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Biomedical subjects

D A Thomas

Publications and source records attributed to D A Thomas.

At least 19 recordsLinked to original sources
PubMed1995

Combination therapy with 5-fluorouracil and L-canavanine: in vitro and in vivo studies.

L-Canavanine (CAV) is a potent L-arginine antagonist, produced by legumes such as the jack bean, Canavalia ensiformis. CAV is cytotoxic to MIA PaCa-2 human pancreatic cancer cells. We sought to determine whether CAV's efficacy as an anticancer agent might be increased in combination with 5-fluorouracil (5-FU), a pyrimidine antimetabolite with activity against solid tumors. Using optimal conditions for the expression of CAV's cytotoxicity against MIA PaCa-2 cells, CAV was more cytotoxic to the cells than 5-FU. The combination of both drugs at a fixed molar ratio of 1:1 exhibited synergistic effects in the cells as determined by combination index analysis. The combination of 5-FU:CAV was tested at a ratio of 5:1 and exhibited antagonism at lower effect levels, additivity at 50% effect levels and slight synergism at higher effect levels. A 10:1 combination of both drugs (5-FU:CAV) exhibited antagonistic effects at all levels. When the drugs were combined at a molar ratio of 20:1, increased antagonism was observed. When CAV (1.0 or 2.0 g/kg daily) and/or 5-FU (35 mg/kg daily) was administered to colonic tumor-bearing rats for five consecutive days, the antitumor activity of the drug combination was significantly greater than the combined effects of either drug alone. However, the body weight loss experienced by CAV-treated rats was increased in those rats exposed to a combination of both drugs. These studies using different tumors provide in vitro and in vivo evidence that combination therapy offers a viable means of improving CAV's intrinsic efficacy while decreasing the concentration of 5-FU required to produce the same cytotoxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Microinjection of baclofen in the ventromedial medulla of rats: antinociception at low doses and hyperalgesia at high doses.

Neurons of the nucleus raphe magnus (NRM) and adjacent nucleus reticularis gigantocellularis pars alpha (NGCp alpha) receive a tonic inhibitory input from gamma-aminobutyric acid (GABA)-ergic neurons that is mediated by GABAA receptors. However, comparatively little is known about the role of GABAB receptors in these nuclei. The present study examined the effects on nociceptive threshold of microinjection of a wide dose range (0.1-150 ng) of the GABAB receptor agonist, baclofen hydrochloride (BAC), in the NRM, NGCp alpha or the nucleus reticularis giganto-cellularis (NGC). Microinjection of low doses of R(+)-BAC (0.1-1.0 ng) in the NRM or the NGCp alpha, but not the NGC increased response latencies in the tail flick test. As the dose of BAC was increased to 30.0 to 50.0 ng, response latencies in the tail flick test diminished to control values. Microinjection of the highest dose, 150 ng, in either the NRM, NGCp alpha or NGC significantly decreased response latencies in the tail flick test. Response latencies in the hot plate test were not increased by microinjection of 0.1 to 5.0 ng of R(+)BAC in the NRM, NGCp alpha or NGC. Although hot plate latency was increased after microinjection of 30.0 to 50.0 ng of R(+)-BAC in these nuclei, the effect was confounded by the occurrence of motor dysfunction. The effects of BAC were stereospecific as nociceptive threshold and motor function were not altered by microinjection of either 0.5 ng or 150 ng of the less active stereoisomer, S(-)-BAC. The biphasic effect of R(+)-BAC suggests the existence of multiple mechanisms by which GABAB receptors modulate the activity of neurons in the ventromedial medulla. It is proposed that the antinociception produced by low doses of R(+)-BAC results from disinhibition (activation) of neurons in the NRM and NGCp alpha as a consequence of the presynaptic inhibition of inhibitory GABAergic and/or noradrenergic inputs. The decrement in antinociceptive effect and hyperalgesia produced by higher doses of R(+)-BAC may result from a presynaptic inhibition of excitatory inputs to the NRM and NGCp alpha, postsynaptic hyperpolarization of neurons in these nuclei or the unmasking of a descending facilitatory pathway originating from the NRM, NGCp alpha and NGC.

Animals↗
PubMed1994

Neonatal capsaicin treatment in rats results in scratching behavior with skin damage: potential model of non-painful dysesthesia.

We administered capsaicin or vehicle in 2-day-old rat pups, and for over 6 months examined the rats for damaged skin and for the behaviors of scratching, gnawing and biting their skin. By 35 days of age, all rats in the capsaicin group (n = 10) had damaged skin (i.e., lesions, hair loss and red skin) on the rostral half of their bodies. Skin damage remained prevalent over 6 months, whereas vehicle-treated rats (n = 8) had virtually no skin damage. Gnawing and biting behaviors were rarely observed, however, rats in the capsaicin group frequently scratched themselves. There was a significant positive correlation between the frequency at which rats scratched themselves and the total area of skin damage. Morphine (3.0 mg/kg, i.p.) greatly increased scratching behavior in only the capsaicin-treated rats and naloxone (0.5 mg/kg, i.p.) significantly reduced scratching in these rats. Thus, neonatal capsaicin, in its destruction of the majority of primary afferent C-fibers, is capable of inducing opioid-sensitive scratching behavior.

Animals↗
PubMed1992

Effects of central administration of opioids on facial scratching in monkeys.

Epidural and intrathecal administration of opioids to humans can produce facial pruritus and scratching that is naloxone reversible. It has been proposed that opioids may act at the level of the medulla to produce facial pruritus and associated scratching behavior. We investigated the effects of mu, delta and kappa opioid-receptor agonists microinjected unilaterally into the medullary dorsal horn (MDH) on facial scratching in cynomolgus monkeys. The selective mu opioid-receptor agonist, DAMGO (3.1-25.0 ng) produced large dose-dependent, naloxone-reversible increases in facial scratches. The selective delta opioid-receptor agonist, DPDPE (1.0-5.0 micrograms) and the selective kappa opioid-receptor agonist, U-50,488H (0.1-5.0 micrograms) did not produce significant increases in facial scratching behavior. We conclude that the MDH is a site where DAMGO, a mu opioid-receptor agonist, can act to produce facial scratching in monkeys, and that the MDH is likely the site where centrally administered opioids act to produce facial pruritus in humans.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

FG 7142 selectively decreases nonpunished responding, but has no anxiogenic effects on time allocation in a conflict schedule.

Previous work (Thomas et al. 1990) showed that an anxiolytic benzodiazepine increased the time allocated to responding in a conflict situation (where responses were both food-reinforced and shock-punished) versus a nonpunishment situation. The present experiment tested whether a benzodiazepine-receptor inverse agonist (FG 7142, 1-30 mg/kg) would have the opposite effect (i.e., decrease time spent responding in a punishment situation). Chain pulls determined whether a rat's lever presses were reinforced on 1) a lean variable-interval schedule, or 2) a richer variable-interval schedule in which responding also produced shock intermittently. FG 7142 dose-dependently decreased nonpunished lever responding, but did not affect punished responding. The drug nonselectively decreased chain pulling (the schedule-switching response). Like chlordiazepoxide, FG 7142 increased the time spent in the punishment component, showing that not all effects of benzodiazepine-receptor agonists and inverse agonists are opposite. These results are inconsistent with expectations that anxiogenic actions of FG 7142 should 1) decrease punished responding; 2) increase the rate of responses that terminate the punishment condition; and 3) decrease time spent in the punishment component. Rather, nonsuppressed responding seems most sensitive to decreases by FG 7142.

Animals↗
PubMed1991

Purification and kinetic characterization of equine infectious anemia virus reverse transcriptase.

The reverse transcriptase of Equine Infectious Anemia Virus (EIAV) was partially purified from virus particles and appeared to be a heterodimer with subunit molecular masses of 70 kdal and 59 kdal. The polymerase activity of this enzyme had an absolute requirement for a divalent cation, preferring Mg++ over Mn++. Addition of a monovalent cation to the reaction mixture enhanced, but was not required for enzyme activity. Kinetically, the reverse transcriptase of EIAV is similar to the reverse transcriptase of Human Imunodeficiency Virus Type 1 (HIV-1). Both enzymes have similar Km values for 2'-deoxynucleoside-5'-triphosphates on the synthetic template/primers tested, both exhibit substrate inhibition, and both are inhibited to similar extents by most nucleoside-triphosphate analogs. The results of this study suggest that the reverse transcriptase of EIAV may be a good model for studying structure/function relationships of retroviral reverse transcriptases.

Animals↗
PubMed1991

Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia: possible involvement of noradrenergic mechanisms.

We have examined the spinal analgesic activity of opioid agonists and antagonists in a model of short term, unilateral, carrageenan-induced inflammation/hyperalgesia. Rats received a single s.c. injection of carrageenan (2-6 mg in saline) 3-24 h prior to testing hindpaw withdrawal latencies to noxious thermal stimuli. Dose-response curves for intrathecally administered agonists with mu- and/or delta-opioid activity were shifted to the left for inflamed hindpaws when compared to contralateral non-inflamed paws. The selective kappa-receptor agonist U-50,488H had no activity in this analgesic assay on either inflamed or non-inflamed paws when administered intrathecally. However, systemic administration of U-50,488H did produce significant elevations of paw withdrawal latencies in inflamed paws. The alpha 2-adrenoceptor agonist clonidine also produced dose-dependent antinociception in the paw withdrawal assay after systemic or intrathecal administration. Inflamed hindpaws were significantly more sensitive to the antinociceptive effect of morphine on inflamed hindpaws was blocked by the opioid antagonist naloxone or the alpha 2-adrenoceptor antagonist idazoxan. The effect of clonidine was only blocked by idazoxan. Antagonists alone had no significant effect on withdrawal latencies. The data indicate that the analgesic action of opioids during conditions of inflammation may depend on an interaction with spinal noradrenergic pathways.

Adrenergic alpha-Antagonists↗
PubMed1991

Mass spectrometric signature of S-prenylated cysteine peptides.

The fast atom bombardment mass spectra of peptides containing S-prenylated cysteine display signature fragmentations characteristic of this modified amino acid. The fragmentation is independent of the nature of the cysteine carbonyl substituent, easily differentiates prenyl from nonprenyl alkylation, and readily identifies the oligomer count of the prenyl. This screening method, which requires little time, effort, or material (compared with previous analysis methods based on chemical degradation), greatly facilitates the identification of these prenylated proteins.

Amino Acid Sequence↗
PubMed1991

Acute effects of liposome aerosol inhalation on pulmonary function in healthy human volunteers.

Administering liposome-encapsulated drugs by aerosol is a feasible way of targeting drugs to the lungs. Prior to clinical application of aerosolized liposomes as drug carriers, their relative safety must be established. We evaluated the effects of inhaling nondrug-containing liposomes (15 and 150 mg of lipid per milliliter) for 1 h on pulmonary function and on oximetry in ten healthy nonsmoking volunteers. Spirometry was performed prior to and at intervals after inhalation, and subjects were monitored with pulse oximetry. Liposome inhalation was well tolerated, and no oxygen desaturation, decrements in pulmonary function, or side effects were noted. We conclude that inhalation of small particle aerosols of SPC liposomes produces no acute deleterious effects on pulmonary function in healthy subjects.

Adult↗
PubMed1990

Effects of chlordiazepoxide and flumazenil on preference for punished and unpunished response alternatives in rats.

Male food-restricted hooded rats were trained to respond on a two-component multiple schedule. Reinforcement density was several times higher in one component than in the other. However, responses were intermittently punished with shock in the richer reinforcement component (conflict situation). Shock intensities were adjusted to produce mild and strong suppression of responding in two separate phases. Half of the rats controlled which component was operating (Preference group) and half did not (Yoked group). The effect of chlordiazepoxide (CDZ; 0, 1, 3, and 10 mg/kg; IP) was measured on component preference and response rate. Chlordiazepoxide increased both time spent in the conflict situation and response rate in that component. This is the first study employing a schedule that permitted these two behavioral indices to be measured independently in a conflict paradigm. Response rates were also increased in the unpunished response alternative, but to a lesser degree than in the conflict situation. The effects of CDZ were at least partially mediated by the benzodiazepine receptor because CDZ's effects were diminished by flumazenil (10 mg/kg; IP), a benzodiazepine antagonist.

Animals↗
PubMed1989

Comparison of anxiety before induction of anaesthesia in the anaesthetic room or operating theatre.

Anxiety before induction of anaesthesia was studied in 100 patients who were allocated randomly to one of two groups. Patients in one group were anaesthetised in an anaesthetic room and those in the other group were anaesthetised inside the operating theatre. Both subjective and objective induces of anxiety were used in the comparison. Other factors that contributed to anxiety were assessed by a simple questionnaire. There was no significant difference in the level of anxiety between the two groups. The site of induction did not emerge as a major contributory factor to anxiety. The advantages and disadvantages of anaesthetic rooms are discussed.

Adolescent↗
PubMed1989

Measuring volunteers for exciting psychology experiments with the Sensation-Seeking Scale.

The sensation-seeking motive was first operationalized by Zuckerman, Kolin, Price, and Zoob (1964) with the development of the Sensation-Seeking Scale (SSS). One area of applied research in which the SSS has been used is the study of volunteering. In this area, evidence suggests that high-sensation seekers volunteer for exciting activities more often than low-sensation seekers, but not for unexciting activities. However, a problem with this research is that no empirical data has been obtained related to the subject's belief of the exciting nature of the activities. In this study, college students were given the most recent form of the SSS and were asked to volunteer for either or both of two studies. SSS scores were higher, p less than .05, for volunteers than for nonvolunteers for a study that subjects rated as exciting, but did not differ for a study that subjects rated as unexciting. This demonstrates that volunteers for exciting studies, but not volunteers for unexciting studies, tend to be higher sensation seekers than nonvolunteers.

Adolescent↗
PubMed1989

Aspergilloma in an open chest cavity.

We present the findings in a patient who underwent pneumonectomy and developed a chronic bronchopleural fistula and empyema and who developed an intrathoracic aspergilloma after open-window thoracostomy. To our knowledge, formation of an aspergilloma in an open intrathoracic cavity has not been reported previously.

Adult↗
PubMed1988

Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function.

The effects of acute inhalation exposure to methyl bromide (MeBr) on the olfactory epithelium of male F-344 rats was investigated by morphologic examination of animals killed at varying timepoints during and following exposure to 200 ppm MeBr 6 hr/day for 5 days. Cell replication rate and histopathology were used to assess the kinetics of repair. In addition, olfactory function, using the buried food pellet test, was assessed and the result compared with morphological recovery. Extensive destruction of the olfactory epithelium was evident in animals killed directly after a single 6-hr exposure to MeBr. Histologic features of these lesions indicate that the primary, or most severe, effect of MeBr exposure was on the sustentacular cells and mature sensory cells; basal cells were generally unaffected. By Day 3, despite continued exposure, there was replacement of the olfactory epithelium by a squamous cell layer that increased in thickness and basophilic cytoplasmic staining over the next 2 days of exposure. One week postexposure, the epithelial region was covered by a layer of polyhedral, basophilic cells, and from 2 to 10 weeks postexposure, the epithelium exhibited progressive reorganization to reform the original olfactory epithelium pattern. By Week 10, 75-80% of the olfactory epithelium appeared morphologically normal. Cell replication showed a single peak of olfactory epithelial cell proliferation at Day 3 of exposure, with a labeling index of 14.5% compared to 0.7% in controls. Cell replication rates returned gradually to control levels by Week 10 postexposure. Behavioral tests of olfactory function in animals after a single 6-hr exposure to 200 ppm MeBr demonstrated a loss of the sense of smell, with recovery of this function by Day 6. Exposure to 90 ppm caused no observable effect on olfactory function or morphology. These findings demonstrate that the olfactory mucosa is highly sensitive to the toxic effects of MeBr and that olfactory epithelial cell proliferation, and possible regeneration, begins and occurs rapidly even in the face of continued exposure. Cell replication was most prominent in the layer of basal cells adjacent to the basal lamina, supporting proposals by other workers that the progenitors of both sustentacular cells and neurons reside in this location. Of interest is the fact that functional recovery occurs prior to complete morphological reorganization, indicating the shortcoming of utilizing olfactory morphology as an index of functional integrity.

Administration, Inhalation↗