Biomedical subjects
Publications and source records attributed to R J Martin.
The anthelmintic drug praziquantel has proved useful in the treatment of schistosomiasis. The precise mechanism by which praziquantel kills the parasites has yet to be elucidated. Here, John Kusel and colleagues review the current theories on praziquantel action and suggest future avenues for research, which becomes urgent in the light of some reports of drug resistance.
BACKGROUND: The decrement in lung function associated with the late asthmatic response after allergen challenge is believed to be mediated by an inflammatory response in the airways. Theophylline has been shown to inhibit the late asthmatic response, but the mechanisms are not clear. OBJECTIVE: The study was designed to determine whether theophylline would inhibit the late asthmatic response by reducing neutrophil activation and subsequent superoxide production. METHODS: Twelve subjects with asthma underwent treatment in this double-blind, randomized, crossover study. Each subject received theophylline and placebo in random order in two treatment periods of 3 weeks each. Each treatment period was followed by an allergen challenge and blood neutrophil function analysis. RESULTS: At therapeutic levels theophylline increased FEV1 at baseline and during the allergen challenge and increased the percentage suppression of neutrophil superoxide production by adenosine. CONCLUSION: Theophylline improved pulmonary function at baseline and during an allergen challenge, in part perhaps, by increasing the neutrophil's response to feedback inhibition by adenosine. However, theophylline did not decrease the severity and duration of the late asthmatic response.
BACKGROUND: Recent information suggests that one of the therapeutic properties of theophylline is an antiinflammatory effect. OBJECTIVE: We evaluated this potential effect of theophylline in eight patients with nocturnal asthma. METHODS: The study design was a randomized, double-blind, placebo-controlled crossover of 2-week treatment periods, separated by a 1-week washout period. Spirometry and bronchoscopy were performed. RESULTS: Theophylline, compared with placebo, significantly improved the overnight decrement in lung function. The higher the nocturnal theophylline level, the greater the improvement in lung function. Theophylline also significantly decreased the percentage of neutrophils in the 4:00 AM bronchoalveolar lavage fluid and stimulated leukotriene B4 levels from macrophages obtained at 4:00 AM. The greater change in neutrophils correlated with increasing serum theophylline concentration. Also, the change in leukotriene B4 production was significantly correlated with the theophylline-induced decrement in lavage granulocytes (neutrophils and eosinophils). CONCLUSION: This study suggests that one action of theophylline is to alter inflammatory cell number and function in nocturnal asthma and that it may do this through an leukotriene B4-mediated mechanism.
Plasma membrane vesicles prepared from the bag region of the somatic muscle cells of the parasitic nematode Ascaris suum contain high conductance, voltage sensitive, Ca-dependent chloride channels, suggested to be involved in the excretion of carboxylic acids produced by the anaerobic respiration of glucose (Valkanov, Martin & Dixon, 1994). The effect of altered pH on this channel was investigated using the patch-clamp technique and isolated inside-out membrane patches. Changes in pH had little effect on channel conductances and only a small effect on reversal potentials. Under control conditions (symmetrical pH 7.2) the channel had the highest probability of opening at approximately -35 mV (the resting membrane potential of the cell). At positive membrane potentials the probability of opening decreased. The Boltzmann equation was used to describe the relationship between membrane potential and probability of channel opening, and to calculate the effective gating charge. Reduction of external pH produced an increase in the probability of channel opening at hyperpolarized membrane potentials. An increase in internal pH caused a voltage-independent increase in the probability of channel opening and made the effective gating charge less negative. The effect of reducing internal pH was marked: the channel then opened most frequently at positive membrane potentials and the probability of opening at -35 mV was greatly reduced. The decrease in internal pH changed the polarity of the effective gating charge. A simple model was constructed to describe the effects of pH on channel gating.
Three groups of anthelmintic drugs act directly and selectively on muscle membrane receptors of parasitic nematodes. These groups of anthelmintics are: (1) The Nicotinic Agonists (levamisole, pyrantel, morantel and oxantel) that act on acetylcholine receptors of nematode somatic muscle; (2) The GABA Agonist, piperazine, that acts on nematode muscle GABA receptors; and (3) The Avermectins that open glutamate gated Cl- channels on nematode pharyngeal muscle. The electrophysiology and pharmacology of muscle and neuromuscular transmission the nematode parasite, Ascaris suum, is outlined and effects of anthelmintics that interfere with transmission described. Resistance to anthelmintics has appeared in some parasitic nematodes but the mechanisms of this resistance remain to be determined.
An electrophysiological preparation of Ascaris suum pharyngeal muscle suitable for recording changes of input conductance using a 2-microelectrode current clamp and pharmacological study is described. The preparation is shown to contain a glutamate-gated Cl (ion sensitive) channel sensitive to the avermectin analogue, milbemycin D. The application of glutamate produces a dose-dependent increase in Cl conductance and the effect of glutamate is potentiated by milbemycin D. Milbemycin D also produced a dose-dependent increase in input conductance.
1. We have investigated activation and block, by the tetrahydropyrimidine anthelmintic, morantel, of nicotinic-acetylcholine receptor (AChR) currents in membrane vesicles isolated from somatic muscle cells of the nematode parasite Ascaris suum. Standard single-channel recording techniques were employed. Morantel in the pipette (6 nM to 600 microM), activated single nicotinic AChR currents. 2. Kinetic properties of the main-conductance state of morantel-activated currents were investigated in detail throughout the concentration range, 0.6 microM to 600 microM. Open-time distributions were best fitted by a single exponential. Mean open-times were slightly voltage-dependent, increasing from 0.9 ms at +75 mV to 1.74 ms at -75 mV in the presence of 0.6 microM morantel. At low concentrations, closed-time distributions were best fitted by the sum of two or three exponential components. 3. As the concentration of morantel was increased (100-600 microM), fast-flickering open channel-block was observed at positive potentials, even though morantel, a cation, was only present at the extracellular surface of the membrane. The block rate was dependent on morantel concentration and both block rate and duration of block increased as the potential became less positive. A simple channel-block mechanism did not explain properties of this block. 4. At negative potentials, as the morantel concentration increased, a complex block was observed. With increases in morantel concentration two additional gap components appeared in closed-time distributions: one was short with a duration (approximately 13 ms) independent of morantel concentration; the other was long with a duration that increased with morantel concentration (up to many minutes). In combination, these two components produced a marked reduction in probability of channel opening (Po) with increasing morantel concentration. The relationship between the degrees of block and morantel concentration had a Hill coefficient of 1.6, suggesting the involvement of at least two blocking molecules. The data were analysed by use of a simple sequential double block kinetic model.
Isolated muscle bags from the parasitic nematode Ascaris suum were prepared by collagenase treatment and dissection. Single bags were mounted in a V-shaped plastic pipette for voltage clamp application and intra- and extracellular perfusion. With 'physiological' intra- and extracellular solutions, depolarizing voltage steps from near the normal resting membrane potential, -40 mV, produced in leak-corrected currents, a slowly activating outward current at potentials more positive than -20mV. At the end of the depolarizing pulse there was a slow inward tail current with a reversal potential near -20mV. Hyperpolarizing voltage steps produced an outward current relaxation and an outward tail current with the same reversal potential. The observations can be explained by the presence in the bag of a non-selective cation channel current, Ibcat, that activates spontaneously at the holding potential; depolarization increases opening of the channel and hyperpolarization decreases opening. Bath-applied acetylcholine in concentrations greater than 10(-7) M produced an increase in the amplitude of Ibcat. The effect of acetylcholine was not antagonized or prevented by 100 microM tubocurarine, suggesting the presence of a non-nicotinic acetylcholine receptor. Atropine (100 microM) had no detectable influence on the effect of acetylcholine but the FMRFamide peptide, PF1, in concentrations > 1 microM, reduced the amplitude of Ibcat. Ibcat was maintained when Cs+ was used to replace intra- and extracellular cations, showing that the channels were permeable to Cs+. It is concluded that the bag membrane possesses a slow voltage-activated non-selective cation channel current, Ibcat. The effect of acetylcholine in the presence of nicotinic antagonist indicates the presence of non-nicotinic acetylcholine receptors on the bag membrane. The effect of PF1 indicated the presence of PF1 receptors on the bag membrane.
The effects of chronic type I and type II corticosteroid receptor stimulation were examined in adrenalectomized Sprague-Dawley rats to quantify the relative contribution of body energy and body water changes to changes in body weight. Adrenalectomy caused a decrease in both body energy and water. Aldosterone (type I agonist) treatment increased body weight gain and returned energy accretion to the level of sham-operated animals. However, most of the change in body weight (72%) was attributable to a change in body water. The aldosterone-induced increase in body weight gain and carcass water were attenuated by RU-28362 (type II receptor agonist) infusion, suggesting that type II receptor stimulation can antagonize the effect of type I receptor stimulation. Changes in carcass water were paralleled by changes in soluble carcass sodium. Despite alterations in soluble body sodium, no measurable differences in cumulative sodium retention were found. These findings confirm previous studies suggesting an effect of type I receptor stimulation on energy accretion. However, they also caution that changes in body weight cannot be equated with changes in body energy.
We determined how postnatal maturation affects the relative contributions of airways and lung parenchyma to pulmonary resistance (RL) and whether there are developmental differences in their respective responses to constrictive agents. We studied open-chest ventilated anesthetized piglets of three ages: 2-4 days, 2-3 wk, and 10 wk. RL as partitioned into tissue (Rti) and airway (Raw) resistance by means of alveolar capsules under baseline conditions and after intravenous histamine. Postnatal maturation was associated with a progressive decline in RL, Rti and Raw and with an increase in the contribution of Rti and RL from 38 +/- 8% at 2-4 days to 72 +/- 2% at both 2-3 and 10 wk. Histamine caused RL to increase at all ages. When partitioned into Rti and Raw, the percent increase in Rti significantly exceeded that of Raw at both 2-4 days and 2-3 wk. In contrast, the percent increase in Raw significantly exceeded that of Rti at 10 wk. Administration of atropine before histamine in piglets aged 10 wk reduced the response of Rti and Raw to histamine. Histamine-induced responses of RL were blocked by prior H1-receptor blockade with pyrilamine (2 mg/kg). These results indicate that 1) the contribution of Rti and Raw to RL changes during maturation and that 2) contractile responses to exogenous histamine are manifest predominantly in most distal airways and lung parenchyma during early postnatal life; with advancing maturation there is greater contribution of airways to the increase in RL induced by histamine.
Our previous studies indicated that thyroxine (T4) markedly enhanced adipose tissue development and metabolism when administered to hypophysectomized fetal pigs from days 70 to 90 of gestation. In this study, hypophysectomized (day 70) fetal pigs were implanted with T4 pellets, and blood and adipose tissue samples were obtained upon removal on days 73, 75, 80, or 85 of gestation to examine the time course of T4 response. T4 treatment in hypophysectomized fetuses resulted in an elevation in serum T4 levels by day 73 of gestation, with no further increase on day 80 or 85. Quantitative analysis of subcutaneous adipose tissue indicated that hypophysectomy per se had no influence on lipid deposition, whereas the extent of T4-stimulated lipid deposition increased with fetal age beginning on day 75. Glucose oxidation and lipogenesis in subcutaneous adipose tissue slices was increased by T4 treatment in hypophysectomized fetuses by day 73 of gestation and further increased with additional time of treatment. Hypophysectomy per se induced a slight increase in lipogenesis only on days 80 and 85 of gestation. Basal lipolysis was unaffected by age, hypophysectomy, or T4 treatment. The responsiveness for a variety of lipolytic stimuli was both accelerated and enhanced by T4 treatment in hypophysectomized fetuses. The results indicate that the T4 influence on adipose tissue development (1) is already apparent following only 3 days of hormone treatment in the hypophysectomized fetuses, (2) clearly precedes hypophysectomy-induced alterations in cellular and metabolic development of adipose tissue, and (3) is not mediated exclusively by serum concentrations of the hormone.
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As physiologic and autopsy evidence suggests that peripheral airways and parenchyma are involved in asthma, we hypothesized that significant alveolar tissue inflammation is present in patients with stable, chronic asthma. Eleven patients with nocturnal asthma (NA) and 10 patients with non-nocturnal asthma (NNA) were studied. Each subject underwent two bronchoscopies with proximal airway endobronchial and distal alveolar tissue transbronchial biopsy in a random order at 4:00 P.M. and 4:00 A.M. Morphometric analysis was used to determine the number per volume (Nv) of inflammatory cells. Between-group comparisons showed that the Nv of eosinophils was greater in the NA alveolar tissue 4:00 A.M. compared with the subjects with NNA (40.2 x 10(3) [26.4-57.1 x 10(3), IQ] versus 15.7 x 10(3) [2.1-35.2 x 10(3), IQ], p = 0.05). In regard to the airway biopsies, no difference in the inflammatory and epithelial cells between the two groups was seen at either time. The NA group exhibited greater eosinophils and macrophages in the alveolar tissue at 4:00 A.M. compared with 4:00 P.M. (40.2 x 10(3) [26.4-57.1 x 10(3), IQ] versus 10.3 x 10(3) [2.7-16.8 x 10(3), IQ], p = 0.016 for eosinophils and 215.1 x 10(3) [129.9-356.1 x 10(3), IQ] versus 166.3 x 10(3) [150.7-212.6 x 10(3), IQ], p = 0.031 for macrophages). Only alveolar tissue eosinophils, not proximal airway tissue eosinophils, correlated with the nocturnal decrement in lung function (r = -0.54, p = 0.03). These findings suggest that eosinophils and macrophages accumulate to a greater extent in the alveolar tissue and these changes contribute more to the variation in lung function compared with inflammation in the more proximal tissue.
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Epidural abscess of the spinal column is a rare but potentially devastating disease. When recognized early and treated appropriately, the outcome can be excellent. Abscesses in the spinal subdural space or in the spinal cord proper are even more unusual but can also lead to complete and irreversible loss of neurologic function if not diagnosed and treated rapidly. Although infection frequently can result in arachnoiditis, there are other more common causes, such as surgery and chemical irritants. It remains a difficult condition to treat, and long-term therapeutic results are mediocre. Newer technology with spinal cord stimulation seems to show improved results but pain relief is incomplete, and the percentage of patients with poor results remains high.
Corticotropin-releasing factor (CRF) has been reported to reduce food intake and body weight, and numerous studies suggest a role for CRF in putative mechanisms for the regulation of body energy. This study investigated the effects of ICV-administered antisense phosphorothioate oligonucleotides, directed against the CRF mRNA, on feeding behavior and body weight in rats. Sixteen male HSD rats were cannulated in the lateral ventricle, and given ad libitum access to tap water and a ground chow diet. Feeding behavior was recorded by computer, and meal patterns were assessed. Rats were given 3 micrograms each of two anti-CRF oligonucleotides (aCRF) or two control oligos in the hour before the onset of the nocturnal cycle for ten consecutive days. Cumulative food intake was assessed at 3, 6, 12 and 24 h after each injection, as well as over the 10-day injection period. Compared to missense controls, rats receiving the antisense oligonucleotides ate significantly more at 6 h (P = 0.01), but not at 3, 12, 24 h, or during the entire 10-day injection period (P > 0.05). There was no effect on body weight change, meal size, or meal interval (P > 0.05). These data indicate that daily administration of anti-CRF oligonucleotides has a significant short-term stimulatory effect on feeding behavior, but does not have a long-term effect on feeding or body weight gain.
Neuropeptide-Y (NPY) is a potent stimulator of feeding, and chronic administration of the peptide has been shown to increase body weight. This study determined the chronic effects of repeated daily injections of an antisense phosphorothioate oligonucleotide complementary to the rat mRNA for NPY (aNPY) on food intake, feeding behavior and body weight change in rats. Five micrograms of the aNPY oligonucleotide in ten microliters of vehicle or a missense control oligonucleotide were administered intracerebroventricularly (ICV) for seven consecutive days. Cumulative food intake, meal size and meal duration were significantly lowered in aNPY-treated animals. Body weight change of aNPY-injected animals was significantly lower than controls, and the effect was reversed after treatments ceased. A two-bottle taste aversion paradigm was employed to determine the behavioral specificity of the anorectic effect, and the phosphorothioate oligonucleotide was found not to be aversive at the dosage used. Following an additional five day injection period, animals were killed and paraventricular nuclei (PVN) were dissected. In vitro release and tissue content of NPY from this brain area were evaluated by heterologous radioimmunoassay. Content of NPY was unchanged in this brain area. Paradoxically, in vitro release of NPY was increased in aNPY-treated animals.
The structure-activity relationships of 35 novel derivatives of 2-(carboxypropyl)-3-amino-4-methyl-6-phenyl pyridazine (SR 95103) were examined as gamma-aminobutyric acid (GABA) antagonists in the flap preparation of the parasitic nematode, Ascaris suum, using a two-microelectrode current-clamp technique. All but one of the potent antagonists displaced GABA dose-response curves to the right without reduction in the maximum response. The dissociation constants of the more potent competitive antagonists were described using a model which assumed that two molecules of GABA were required to open the ion channel but that only one molecule of antagonist acted on each ion channel. By exploring the structure-activity relationship, the potency of the antagonist was increased from a KB of 64 microM for SR 95103 to a KB of 4.7 microM for NCS 281-93 (2-(3-carboxypropyl)-3-amino-4-phenylpropyl-6-phenyl pyridazine).