5-substituted quinazoline antifolates.
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Biomedical subjects
Publications and source records attributed to T R Jones.
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The ultrastructure of guinea pig tracheal smooth muscle and its innervation was studied by transmission electron microscopy. Smooth muscle cells were arranged into bundles separated by collagen and connective tissue cells. Gap junctions were found only rarely between adjacent smooth muscle cells. Bundles of axons (predominantly unmyelinated) were seen on the periphery of the muscle bundles. Some penetrated deep into the bundles and a few made close neuromuscular contacts (less than 20 nm). Such a spatial arrangement of nerves and smooth muscle suggests a potential for nervous control and limited myogenic activity. Axon profiles containing small agranular vesicles characteristic of cholinergic nerves and small granular vesicles characteristic of adrenergic nerves were seen in close association with airway smooth muscle and with one another. Some large granular vesicles were associated with varicosities of both nerve types. Quantitative studies demonstrated a preponderance of cholinergic over adrenergic nerve profiles in both upper and lower segments. Varicosities, characteristic of adrenergic nerves, were observed more frequently in upper compared with lower segments; however, observed differences were not significant. The morphological findings are consistent with the control functions exerted by cholinergic and adrenergic nerves but provide no basis for control by nonadrenergic inhibitory nerves.
Vanadate inhibited K+-activated and K+-activated ouabain-sensitive p-nitrophenyl phosphatases of rat myometrium at nanomolar concentrations. The vanadate concentrations required for 50% inhibition were 220 +/- 30 nM for the K+-activated component of the enzyme and 200 +/- 30 nM for the K+-activated ouabain-sensitive component. Micromolar concentrations of vanadate inhibited acid and alkaline p-nitrophenyl phosphatases. ATP-dependent Ca uptake by the plasma membrane vesicles was not inhibited by 10nM - 1 mM vanadate. Mg2+-ATPase was also not affected. Thus K+-activated and K+-activated ouabain-sensitive p-nitrophenyl phosphatase activities of the plasma membrane were most sensitive to inhibition by vanadate. Preliminary experiments demonstrated that similar to ouabain, vanadate inhibited potassium-induced abolition of spontaneous contractile activity of isolated rat myometrium in K-free Krebs. This effect of vanadate is consistent with vanadate inhibition of K+-activated ouabain-sensitive p-nitrophenyl phosphatase.
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Competitive steroid-binding studies were performed with intact rat thymus cells and with cytosol preparations at different temperatures using [1,2-3H]dexamethasone as the labelled ligand. Steroids lacking a 17 alpha-hydroxyl group, such as corticosterone, were better able to compete with [1,2-3H]dexamethasone for binding to glucocorticoid receptors at 0 degrees C than compounds containing a 17 alpha-hydroxyl substituent, such as cortisol. At 37 degrees C the reverse was true. This temperature-dependent change in relative affinities appeared to be unrelated to steroid metabolism or receptor activation, and to depend only on the thermodynamic parameters of the steroid--receptor interaction. Relative biological activities for different steroids agree more closely with the relative affinities determined at 37 degrees C than with those determined at lower temperatures.
Three cases of familial polyposis coli with associated periampullary malignancies are reported and the literature reviewed, which disclosed 16 additional cases. An additional five unreported cases are known to exist. The authors believe that the development of periampullary malignancy in FPC is a definite extracolonic manifestation of the disease and should be considered a variant of Gardner's syndrome. It is recommended that all FPC patients with colon polyps undergo routine surveillance of the upper gastrointestinal tract and that all duodenal polyps discovered be surgically removed when feasible.
Fluorescent histochemical studies indicate that guinea pig tracheal smooth muscle has sparse adrenergic innervation with the greatest nerve density being located at the laryngeal end. In the present study, log dose-response lines were obtained for dl-isoprenaline (ISO), l-adrenaline (ADR) l-noradrenaline (NOR), salbutamol (SALB), and orciprenaline on isolated tracheal chains prepared from both the laryngeal (L) and bronchial (B) ends of the trachea. Responses were obtained in the absence and presence of the Uptake1 blocker, cocaine (0.67 and 6.7 muM) which markedly potentiated responses to NOR and ADR but failed to significantly alter responses to ISO and SALB on L preparations. The degree of potentiation obtained on B preparations was significantly less for NOR and ADR and was not significant for the other agents. In addition, experiments were carried out on tracheal chains which developed their normal tone in the absence of carbachol, and also on preparations obtained from 6-hydroxydopamine treated animals. The present findings, based on selective potentiation of NOR and ADR, support evidence that the degree of adrenergic innervation to the guinea pig trachea is greater at the laryngeal end, and the results obtained with cocaine strengthen the argument that it has a pre-synaptic site of action.
The widely used bacteriostatic preservative methyl paraben (M.P.) produced a concentration-dependent relaxation of the carbachol-contracted guinea pig trachea and the isolated rabbit jejunum. The relaxant effects on the trachea were not blocked by dl-propranolol and the responses on the rabbit jejunum were not blocked by bretylium tosylate which abolished the responses to sympathetic nerve stimulation. Sub-threshold concentrations of M.P. (130 muM) produced a marked and significant enhancement of the responses of the trachea to the three catecholamines dl-isoprenaline (I), 1-noradrenaline (N), 1-adrenaline (A), a slight but significant enhancement of the responses of the trachea to the two non-catechol beta sympathomimetics salbutamol (S), and orciprenaline (O), but no significant enhancement of the responses to aminophylline (AM). It is concluded that the relaxant effect of M.P. is characteristic of a "non-specific" spasmolytic and this is consistent with its reported local anaesthetic activity. In addition, the specific ability of M.P. to enhance responses to catecholamines suggests that it may be interacting with a mechanism responsible for catecholamine removal (i.e., tissue uptake or uptake 2). In view of the widespread use of M.P. in pharmaceutical preparations in concentrations often equivalent to or greater than those employed in the present investigation, the fact should be stressed that its presence should not be overlooked in the interpretation of experimental and clinical studies.
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The diagnostic performance of commercial capillary tubes containing acridine orange dye (QBC) was compared with the standard diagnosis of malaria by microscopical examination of Giemsa-stained thick blood films (GTS) in remote field conditions. The comparison was conducted among 165 volunteers living in northeastern Irian Jaya, Indonesia, an area having hyperendemic malaria transmission. By GTS, 65 volunteers were positive for malaria, but only 49 were judged positive by QBC. Among the 100 blood films found negative by GTS, 5 were considered positive by QBC. Thus, relative to a GTS standard, the sensitivity and specificity of the QBC was 75% and 95%, respectively. The mean limit of detection for the QBC was approximately 60 parasites per microliter blood, whereas the limit of detection for GTS was 20 parasites per microliter blood. Also, a number of practical difficulties were encountered using the QBC at the field site. The QBC approach to diagnosis of malaria was less sensitive and more inconvenient than GTS under the conditions in remote Irian Jaya.
Combination therapy is one method of overcoming the global challenge of drug-resistant Plasmodium falciparum malaria. We conducted a hospital-based 28-day in vivo test comparing chloroquine/doxycycline to chloroquine or doxycycline alone for treating P. falciparum and Plasmodium vivax malaria in Irian Jaya, Indonesia. Eighty-nine patients with uncomplicated falciparum malaria were randomized to standard dose chloroquine (n = 30), doxycycline (100 mg every 12 hours [7 days], n = 20), or chloroquine with doxycycline (n = 39); corresponding numbers for vivax malaria (n = 63) were 23, 16, 24. Endpoints were parasite sensitivity (S) or resistance (RI/RII/RIII). Of the 105 evaluable patients, chloroquine/doxycycline cured (S) 20/22 (90.9% [95% CI 78.9-100%]) patients with P. falciparum malaria; 2/22 (9.1% [0-21%]) were RIII resistant. Doxycycline cured 11/17 (64.7% [42.0-87.4%]) patients, and chloroquine 4/20 (20% [2.5-37.5%]). Against P. vivax, chloroquine/doxycycline cured (S) 12/17 (70.6% [48.9-92.2%]) patients, doxycycline 4/12 (33.3% [6.6-59.9%]), and chloroquine 5/17 (29.4% [7.7-51.1%]). Chloroquine/doxycycline was effective against P. falciparum but only modestly effective against P. vivax. These findings support the use of chloroquine/doxycycline as an inexpensive alternative to mefloquine for treating chloroquine-resistant P. falciparum but not chloroquine-resistant P. vivax in this setting.
A malaria prevalence study was performed in a village in Irian Jaya, Indonesia, that contains a population of people who have been exposed lifelong to hyperendemic malaria and another population of people who had arrived 18 months previously from areas of very low endemicity. Mean spleen sizes correlated positively with prevalence of malaria, not resistance to it. Prevalence of sexual and asexual blood stage parasites was higher in transmigrants than in the natives. The data also show that clinical resistance to malaria in this part of the world includes resistance to Plasmodium falciparum gametocytemia and that this is not the passive byproduct of a reduction in asexual parasites. This indicates that the introduction of native people into a populated malarious area will increase the percent of gametocyte carriers and may, thereby, increase the entomologic inoculation rate.
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