as a homogeneous layer but look like a string of pearls. This layer may be called the "uterine layer". It has a thickness of 40-80 nm. In the microfilaria of L. carinii, the thickness of the original sheath is reduced to 2-3 nm and the uterine layer has a thickness of 7 nm. The uterine layer does not react with any of the lectins, which shows that the surface lacks N-acetylglucosamine, N-acetylgalactosamine and galactose residues. The uterine layer appears to be an ancestral (plesiomorphic) feature which is present in free-living nematodes and the highly specialized bloodforms of filariae. The uterine layer seems to protect and disguise the original sheath against the immune reactions of the host.

Animals↗
PubMed1987

Isolation of pure sheaths of Litomosoides carinii microfilariae.

A method is described for the isolation of pure, chemically intact sheaths of blood microfilariae of Litomosoides carinii. Microfilariae were isolated according to standard techniques. Exsheathment was performed by freezing-thawing-shaking procedures, repeated 5-10 times, i.e., larvae were frozen in liquid nitrogen, thawed at room temperature, and shaken vigorously for 5 s. Exsheathment rates were about 50%. Sheaths were separated from ensheathed and exsheathed microfilariae and microfilariae fragments by filtration through a polycarbonate filter (2 micron pore size). The achievable yield (about 15% of the sheaths of a batch of microfilariae) was approximately 1 microgram of sheaths per 10(6) microfilariae.

Animals↗
PubMed1987

Detection of circulating and urinary antigens in Mastomys natalensis experimentally infected with Brugia malayi, Brugia pahangi, or Litomosoides carinii.

The time-course of the detection of circulating and urinary filarial antigens was followed with a 2S-IRMA assay, using a mouse monoclonal antibody raised against Brugia malayi larvae, in Mastomys natalensis experimentally infected with Brugia malayi, Brugia pahangi, or Litomosoides carinii. In the prepatent phase of the infections, filarial antigen was detected 4-7 weeks before microfilariae appeared in the peripheral blood. Moreover, the sensitivity of the test was greater with urine than with serum. During the patent phase of infection, the level of circulating antigens detected varied considerably. However, there was a positive correlation (P less than 0.05) between antigenemia and microfilaremia. In L. carinii infection, filarial antigen could be easily detected in spite of the disappearance of microfilariae in peripheral blood, 49 weeks post infection. If these results are extrapolated to man, the 2S-IRMA should be useful for epidemiological surveys in endemic areas where transmission has been eliminated.

Animals↗
PubMed1987

Reaginic and homocytotropic IgG antibody response of Mastomys natalensis in experimental infections of filarial parasites (Litomosoides carinii, Dipetalonema viteae, Brugia malayi, B. pahangi).

Reaginic and homocytotropic IgG antibodies in sera using passive cutaneous anaphylaxis (PCA) test and antigen from Litomosoides carinii were followed in Mastomys natalensis, infected with L. carinii, Dipetalonema viteae, Brugia malayi or B. pahangi. Groups of animals with infections of various ages so as to cover a total infection period of up to 300 to 420 days post-infection (p.i.), depending on the species of parasites, were bled at 1- to 3-week intervals over periods of 50-112 days. In addition, intradermal tests were performed on animals infected with L. carinii to detect immediate type hypersensitivity. Reaginic antibodies were usually first detected in the 3rd week after infection. Thereafter, a marked increase of PCA titres was observed in the 4th week p.i. leading to maximum titres 4 weeks after infection with D. viteae and B. pahangi and 6 weeks after B. malayi infection. Mean maximum titres were between 1:40 and 1:160. Following the peak response, titres decreased markedly until the beginning of patency in infections with D. viteae, B. malayi and B. pahangi whereas a constant course was observed at this time in animals infected with L. carinii. A further rise in PCA titres occurred in all infections around the beginning of patency, resulting in maximum reagin levels in L. carinii infections (mean titre 1:80) and moderate titres in the other infections. During early patency there was an inverse relationship between microfilaraemia density and levels of reaginic antibodies. However, in the phase of decreasing parasitaemia in L. carinii infected animals, microfilariae counts and PCA titres were directly correlated. Homocytotropic IgG antibodies showed relatively constant PCA titres of about 1:20 in L. carinii infected Mastomys throughout the observation period. In D. viteae infections they were demonstrated at 30 days p.i., reaching titres of about 1:40. B. malayi infected animals showed a maximum titre of 1:40 40 days p.i.. Thereafter, titres decreased continuously and homocytotropic IgG antibodies were absent at 110 days p.i.. High titres were observed at day 150 but thereafter sera were negative. B. pahangi infected animals showed moderate titres (1:5) 35 days p.i.. Thereafter, antibodies were found at low titres until 115 days p.i.. Intradermal reactions in L. carinii infected animals generally increased in size from 30-60 but decreased when microfilariae appeared in the blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

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)

Animals↗