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Biomedical subjects

D J Cannon

Publications and source records attributed to D J Cannon.

At least 19 recordsLinked to original sources
PubMed1994

Mobilization of iron by chiral and achiral anionic 3-hydroxypyrid-4-ones.

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.

Animals↗
PubMed1994

Vigabatrin.

The discovery of gamma-aminobutyric acid (GABA) as the first major inhibitory neurotransmitter and a program exploring the use of enzyme inhibition as a therapeutic tool provided the basis for the conception of vigabatrin (VGB, Sabril). This molecule, an analogue of GABA, has a highly specific activity as an enzyme-activated irreversible inhibitor of GABA-transaminase causing several-fold increases in the concentration of brain GABA. In animal models for epilepsy, it was found to have a rather different spectrum of activity than conventional antiepileptic drugs (AEDs). The clinical development of VGB was delayed by the finding of focal areas of reversible microvacuolation in the white matter of the brains of rodents and dogs. An extensive human safety program has confirmed that this finding is species specific and does not occur in humans. Clinically, VGB is well tolerated and has been shown to be specially effective in the management of partial seizures that have failed to respond to other AEDs. In most controlled studies, about 50% of patients with previously uncontrolled seizures have a 50% reduction in frequency and about 4-5% become seizure-free. In children, it also appears to be especially effective in the management of infantile spasms as well as in partial seizures. VGB offers a significant improvement in the management of epilepsy and is now under development as a first-line agent.

Animals↗
PubMed1991

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Adolescent↗
PubMed1990

Zinc nutrition in fetal alcohol syndrome.

Because alcohol has an adverse effect on zinc homeostasis, this study was designed to study if zinc content of the diet modifies the severity of fetal alcohol syndrome in a mouse model. The effect of varying zinc intake on the progeny of pregnant mice fed a liquid diet containing 15% of the calories as ethanol was studied. Prenatal mortality was higher when the mothers consumed alcohol with inadequate zinc intake. Because of the adverse effect of alcohol on zinc homeostasis and because zinc deficiency has been shown to potentiate alcohol embryopathy, one group was given zinc supplementation to four times the Recommended Dietary Allowance. Supplemental zinc above the Recommended Dietary Allowance was not protective and appeared to have an adverse effect on fetal weight and prenatal mortality. These results suggest that zinc intake should be optimized during pregnancy but that zinc supplementation above the Recommended Dietary Allowance does not reduce the incidence or severity of fetal alcohol syndrome.

Animals↗
PubMed1989

Urine screening for abused drugs in new admissions to a VA hospital.

The urine samples from two groups of Veteran's Administration patients newly admitted to general psychiatry units were screened in 1985 and in 1987-88 for abused drugs. The results were compared with urine samples from controls with similar age distributions admitted to an alcohol and drug abuse unit or to medical-surgical units. About 40% of all newly admitted patients were positive for one or more controlled drugs, but there were no significant differences among patient groups in the percentage of urine samples positive for these drugs. Marijuana and benzodiazepines were detected frequently in all patient groups and often in combination, although opiates also were frequently detected in the urine samples from the medical-surgical patients. There was a clear decrease in drug-positive samples with age in all patient groups, much of which could be accounted for by decreased marijuana detection.

Adult↗
PubMed1989

Antipseudomonal effects of selected dithiocarbamates alone and in combination with gentamicin or aztreonam.

The antipseudomonal effects conferred by combinations of substituted dithiocarbamates, gentamicin or aztreonam (Azactam) were measured and compared to those produced by single agents alone in female BALB/C mice bearing overwhelming Pseudomonas aeruginosa infections. Dimethyldithiocarbamate (DMDTC), diethyldithiocarbamate (DEDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMGDTC) were chosen as representative substituted dithiocarbamates. All three dithiocarbamates rescued some cisplatin-immunosuppressed mice from pseudomonal infections but DMDTC and NMGDTC produced better results than DEDTC. Single daily injections of DMDTC at doses of 5 mg/kg/day or higher for a total of 7 days rescued 14 of 18 mice given 10(6) viable Pseudomonas aeruginosa by tail vein inoculation. Similar dose regimens of 10 mg/kg/day or higher NMGDTC for a total of 7 days rescued 15 of 18 mice. DEDTC at doses of 5 mg/kg/day or higher for 7 days rescued 7 of 18 mice. Combinations of DMDTC or NMGDTC with gentamicin failed to produce better results than each agent alone in mice immunosuppressed with methyl-prednisolone (Solumedrol) at the dose range evaluated in mice inoculated with 10(6) viable organisms via tail veins. Combinations of DMDTC and aztreonam were effective in mice immunosuppressed with methylprednisolone and given overwhelming numbers of viable Pseudomonas aeruginosa (10(7) or more, ip). Combinations of 6 mg/kg/day or higher of each agent with multiple daily injections rescued 11 of 18 mice. The results yielded by either agent alone were not impressive. Similar results were obtained when mice immunosuppressed with cisplatin were given ip injections of 10(8) or more viable bacteria. No mice were rescued by the use of DMDTC, NMGDTC, aztreonam or gentamicin only. Combinations of DMDTC (6 mg/kg) and aztreonam (6 mg/kg) with multiple daily injections for seven days rescued 11 of 20 infected mice while combinations of NMGDTC with aztreonam were less effective (3 of 20 rescued). The concurrent administration of DMDTC and aztreonam offers considerable promise in the treatment of overwhelming pseudomonal infections in mice and may prove to be of value in human patients as well.

Animals↗
PubMed1989

Effects of repeated drug holidays on serum haloperidol concentrations, psychiatric symptoms, and movement disorders in schizophrenic patients.

In a crossover experiment the authors investigated the effects of repeated weekly, 2-day, haloperidol drug holidays on serum haloperidol concentrations, mental status, and neuroleptic-induced movement disorders in seven chronic schizophrenic patients. Haloperidol concentrations decreased about 64% during the initial 36 hours of drug holiday and subsequently increased slightly during the next 24 hours of drug holiday. Two-day weekly drug holidays for 6 weeks resulted in an average reduction of 25% in serum haloperidol concentrations at all drug holiday points. Mental status and movement disorders scores, rated by observers blind to the drug-holiday condition, were not significantly affected by drug holidays.

Drug Administration Schedule↗
PubMed1987

Effects of diethyldithiocarbamate and structural analogs in mice with systemic candidal infections.

Three different substituted dithiocarbamates: sodium diethyldithiocarbamate (DDTC), sodium dimethyldithiocarbamate (DmDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMG-DTC) were evaluated for their ability to combat the growth and development of three human pathogenic strains of Candida albicans, in vitro and in vivo, in mice. DDTC and DmDTC produced marked growth inhibition on agar plates, in vitro, of three different strains of Candida albicans, while NMG-DTC displayed little inhibitory effect. Low, nontoxic doses of each compound administered to immunosuppressed mice exhibited impressive therapeutic effects in treating candidiasis. NMG-DTC showed the best consistent therapeutic antifungal effect against Candida albicans in mice immunosuppressed with Solu-Medrol. Combinations of low doses of DDTC and Amphotericin-B appeared to be effective in treating systemic candidal infections, and the results suggested that these combinations may offer therapeutic advantages over those produced by the use of either agent alone.

Amphotericin B↗
PubMed1987

Instrumentation and techniques for therapeutic drug monitoring.

This article describes and compares the predominant systems for performing therapeutic drug monitoring. Advantages and disadvantages, costs, and future trends are noted. Useful information for the initiation or expansion of this clinical service is provided.

Chromatography, Gas↗
PubMed1986

Relationship of plasma phencyclidine levels to phencyclidine discrimination in the pigeon.

Plasma phencyclidine levels were determined in pigeons trained to discriminate 1.5 mg/kg phencyclidine from saline under a second-order schedule using a color-tracking procedure. With both cumulative and non-cumulative dosing procedures, pigeons reliably discriminated plasma phencyclidine levels above 200 ng/ml. When the time course of phencyclidine discrimination was determined and compared with the time course of phencyclidine levels in plasma in a different group of birds, a similar relationship between discrimination and plasma phencyclidine was generally observed. Plasma phencyclidine levels did not correlate well with position responding observed in some birds after lower phencyclidine doses.

Animals↗
PubMed1984

Abdominal aortic aneurysm, Leriche's syndrome, inguinal herniation, and smoking.

We previously found an increase in serum proteolytic activity in smokers with direct inguinal herniation and a similar imbalance in smokers with abdominal aortic aneurysm (AAA), but not in smokers with Leriche's syndrome (LS). If the protease imbalance in the blood of smokers with AAA or herniation is a causal factor, these conditions should be associated. Therefore, we determined whether this is true using patients with LS as control subjects. The frequency of inguinal herniation was significantly higher in the AAA population (N = 341; 25.8%) than in patients with LS (N = 417; 14.6%). In addition, patients with AAA had more severe herniation (direct, bilateral, recurrent, or earlier onset) and had more pronounced leukocytosis (9,000/cu mm v 8,190/cu mm). These data suggest that increased blood proteolytic activity may play a role in the development of both AAA and adult inguinal herniation but not LS. Men who smoke manifest different systemic effects.

Aged↗
PubMed1984

Mechanisms of transport of L-histidine and beta-alanine in hamster small intestine.

Whole rings of hamster jejunum and ileum were used to study the uptake of L-histidine (L-His) and beta-alanine (beta-Ala), the constituents of the dipeptide carnosine. The rate of uptake of L-His and beta-Ala (1 mM) was not significantly different in the jejunum compared with the ileum. Results of total influx (2 min) of 0.5-100 mM L-His suggested that transport was by more than one pathway, and the contribution of nonmediated component was calculated to be 0.24 mumol X g-1 X 2 min-1 X mM-1 for both jejunum and ileum. The apparent affinity of L-His for a transporter was higher in the ileum (K iota, 8.0 mM) than the jejunum (Kt, 11.7 mM). Influx (2 min) of beta-Ala was found to be linearly related to substrate concentration over the range 0.5-100 mM. The Kd (rate constant for nonmediated uptake of beta-Ala) was 0.23 and 0.14 mumol X g-1 X 2 min-1 X mM-1 for jejunum and ileum, respectively. Steady-state (20-min) uptake of L-His was significantly higher in the ileum than jejunum at substrate concentrations of 75 mM. L-His accumulated in the tissue up to a medium concentration of 50 mM in the jejunum and 75 mM in the ileum. In contrast, no evidence of tissue accumulation of beta-Ala was found in 20-min incubations. beta-Ala steady-state uptake in the ileum was significantly higher than in the jejunum at substrate concentrations of 30 and 75 mM.

Alanine↗
PubMed1983

The effects of preoperative radiation on healing of rat colonic anastomoses.

The effect of delaying surgery, after a nominal standard dose of 4500 rad was administered to the abdomen of rats, on the healing of colonic anastomoses was evaluated. Healing, as determined by bursting pressure of colonic segments, was significantly depressed (p less than 0.05) at five days after surgery in groups irradiated five or 15 days prior to surgery as compared with groups receiving either no radiotherapy or irradiation ten days prior to surgery. Five-day healing was not significantly depressed in the group irradiated ten days prior to operation as compared with the group receiving no irradiation. No significant (p less than 0.05) differences were noted at ten or 15 days after surgery between groups that were and were not irradiated. At ten days after surgery all groups had higher bursting pressures than the control group at five days after surgery. Thus, there appears to be an optimal time interval between radiation and surgery to ensure maximal colonic healing.

Animals↗
PubMed1983

Serum proteolytic and antiproteolytic activity in acute pancreatitis.

This study has demonstrated an imbalance between the blood proteolytic and antiproteolytic system in acute pancreatitis. Serum elastase activity is markedly increased and elastase inhibitory capacity is decreased in this disease as compared with those in chronic pancreatitis and the control values. We have found that a return to normal values represents better evidence of resolution than amylase determinations. These results offer the clinician a biochemical guideline for the medical management of acute pancreatitis.

Acute Disease↗