RESUMO
Immune responses are orchestrated by CD4 T lymphocytes, which receive a cognitive signal when clonally distributed receptors are occupied by major histocompatibility complex (MHC) class II-bound peptides on antigen-presenting cells (APCs). The APCs provide costimulatory signals, through macromolecules such as CD80, that regulate outcomes in terms of T-cell activation or anergy. We have studied essential complementary chemical events in the form of Schiff base formation between carbonyls and amines that are constitutively expressed on presenting cell and T-cell surfaces and provide a new target for manipulation of immune responses. Here we show that small Schiff base-forming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a mechanism that activates clofilium-sensitive K+ and Na+ transport. One such molecule, tucaresol, enhances CD4 Th-cell responses, selectively favouring a Th1-type profile of cytokine production. In vivo tucaresol potently enhances CD4 Th-cell priming and CD8 cytotoxic T-cell priming to viral antigens, and has substantial therapeutic activity in murine models of disease.
Assuntos
Adjuvantes Imunológicos/farmacologia , Benzaldeídos/farmacologia , Benzoatos/farmacologia , Bases de Schiff/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Aminas/imunologia , Animais , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/biossíntese , Microanálise por Sonda Eletrônica , Humanos , Camundongos , Potássio/metabolismo , Sódio/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologiaRESUMO
A subclone of the human colon adenocarcinoma cell line DLD-1, which grew reproducibly as subcutaneous tumors in nude mice, was isolated. Such cells, when engineered to generate nitric oxide (NO) continuously, grew more slowly in vitro than the wild-type parental cells. This growth retardation was reversed by the addition of N-iminoethyl-L-ornithine. In nude mice, however, the tumors from these cells grew faster than those derived from wild-type cells and were markedly more vascularized, suggesting that NO may act as part of a signaling cascade for neovascularization. Recent observations that the generation of NO in human breast and gynecological cancers correlates positively with tumor grade are consistent with this hypothesis. We suggest that NO may have a dual pro- and antitumor action, depending on the local concentration of the molecule.
Assuntos
Adenocarcinoma/patologia , Aminoácido Oxirredutases/metabolismo , Neoplasias do Colo/patologia , Óxido Nítrico/fisiologia , Aminoácido Oxirredutases/biossíntese , Animais , Sequência de Bases , Divisão Celular , Linhagem Celular , Primers do DNA , DNA Complementar , Expressão Gênica , Humanos , Cinética , Macrófagos , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Óxido Nítrico Sintase , Sondas de Oligonucleotídeos , Reação em Cadeia da Polimerase , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Fatores de Tempo , Transfecção , Células Tumorais CultivadasRESUMO
A panel of human colonic adenocarcinoma cell lines was examined both for expression of mRNAs of the nitric oxide synthase (NOS) gene family and for evidence of enzymic activity based on citrulline and nitrite (NO2-) formation. Reverse transcription-polymerase chain reaction (RT-PCR), revealed that all lines (SW480, SW620, DLD-1 and WiDr) expressed mRNA for the Ca(2+)-dependent endothelial (e)NOS, while SW480 cells also expressed the Ca(2+)-dependent neuronal (n)NOS. The mRNA for the Ca(2+)-independent inducible (i)NOS was expressed both by cytokine-stimulated and by unstimulated SW480, SW620 and DLD-1 cells, but none was seen at any time in the WiDr cells. There was, however, little correlation between mRNA expression and enzymic activity based on citrulline and NO2- formation. Thus none of the cell lines exhibited measurable Ca(2+)-dependent NOS activity, while Ca(2+)-independent NOS activity was seen in all but the WiDr cells. Furthermore, DLD-1 cells generated citrulline with resultant NO2- formation only after stimulation with lipopolysaccharide (LPS) and/or cytokines, while SW480 and SW620 did so constitutively. Thus RT-PCR studies indicate that tumour cells of similar epithelial origin display a diverse pattern of NOS gene family expression, and parallel biochemical studies clearly indicate that such expression does not always result in measurable enzymic activity leading to the generation of NO.
Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Óxido Nítrico/biossíntese , Arginina/farmacocinética , Sequência de Bases , Citrulina/farmacocinética , Neoplasias do Colo/metabolismo , Expressão Gênica , Humanos , Lipopolissacarídeos/farmacologia , Dados de Sequência Molecular , Óxido Nítrico Sintase , RNA Mensageiro/genética , Células Tumorais CultivadasRESUMO
Two carbon-bridged analogues 11 and 15 of the potent microtubule inhibitor BW1069C85 (1) have been synthesised and evaluated for antitubulin and antitumour activity in vitro. Though the compounds were somewhat less potent than BW1069C85, significant activity against tubulin polymerisation and cell proliferation was demonstrated in the assays.
Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Carbamatos/farmacologia , Imidazóis/síntese química , Piridazinas/síntese química , Piridazinas/farmacologia , Animais , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Cavalos , Imidazóis/farmacologia , Leucemia P388/patologia , Camundongos , Tubulina (Proteína)/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
In order to identify drugs active against mutated ras oncogenes we have developed an in vitro assay employing two clones of the human fibrosarcoma cell-line, HT1080 which carries an N-ras gene mutated at codon 61. Clone, HT1080scc2, retains the transformed phenotype of the parental line, whilst the other, HT1081c, is a morphologically flat, non-tumourigenic, revertant with under-representation of the chromosome carrying the transforming N-ras allele. The clear implication of mutant ras in maintaining the transformed nature of HT1080scc2 was confirmed when these cells were microinjected with the pan ras neutralising antibody Y13-259, which resulted in the morphological detransformation of these cells to a phenotype resembling that of the HT10801c clone. A number of known anti-cancer drugs with modes of action unrelated to ras function were found to be equipotent against both clones. However, when compounds chosen on the grounds of their potential selective cytotoxic or differentiating activity were tested some interesting results were obtained. Thus 8-bromo cAMP affected some morphological detransformation of HT1080scc2 cells and reduced their colony forming potential. The IMP-dehydrogenase inhibitors, tiazafurin and mycophenolic acid also flattened the morphology of the transformed clone. Fumagillin, an antibiotic reported to exhibit selective activity against ras transformed cells showed very marked and selective cytostatic effects against HT1080scc2 cells with IC50 values as low as 1 x 10(-11) M.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Genes ras/efeitos dos fármacos , Anticorpos Monoclonais , Divisão Celular/efeitos dos fármacos , Cicloexanos , Ácidos Graxos Insaturados/farmacologia , Fibrossarcoma/patologia , Humanos , Sesquiterpenos , Células Tumorais CultivadasRESUMO
Previous reports have indicated that reconstituted basement membrane (matrigel), when co-injected with either established or primary human tumour cells, can improve the growth of subcutaneous xenografts in nude mice. The human adenocarcinoma cell lines A549, SW480, and WiDr, and the human fibrosarcoma cell line HT1080scc2 exhibit varying degrees of tumourigenicity in nude mice. All these lines showed increased tumorigenicity and/or growth rate, together with a change towards a more differentiated tissue morphology, when co-injected with matrigel into nude mice. Experiments using A549 cell line have indicated that the effect of matrigel is concentration-dependent and that increased growth rate is not maintained when xenografts grown with matrigel are passaged into further mice. These results strongly suggest that increased tumour growth results from the improved growth conditions afforded by matrigel, rather than from the selection of subpopulations of the most tumourigenic cells. Increased growth of intracaecal tumours arising from the co-injection of SW480 cells with matrigel, indicate a possible use for matrigel in the development of more relevant animal models using the orthotopic site. Purified laminin significantly increased the growth of sc tumours resultant from co-injection with either WiDr or A549 cells, whereas collagen IV or laminin with entactin showed no such effect. A role for free laminin in the stimulation of cell growth in the absence of an intact basement membrane is discussed.
Assuntos
Neoplasias Experimentais/patologia , Células Tumorais Cultivadas/patologia , Animais , Membrana Basal/fisiologia , Divisão Celular , Colágeno/farmacologia , Combinação de Medicamentos , Humanos , Técnicas In Vitro , Laminina/farmacologia , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteoglicanas/farmacologiaRESUMO
The existence and role of an L-arginine:nitric oxide (NO) pathway in two human colorectal adenocarcinoma cell lines, SW-480 and SW-620, were investigated. Both cell lines, which derive from the same patient, SW-480 from the primary tumor and SW-620 from its metastatic lesion, were shown to have a cytosolic, Ca(2+)-independent, NADPH-dependent NO synthase, the activity of which was lower in the cytosol of SW-620. These cells were more potent inducers of platelet aggregation. In contrast, SW-480, which had more NO synthase activity, were less potent inducers of platelet aggregation. Pretreatment of both cell lines with NG-monomethyl-L-arginine, an inhibitor of NO synthase, potentiated their proaggregating effect and made them equally active. Exogenous L-arginine, NO, and related nitrovasodilators all inhibited platelet aggregation induced by SW-620. The antiaggregating activity of NO was further potentiated by prostacyclin and by M&B22948, a selective inhibitor of cyclic GMP phosphodiesterase. We propose that the generation of NO by tumor cells inversely correlates with their metastatic potential. Furthermore, we show that the lower activity of NO synthase in metastatic cells is due to the presence in these cells of a low molecular weight inhibitor of the NO synthase. In addition, agents which modulate platelet function by a cyclic GMP-dependent mechanism may be useful in the prevention of tumor metastasis.
Assuntos
Adenocarcinoma/sangue , Neoplasias Colorretais/sangue , Óxido Nítrico/metabolismo , Agregação Plaquetária , Adenocarcinoma/patologia , Aminoácido Oxirredutases/metabolismo , Arginina/análogos & derivados , Arginina/farmacologia , Neoplasias Colorretais/patologia , Epoprostenol/farmacologia , Humanos , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase , Agregação Plaquetária/efeitos dos fármacos , Purinonas/farmacologia , Células Tumorais Cultivadas , Vasodilatadores/farmacologia , ômega-N-MetilargininaAssuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Serotonina/farmacologia , Adenocarcinoma/irrigação sanguínea , Animais , Neoplasias do Colo/irrigação sanguínea , Dimetilidrazinas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/induzido quimicamente , Serotonina/uso terapêutico , Transplante HeterólogoRESUMO
The primary objective of the Wellcome Foundation/World Health Organisation Onchocerciasis Chemotherapy Project, which began in July 1982, was the discovery and development of a safe and effective macrofilaricide for the treatment of onchocerciasis in man. A multidisciplinary Team of biologists, biochemists and medicinal chemists was assembled. They investigated a variety of potential targets in filariae and carried out in-depth lead optimisation studies on a number of different chemical series. A valuable contribution was made to our understanding of filarial biology and biochemistry and the susceptibility of filariae to various metabolic inhibitors. However, the ultimate goal of identification of a compound worthy of evaluation in man was not achieved and the programme was closed at the end of June 1989. Factors that contributed to this situation and some overall conclusions are discussed.
Assuntos
Anti-Helmínticos , Filaricidas , Oncocercose/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Filarioidea/efeitos dos fármacos , Humanos , Onchocerca/efeitos dos fármacos , Tecnologia Farmacêutica , Organização Mundial da SaúdeRESUMO
A 28-year-old woman developed complex partial seizures at the age of 17 years and was treated with phenytoin sodium. Five years later she developed myasthenia gravis, and phenytoin was replaced by valproic acid and phenobarbital. She required plasmapheresis (PP). During one course of PP, total and unbound concentrations of valproic acid and phenobarbital were measured in serum sampled before, during, and after PP and in plasma removed by PP. It was determined that the magnitude of loss of valproic acid or phenobarbital by PP was small, and the changes of unbound/total ratio did not reach clinical importance.
Assuntos
Anticonvulsivantes/sangue , Epilepsia do Lobo Temporal/terapia , Miastenia Gravis/terapia , Plasmaferese/métodos , Adulto , Anticonvulsivantes/administração & dosagem , Terapia Combinada , Quimioterapia Combinada , Epilepsia do Lobo Temporal/sangue , Feminino , Fluorimunoensaio , Humanos , Miastenia Gravis/sangue , Fenobarbital/administração & dosagem , Fenobarbital/sangue , Ligação Proteica/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Ácido Valproico/sangueRESUMO
A simple three-step colorimetric assay based on the tetrazolium salt MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) has been developed for quantifying filarial viability. Living (but not dead) filariae take up MTT and rapidly reduce it to formazan, so staining themselves dark blue. This colour change which is easily seen provides a rapid qualitative test for filarial viability. Quantitative data can be obtained by solubilizing formazan out of the worm with DMSO and measuring the absorbance of the resulting solution at 510 nm. To date the technique has been demonstrated in several species of filariae including Onchocerca volvulus. MTT reduction is thought to be selective for NADH-dependent dehydrogenase activity in viable worms. The reaction occurs readily in all developmental stages of Dipetalonema viteae including fragments of filarial tissue. Enzyme activity in viable intact D. viteae appears to be primarily associated with the hypodermis/muscle cells, with minimal formazan formation in the gut and reproductive tracts. The application of this MTT assay as a parameter for quantifying in vitro drugs effects is described. Assay procedures have been developed and optimized with D. viteae and Brugia pahangi for the assessment of effects of macrofilariae and microfilarial release, and the activity of a range of antifilarial standards reported. Several potential applications of the technique to studies on filarial biology are discussed.
Assuntos
Brugia/crescimento & desenvolvimento , Dipetalonema/crescimento & desenvolvimento , Animais , Colorimetria , Feminino , Microfilárias/crescimento & desenvolvimentoRESUMO
The cidal properties of some phenolic, halogenated diphenyl, salicylanilide, benzimidazole and diaminophenoxyalkane anthelmintics, against 6-week-old worms of Fasciola hepatica were assessed in vitro. In a conventional fluke culture medium containing RPMI 1640, supplemented with serum with or without rabbit erythrocytes or pink-ghosts, only the halogenated diphenyl and salicylanilide compounds showed activity at concentrations equal to or less than 100 microM. However, when basal, serum and cell-free RPMI 1640 was used, all compounds other than diamphenethide were highly active, their minimum lethal concentrations being some 25-125 times lower under these conditions. The inclusion of rabbit liver microsomes in the basal culture medium resulted in diamphenethide exhibiting cidal activity equivalent to that seen when its free-amine active metabolite was assayed. The possibility that the activity of many of these compounds was masked in vitro because of their serum binding properties is discussed. Recommendations are made that in vitro screens for new fasciolicides should be carried out in serum-free medium and that additional replicates containing mammalian liver microsomes and liver cytosolic extracts be included as means for the metabolic activation of certain otherwise undetectable prodrugs.
Assuntos
Anti-Helmínticos/farmacologia , Fasciola hepatica/efeitos dos fármacos , Animais , Benzimidazóis/farmacologia , Biotransformação , Bitionol/farmacologia , Sangue , Meios de Cultura , Diamfenetida/metabolismo , Diamfenetida/farmacologia , Hexaclorofeno/farmacologia , Microssomos Hepáticos , Nitroxinila/farmacologia , Pró-Fármacos , Salicilamidas/farmacologiaRESUMO
An in vitro anthelmintic primary screen in which the effects of compounds on the aggregation response of newly moulted adult worms of Trichostrongylus colubriformis was monitored is described. Representatives of all the major classes of the anti-trichostrongyle anthelmintics all inhibited worm aggregation completely when present in the culture medium either at or at less than micromolar concentrations. The screen proved highly selective for these broad-spectrum agents, much higher concentrations of the narrower spectrum anthelmintics, active only against blood-sucking nematodes, trematodes and/or cestodes, having little or no effect on this response. This in vitro assay, based solely on the occurrence or absence of worm aggregation following the final moult in culture, proved very easy to interpret rapidly and accurately. It can be recommended therefore for the primary mass screening of synthetic compounds or natural products for intrinsic activity against the trichostrongylid helminths of ruminants.
Assuntos
Anti-Helmínticos/farmacologia , Trichostrongylus/efeitos dos fármacos , Animais , Meios de Cultura , Larva/efeitos dos fármacos , Larva/fisiologia , Coelhos , Trichostrongylus/fisiologiaRESUMO
Interpretation of anthelmintic activity using in vitro screens has, until now, relied on the detection of drug-induced effects on nematode development, viability and motility. A novel biochemical parameter dependent upon the spectrophotometric assay of acetylcholinesterase (AChE), an enzyme secreted in large quantities by certain trichostrongylid nematodes, has been developed to replace these often subjective indices of activity. Using Nippostrongylus brasiliensis, a worm frequently employed for primary screening, the secretion of this enzyme in the presence or absence of a large number of drugs in vitro was determined. During a 4-day incubation period in a complex undefined medium without serum. AChE was secreted by normal 4th larval and immature adult stages of the worm in a linear fashion. All modern broad-spectrum veterinary anthelmintics, regardless of their mode of action, dramatically reduced the amount of enzyme secreted. Correlation between the biochemical and observational parameters was excellent and the selectivity of the assay when based solely on enzyme secretion was not lost. Other advantages were that the time required for the activity of certain slow-acting compounds to be detected was reduced from 7 to 4 days and that close microscopical examination of the worms was not necessary.
Assuntos
Acetilcolinesterase/metabolismo , Anti-Helmínticos/farmacologia , Nippostrongylus/enzimologia , Animais , Avaliação Pré-Clínica de Medicamentos , Nippostrongylus/efeitos dos fármacosRESUMO
Approximately 50 per cent of fourth stage larvae of Trichostrongylus colubriformis taken from the gerbil, Meriones unguiculatus, on day 8 after infection, moulted to the young adult stage when cultured in a complex medium over a seven day period in vitro. Larvae at the late fourth stage of development were highly susceptible to certain benzimidazole, prebenzimidazole, imidazothiazole, pyrimidine, quaternary ammonium, organophosphorus and macrocyclic lactone anthelmintics when any of these were included at very low concentrations in the culture medium. However, few anthelmintics lacking activity against T colubriformis in vivo affected these larvae. An assay employing these larvae in vitro should offer a means for assessing the intrinsic activity of new compounds against T colubriformis in the absence of any complicating host pharmacokinetic factors, and could also be adapted for use as a high capacity preliminary screen. Thus it should now be possible to employ a target parasite at the earliest stages of a lead discovery programme obviating the need to use less relevant free-living nematodes or ones that are natural parasites of rodents.
Assuntos
Anti-Helmínticos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Gerbillinae/parasitologia , Trichostrongyloidea/crescimento & desenvolvimento , Animais , Meios de Cultura , Larva , Trichostrongyloidea/efeitos dos fármacosRESUMO
Hepatitis B vaccination has been recommended for health care personnel having frequent contact with blood. Serologic markers of hepatitis B infection were studied in employees of this regional blood center to determine the prevalence of infection in our population.
Assuntos
Bancos de Sangue , Hepatite B/imunologia , Vacinas contra Hepatite Viral/administração & dosagem , Transfusão de Sangue , Estudos de Avaliação como Assunto , Hepatite B/epidemiologia , Humanos , Risco , Recursos HumanosRESUMO
The response of the free-living stages of Nippostrongylus brasiliensis, Nematospiroides dubius, Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia ostertagi to a wide variety of antiparasitic agents in vitro was investigated. All the major broad spectrum veterinary anthelmintics showed good activity against each of these worms with EC50 values varying from about 0.0002 mg/l for certain benzimidazoles and ivermectin to about 6.5 mg/l for febantel. Of 22 known narrow spectrum anthelmintics useful only against H. contortus and/or helminths other than trichostrongyles, only 10% showed good activity at concentrations equal to or less than 10.0 mg/l. Further, only one of 15 antiprotozoal agents showed good activity in these tests at the 10.0 mg/l level. The screening test employing free-living Nippostrongylus brasiliensis was selected for an extended trial where the evaluation of 1400 miscellaneous organic chemicals was undertaken. Approximately 10% of these showed activity at concentrations equal to or less than 10.0 mg/l. It is concluded that in vitro screening tests employing the free-living stages of these five genera of nematodes afford simple yet effective means for selecting relevant compounds for further evaluation as possible leads to new broad spectrum anthelmintics for use in ruminants. However, tests using the free-living stages of these worms, including H. contortus, are unsuitable for detecting narrow spectrum 'specifics', e.g., for the treatment of haemonchiasis.
Assuntos
Anti-Helmínticos/farmacologia , Antiprotozoários/farmacologia , Trichostrongyloidea/efeitos dos fármacos , Animais , Resistência a Medicamentos , Haemonchus/efeitos dos fármacos , Haemonchus/fisiologia , Nippostrongylus/efeitos dos fármacos , Nippostrongylus/fisiologia , Ostertagíase/parasitologia , Trichostrongyloidea/fisiologia , Tricostrongilose/parasitologiaRESUMO
The effects of mitochondrial inhibitors on the in vitro development of Nippostrongylus brasiliensis have been studied in free-living and parasitic life-cycle stages. Mitochondrial inhibitors were chosen as being representative of established electron transport inhibitors and oxidative phosphorylation inhibitors and uncouplers of the classical mammalian respiratory chain. All mitochondrial inhibitors tested were highly effective in killing or retarding development of free-living stages of N. brasiliensis. Free-living stages were particularly susceptible to such inhibitors upon hatching of embryonated eggs to 1st-stage larvae. Concentrations of inhibitors effective against free-living stages were consistent with their level of inhibition against isolated mitochondria from embryonated eggs and 3rd-stage infective larvae. Results suggest an absolute requirement in the development of free-living stages for the mammalian-like respiratory chain and associated oxidative phosphorylation. Electron transport inhibitors were effective in retarding at least the initial development of 4th-stage larvae to adults, but only antimycin A and azide produced a lasting effect leading to worm death. Oxidative phosphorylation inhibitors and uncouplers were ineffective against developing parasitic stages of N. brasiliensis. Experiments on whole-worm respiration indicated that most electron transport inhibitors were able to penetrate the adult worm, but oxidative phosphorylation inhibitors were without effect on whole-worm respiration. Results suggest that the mammalian-like electron transport chain is a necessary requirement to adult N. brasiliensis, but oxidative phosphorylation in the adult worm may not be required for development and survival in vitro although it could be necessary to support the parasite in vivo.
Assuntos
Nippostrongylus/efeitos dos fármacos , 2,4-Dinitrofenol , Animais , Antimicina A/farmacologia , Azidas/farmacologia , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Dicicloexilcarbodi-Imida/farmacologia , Dinitrofenóis/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nippostrongylus/crescimento & desenvolvimento , Oligomicinas/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Cianeto de Potássio/farmacologia , Ratos , Rotenona/farmacologia , Azida Sódica , Frações Subcelulares , Tenoiltrifluoracetona/farmacologiaRESUMO
Aerobic respiratory pathways have been compared in adult parasitic nematodes, including Trichostrongylus colubriformis, Nippostrongylus brasiliensis, Ostertagia ostertagi, Cooperia oncophora, Haemonchus contortus, Oesophagostomum venulosum, Chabertia ovina, Dictyocaulus filaria, Dictyocaulus viviparus, and Ascaridia galli. Respiration was measured in both whole worm or tissue homogenates and isolated mitochondrial fractions, and delineated into the mammalian type or alternative respiratory pathways on the basis of their inhibition by antimycin A. The alternative, antimycin A-insensitive respiratory pathway was of comparable activity in all parasitic nematodes studied, irrespective of the body diameter or habitat of the worm. The mammalian-type, antimycin A-sensitive respiratory pathway showed variations; the extent of this pathway correlated with both the body diameter and habitat of the worm, being greater in thinner worms and those worms whose habitat is supposedly more aerobic.