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PubMed1988

Characterization of a lipid-rich fraction synthesized by Streptomyces avermitilis.

Isolation of the macrocyclic lactone parasiticide avermectin and other closely related natural products produced by Streptomyces avermitilis also yields a lipid-rich fraction. The latter has been characterized by techniques based on gas-liquid chromatography (GLC) and mass spectrometry (MS). Initial examination of the lipid-rich fraction by direct probe electron-impact (EI) MS and packed-column GLC showed that it consists primarily of a mixture of triglycerides possessing C14-C17 acyl groups. Further examination of this fraction by capillary column GLC-MS demonstrated that it contains low levels of C15-C17 free fatty acids, squalene and diglycerides and, as the major components, at least ten mixed acyl triglycerides (total number of acyl carbon atoms ranging from 43 to 50). Prominent among the triglycerides were a C15-C15-C16 species, a C15-C16-C16 species and a C15-C16-C17 species. Capillary-column GLC and GLC-MS of the fatty acid methyl esters resulting from transesterification demonstrated that the major triglyceride acyl groups are anteiso-C15 (12-methyltetradecanoyl), iso-C16 (14-methylpentadecanoyl), n-C16 (hexa-decanoyl) and anteiso-C17 (14-methylhexadecanoyl). Lower levels of the methyl esters of the following fatty acids were observed: iso-C14 (12-methyltridecanoic), n-C14 (tetradecanoic), iso-C15 (13-methyltetradecanoic), n-C15 (pentadecanoic), iso-C17 (15-methylhexadecanoic) and n-C17 (heptadecanoic). Little evidence was seen for either unsaturated acyl groups or acyl groups of less than 13 or more than 18 carbon atoms. Desorption chemical ionization MS (ammonia reagent gas) analysis confirmed the nature of the lipid-rich fraction, and is an attractive one-step approach for determining the molecular weights and distribution of triglycerides in a mixture.

Chemical Phenomena↗
PubMedDate not supplied

Thalassaemia trait, red blood cell age and oxidant stress: effects on Plasmodium falciparum growth and sensitivity to artemisinin.

Knowledge of innate mechanisms of protection against malaria could be used to bolster the existing limited treatments. Oxidant stress may play a role in the protective mechanism and the effect of red blood cell (RBC) age has recently been recognized. This study investigated the role of oxidant stress in the protection against malaria in thalassaemic trait RBC (alpha and beta) using an experimental approach which controlled for cell age. 'Young', 'intermediate' and 'old' RBC obtained by Percoll fractionation and whole blood were used to set up malaria cultures. Antioxidants (vitamin E and dithiothreitol) and pro-oxidants (riboflavin, menadione and artemisinin) were added to modulate oxidant stress effect. Antioxidants improved parasite growth. The degree of improvement was significantly greater with increasing RBC age (P < 0.0001), and relatively greater in thalassaemic RBC (P < 0.0001). Pro-oxidants had a parasiticidal effect. With the exception of the 'old' RBC fraction, the median inhibitory concentration (IC50) for riboflavin and menadione was significantly higher in normal RBC. In contrast, the IC50 for artemisinin was significantly higher in 'old' thalassaemic RBC but was similar in the 'young' and 'intermediate' fractions and whole blood. These findings suggest that oxidant stress plays a role in mediating the protection against malaria in thalassaemic RBC. Vitamin E and other antioxidant supplementation could feasibly exacerbate clinical malaria. Conversely, pro-oxidant agents could act as useful adjuvants to therapy. It is important to confirm the reduced sensitivity to artemisinin in 'old' thalassaemic trait RBC, as such an effect may promote selective pressure for the emergence of resistant parasite strains with widespread use of artemisinin.

Age Factors↗
PubMed1999

A dichotomous role for nitric oxide in protection against blood stage malaria infection.

Nitric oxide (NO) is cytotoxic and cytostatic to blood stage malaria parasites in vitro, but the precise mechanism(s) by which it mediates an effect in vivo is not known. In particular, whether or not control of acute parasitemia depends on the presence of NO is unclear. We have shown previously that blocking NO synthesis at the time of its induction may cause an increase in peak primary parasitemia during infection of mice with Plasmodium chabaudi, suggesting that NO may be parasiticidal in vivo. However, as recent data indicate that NO suppresses Th1 cell proliferation in vitro by downregulating IL-2 production, we have investigated whether this immunoregulatory function of NO affects its capacity for anti-malarial activity. Treatment of P. chabaudi-infected mice with the iNOS inhibitor aminoguanidine hemisulfate (AG) starting just prior to the peak of primary parasitemia caused a significant elevation and extension of the acute infection and led to a partial but significant abrogation of the suppression of spleen cell proliferation to both mitogen and specific antigen observed when NO synthesis was not blocked. In the absence of NO, levels of IL-2, but not of IFN-gamma, TNF-alpha, or of any Th2-regulated cytokines examined, increased significantly. However, when AG treatment was brought forward to the early ascending phase of primary parasitemia, significantly increased levels of IFN-gamma and TNF-alpha, as well as of IL-2, were observed over those for infected control mice similarly treated with phosphate-buffered saline. Moreover, despite the absence of NO, parasitemias of AG-treated mice were not significantly elevated. The effect of AG therefore appeared to be dependent upon the timing of its administration in vivo. We propose that during malaria infections, there is a dynamic balance between the regulatory and anti-parasitic roles of NO. While the immunosuppressive function of NO leads to a downregulation in vivo of production of IL-2, and indirectly of IFN-gamma and TNF-alpha, this perceived weakening of the host cell-mediated immune response is in part masked by the protective anti-malarial effects of NO itself.

Animals↗
PubMed2001

Bacteria expressing single-chain immunotoxin inhibit malaria parasite development in mosquitoes.

Single-chain immunotoxins are ideal tools to selectively kill infectious agents. In applying this technology to block transmission of malaria parasites in the mosquito vector, we have constructed a single-chain immunotoxin composed of a single-chain antibody fragment (scFv) directed to Pbs2l on the surface of Plasmodium berghei ookinetes linked to a lytic peptide, Shiva-1. The single-chain immunotoxin was expressed in Escherichia coli, and the protein was purified by a Ni-NTA column. The single-chain immunotoxin was initially shown to exhibit greater killing properties for P. berghei ookinetes in vitro compared with the scFv or synthetic Shiva-1 peptide alone. In an attempt to block malaria transmission by genetically engineered bacteria, recombinant E. coli harboring the single-chain immunotoxin gene were introduced into the mosquito midgut by membrane feeding. The number of infected mosquitoes and their oocyst densities were significantly reduced when the mosquitoes were subsequently allowed to feed on P. berghei-infected mice. These results indicate not only that a single-chain immunotoxin with enhanced parasiticidal activity could form a basis for the development of more effective malaria therapeutic agents, but also that introduction of genetically engineered bacteria into anopheline mosquitoes may offer a practical approach to the regulation of malaria transmission.

Amino Acid Sequence↗
PubMed2002

Avian anticoccidial activity of a novel membrane-interactive peptide selected from phage display libraries.

In the present work, we describe the discovery of PW2, a novel peptide presenting in vitro activity against Eimeria acervulina and E. tenella sporozoites. PW2 was selected from phage display (Ph.D.) peptide libraries by an alternative method of panning using living purified E. acervulina sporozoites as targets. Our results showed that the peptide disrupts the sporozoite pellicle, resembling the effect caused by most natural antimicrobial peptides. PW2 peptide was also effective against fungi and showed low activity against Toxoplasma gondii tachyzoites, but no activity against Trypanosoma cruzi, Crithidia fasciculata epimastigotes, and bacteria. Additionally, the parasiticidal concentrations of PW2 produced a very low lytic effect on mammalian and avian cells. The effectiveness against Eimeria sporozoites and the absence of adverse effects to host cells indicates that PW2 may be used as a model to generate new drugs for the control of avian coccidiosis.

Amino Acid Sequence↗
PubMed1999

Effects of winter supplementation and antiparasite treatment on the productive performance of milk herd in the central-south region of Chile.

During the winter of 1994, a survey of productive and reproductive parameters was undertaken in the south-central part of Chile (8th Region) on 71 cows provided by four small farms with low production (< 3000 l/year). A low food intake was recorded (8.6 +/- 0.2-12.4 +/- 0.2 kg DM/day) and, as a result, the cows calved with poor body condition score (1.9 +/- 0.04 points on the scale of one-to-five, had milk production between 10.5 +/- 0.4 and 12.8 +/- 0.6 l/day, had a delayed start of ovulatory activity (78.2 +/- 4.6 days) and an interval between calving and conception of 120.3 +/- 4.6 days. In addition, low levels of packed cell volume (PCV) and hemoglobin (HEM) were found, which were considered to be a combined effect of low feed ingestion and parastic infection by Fasciola hepatica. To improve the productive and reproductive parameters, treatments were undertaken in three of the four small farms; a parasiticide treatment was used against the F. hepatica at the beginning of the winter and the availability of forage was increased via the use of supplementary green oats. Spring crops were also cultivated: corn for silage and oats with peas to make hay. The antiparasite treatment and supplementation of forage was associated with better body condition score at calving, improved hematological parameters, increased milk production (17%), reduced number of days to conception (120 vs. 91) and increased conception rate at first service (36 vs. 60%). In the fourth small farm where no interventions were undertaken, the parameters obtained during 1994 remained unchanged.

Animals↗
PubMed1998

[Heart pathology of extracardiac origin (V). Recent advances in chagasic cardiomyopathy].

INTRODUCTION AND OBJECTIVES: Chronic Chagas' heart disease is an important public health problem in Latin America. Rural migration from endemic to nonendemic countries has aroused widespread interest (United States, Spain) because of the possibility of observing affected patients. METHODS: Review of recent literature. RESULTS: The diagnosis of Chagas' cardiomyopathy is based on the triad of epidemiological history, positive serology and the clinical Chagas' syndrome. About 75% of asymptomatic seropositive subjects had no or almost no heart damage but the disease could be transmitted by blood donation. The other 25% may develop arrhythmias, heart failure and/or embolisms. Specific parasiticidal drugs are mainly used in the acute phase. CONCLUSIONS: In countries where Chagas' disease is infrequent, patients may be inadvertently diagnosed as having primary dilated or ischemic cardiomyopathy. Disease reactivation in immunodepressed patients due to AIDS, chemotherapy for cancer or for organ transplantation constitutes a formidable clinical challenge. Sanitary prophylactic measures are the strategies of choice.

Acute Disease↗
PubMed2000

Epidemiology of ovine oestrosis (OEstrus ovis Linné 1761, Diptera: Oestridae) in Sicily.

A survey for oestrosis was carried out in the slaughterhouse at Messine (Sicily) from May 1996 to April 1998. The heads of sheep from local flocks were collected each month. A total of 841 heads were examined according to a validated procedure. 469 (55.8%) were infested by OEstrus ovis larvae. 4423 larvae were harvested: 1829 first instar larvae or L1 (41.4%), 1286 second instar larvae or L2 (29.1%) and 1308 third instar larvae or L3 (29.6%). The mean larval burden for infected sheep was 9.4 larvae with an average of 3.9 L1, 2.7 L2 and 2.8 L3. No period of hypobiosis was recorded. The proportions of larvae in each of the different larval stages was similar from January to September, however, from October to December the percentage of L1 was higher, indicating a period of slowed development. In order to lower the overall prevalence of this disease, it would be necessary to use a parasiticide effective against O. ovis, for all routine parasite control treatments.

Animals↗
PubMed2003

Amphidial structure of ivermectin-resistant and susceptible laboratory and field strains of Haemonchus contortus.

The development of anthelmintic resistance by nematode parasites is a growing problem for veterinarians, pet owners, and producers. The intensive use of the macrocyclic lactones for the treatment of a variety of parasitic diseases has hastened the development of resistance to this family of parasiticides. As a result, resistance to ivermectin, moxidectin, nemadectin, and doramectin by Haemonchus contortus has been documented throughout the world. Sensory neurons located in the cephalic end of nematodes are in close contact with the external environment. Through these neurons, important chemical and thermal cues are gathered by the parasite. Examination of serial electron micrographs of ivermectin-susceptible and ivermectin-resistant H. contortus allows for comparison of neuronal structure, arrangement of neurons within the amphidial channel, and distance of the tip of the dendritic processes to the amphidial pore. The latter of these characteristics provides a useful means by which to compare the association between the neurons and the external environment of the worm. Comparison of parental laboratory strains of ivermectin-susceptible strains of H. contortus with related selected, ivermectin-resistant strains and with a wild-type ivermectin-susceptible field strain of H. contortus from Louisiana reveal that the ivermectin-resistant worms examined have markedly shorter sensory cilia than their ivermectin-susceptible parental counterparts. Additionally, the amphidial neurons of ivermectin-resistant worms are characterized by generalized degeneration and loss of detail, whereas other neurons outside of the channels, such as the labial and cephalic neurons, are normal in structure. These findings raise a number of questions regarding the relationship between amphidial structure and ivermectin resistance as well as the role of amphids as a means of entry for ivermectin. While shortened amphidial sensilla are associated with ivermectin resistance, it remains unclear if such a structural modification facilitates survival of nematodes exposed to macrocyclic lactones.

Animals↗
PubMed1999

Historical perspective of cyathostomes: prevalence, treatment and control programs.

Small strongyles are highly prevalent in horses and can be found worldwide. Even though over 50 species of these parasites have been described, about 10 species comprise the bulk of the total number present in horses. Efforts to control small strongyles and other equine internal parasites have been undertaken for many years. Some of the early medications and control measures provided questionable activity against endoparasites; whether effective or not, they could be detrimental to the horse. Beginning in the early 1900s, scientific effort was used to evaluate activity of antiparasitic compounds. Only a relatively low number of classes of compounds has been used for parasite control. Progressively, in time, newer drugs have become broad-spectrum, safer, and available in lower dose rates than previously. With extensive use of parasiticides, small strongyles have been found to be resistant to all commercially-available classes of compounds except the macrocyclic lactones. Innovative parasite-control programs, relying less on drugs, need to be developed.

Animals↗
PubMed1999

Utility of adult antigens of Dirofilaria immitis for the early detection of dirofilariosis and for the evaluation of chemoprophylactic treatment in experimentally infected cats.

Early detection of feline dirofilariosis was achieved by ELISA testing using adult somatic (SA) and excretory/secretory (E/S) antigens. Sera from experimentally infected cats showed significantly higher IgG levels at 2 months post-infection (p.i.) when compared to sera obtained prior to infection. This difference was apparent at all serum dilutions (1:100 to 1:800) in ELISA(SA) and at all dilutions except 1:800 when tested with ELISA(E/S). Changes in specific anti-SA and anti-E/S IgG levels were found in infected cats treated with the macrolid parasiticide. ELISA(E/S) was able to detect a significant decrease in IgG levels in ivermectin treated cats at 3 months post-treatment (p.t.), compared to infected, untreated controls. However, testing with ELISA(SA) showed a significant decrease in antibody levels in treated cats only at 4 months after treatment. Sera from untreated cats recognized previously identified specific markers for feline dirofilariosis on SA (22, 26, 30 and 40 kDa) and on E/S (22 and 25 kDa) in Western blot analysis. Sera from treated cats, on the other hand, gave only weak bands or none at all, indicating a decrease in antibody concentration. These results suggest that serologic testing with ELISA is useful in the early detection of Dirofilaria immitis infection and, together with Western blot analysis, can assist in the evaluation of response to chemoprophylactic treatment of feline dirofilariosis, two aspects of prime importance in the prevention of this disease in cats.

Animals↗
PubMed2002

DNA single strand breaks in peripheral blood lymphocytes induced by three nitroimidazole derivatives.

Tinidazole (TNZ), ornidazole (ONZ) and metronidazole (MTZ) are antiparasitic drugs (nitroimidazole derivatives) that have proven to be effective against Trichomonas vaginalis, Entoamoeba histolytica, Giardia lamblia and Helicobacter pylori. The reduction of the nitro group and the generation of short-lived reactive intermediates are the basis of its parasiticidal activity. This reduction is associated with its mutagenic activity in bacteria, although in mammalian cells DNA damage seems to be related to the production of reactive oxygen species (ROS). Using alkaline single cell electrophoresis, a significant increase in single strand breaks and alkali labile sites in human peripheral blood lymphocytes (PBL) exposed to MTZ, ONZ and TNZ at 10, 100 and 500 microg/ml is observed. MTZ causes less damage, especially at higher concentrations, when compared with TNZ, the most harmful of the drugs tested. These findings suggest that primary damage is induced under aerobic conditions and confirms that these nitroimidazoles are DNA damaging agents.

Adult↗
PubMed1998

Regulation of protective immunity against Leishmania major in mice.

Resolution of lesions induced by Leishmania major in mice results from the development of Th1 responses. Cytokines produced by Th1 cells activate macrophages to a parasiticidal state. The development of Th2 responses in mice from a few strains underlies susceptibility to infection. Cytokines produced by Th2 cells exacerbate the development of lesions because of their deactivating properties for macrophages. This murine model of infection has provided significant insight into the mechanisms intrinsic to the differentiation of disparate CD4+ T cell subsets in vivo in animals from different genetic backgrounds.

Animals↗
PubMed1999

Apicomplexan plastids as drug targets.

Prokaryotic metabolic pathways in the relict plastid of apicomplexan parasites make this organelle a promising target for drug development. The parasiticidal activity of several herbicides and antibacterial antibiotics is suspected to be a result of their ability to inhibit key plastid activities.

Animals↗
PubMed2000

A formulary for lizards, snakes, and crocodilians.

A formulary of drug dosages for use in lizards, snakes, and crocodilians based primarily on a survey of the existing literature is provided. The formulary is presented as a series of four tables: antimicrobial drugs; parasiticide drugs; anesthetic and analgesic drugs; and miscellaneous drugs. An extensive bibliography is included.

Alligators and Crocodiles↗
PubMed1997

Genotoxic activity of praziquantel.

Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of endpoints including tests in bacteria, yeasts, mammalian cells and Drosophila and each one gave negative results. Effects on reproductive cells of mice were negative as well. However, host mediated studies in mice and humans were contradictory and a comutagenic effect with several mutagens and carcinogens was found. Later studies, including monitoring in humans and pigs have shown that Praziquantel induces a greater frequency of hyperploid lymphocytes as well as structural chromosomal aberrations, but not in all the individuals treated. In vitro studies have demonstrated that Praziquantel can induce micronuclei in syrian hamster embryonic (SHE) cells and in lymphocytes of some individuals. The same was found about structural chromosomal aberrations. Fetal death and fetal resorption were found when Praziquantel was administered in high doses to pregnant rats between the 6th and 10th day of gestation. Due to its efficiency as a parasiticide, Praziquantel is in use in Latin-American, Asiatic, African and East-European countries where infections by trematodes and cestodes are frequent. However, the extensive use of Praziquantel in multiple reinfections, in non-infected and non-diagnosed individuals for prevention, in higher doses or repeated doses for cysticercosis treatment and in individuals exposed to environmental mutagens, in conjunction with new findings about its metabolism and genotoxic properties, make it necessary to further evaluate the potential of this drug not only to be mutagenic per se, but to contribute in the development of neoplasm.

Animals↗
PubMed2002

How might qinghaosu (artemisinin) and related compounds kill the intraerythrocytic malaria parasite? A chemist's view.

The antimalarial mechanism of qinghaosu (artemisinin) has been a problem since the late 1970s. During the past decade, several molecular level theories were postulated. However, their further development has been very difficult. By looking into the QHS cleavage process and all possible reaction paths available to the resulting transient radicals, the present commentary reveals those major hidden problems with the existing theories and tries to identify some essential features of the parasiticidal events that may take place within the intraerythrocytic malaria parasite. A seemingly more reasonable theory is also introduced.

Antimalarials↗
PubMed2000

Methyl-substituted dispiro-1,2,4,5-tetraoxanes: correlations of structural studies with antimalarial activity.

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethyl-substituted dispiro-1, 2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results.

Alkanes↗