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Biomedical subjects

P Dowd

Publications and source records attributed to P Dowd.

15 recordsLinked to original sources
PubMed1991

Mechanism of cyanide inhibition of the blood-clotting, vitamin K-dependent carboxylase.

Cyanide is a competitive inhibitor of carbon dioxide in the vitamin K-dependent glutamate carboxylase system, which plays a central role in the function of the blood clotting cascade. The mechanism of cyanide inhibition has been obscure for some time. At pH 7.2, cyanide (pKa = 9.21) will exist in solution as hydrogen cyanide to the extent of 99%. Hydrogen cyanide is linear triatomic molecule able to serve as a surrogate for carbon dioxide at the enzyme active site. Hydrogen cyanide is an acid; it will quench the deprotonated glutamate carbanion precursor to gamma-carboxyglutamate, resulting in inhibition of the carboxylation sequence.

Amino Acid Sequence↗
PubMed1991

The use of interferon-alpha in virus infections.

The interferons (IFN) act too slowly to arrest acute viral infections, but interferon-alpha (IFN alpha) preparations have proved useful in some chronic infections and will clearly be used increasingly in these in the future. In the preparations derived from human leucocytes or cultured B lymphoblastoid cells, which are in routine clinical use, mixtures of a number of distinct subtypes of human IFN alpha have been identified. There are also 3 slightly different versions of the same single subtype, IFN alpha-2, made by recombinant DNA procedures in bacteria. IFN alpha preparations are injected intramuscularly or subcutaneously. Dose-related side effects are common but usually tolerable, but prolonged treatment may cause increasing fatigue and depression. Some patients form neutralising antibodies which block the effects of the IFN; these appear to be relatively more common after recombinant IFN alpha-2 than after IFN derived from human cells. Given intranasally, IFN alpha can prevent a subsequent experimental rhinovirus infection, or the spread of natural colds within a family. Repeated administration progressively damages the nasal mucosa, so that long term prophylaxis is not possible. IFN alpha has proved useful in patients with papillomavirus warts of the larynx, ano-genital region (condyloma acuminata) and skin (common warts). Treatment regimens remain to be optimised and are likely to include surgery or other treatments. IFN alpha and zidovudine (azidothymidine) synergistically inhibit the growth of HIV in vitro, and combination are on trial in patients with early AIDS. Very large doses of IFN alpha are effective against Kaposi's sarcoma in some AIDS patients. In chronic hepatitis B, continuing virus replication may lead to cirrhosis or primary liver cancer. Earlier clinical trials with IFN alpha gave inconclusive results, but recent large studies have confirmed that 25 to 40% of patients obtain benefit; this probably results from both the antiviral and the immunomodulatory effects of IFN alpha. In patients with chronic hepatitis C, the biochemical markers usually improve rapidly during IFN alpha administration, but relapse if treatment is stopped after only a few months; to increase the chances of sustained cure, the treatment period is now being prolonged.

HIV Infections↗
PubMed1990

Vitamin B12S-promoted model rearrangement of methylmalonate to succinate is not a free radical reaction.

To probe for free radical intermediates in the model methylmalonate to succinate rearrangements promoted by vitamin B12s, a model series with a pentenyl side chain radical trap has been devised. The control free radical, generated by tri-n-butyltin hydride treatment of bromomethyl-pentenylmalonate thioester, undergoes rapid cyclization to the six-membered ring, and, as anticipated, no succinate rearrangement product is detected. By contrast when the bromide is treated with vitamin B12s, little cyclized product is observed; the major product is the pentenyl succinate. This result demonstrates that the latter rearrangement does not follow a free radical pathway.

Chemical Phenomena↗
PubMed1989

Suppression of p24 antigen in sera from HIV-infected individuals with low-dose alpha-interferon and zidovudine: a pilot study.

On the basis of the observations that HIV antigenaemia indicates a high risk of progression to AIDS and that zidovudine and alpha-interferon act synergistically against HIV replication in vitro, we performed a pilot trial including 12 HIV-infected asymptomatic patients with detectable p24 antigen in serum. The patients received low-dose lymphoblastoid alpha-interferon alone for 4 weeks followed by a combination of interferon and low-dose zidovudine for a further 16 weeks. The median p24 antigen level decreased significantly (P less than 0.01), the decrease being most pronounced at week 5. Decreases in haemoglobin and neutrophil counts were observed. Four patients required reduction of the zidovudine dose and three patients were transfused. In conclusion, the drug combination was capable of reducing the serum level of HIV p24 antigen and it was tolerated by the patients. Further studies are required to evaluate the clinical implications of these observations.

Acquired Immunodeficiency Syndrome↗
PubMed1988

A double-masked, placebo-controlled trial of acyclovir cream in immunocompetent patients with herpes zoster.

Sixty-four patients with herpes zoster were entered into a randomised double-masked, placebo-controlled trial of 5% acyclovir cream applied five times daily for 5 days. Of these patients, 56 were included in the final analysis (26 acyclovir, 30 placebo). Significant and objective differences in either progression of the rash, severity of acute pain or incidence of post-herpetic neuralgia were not observed. Although significantly more rashes involuted in the acyclovir group, this isolated finding cannot be explained. Twenty-two patients (12 acyclovir, 10 placebo) experienced erythema or desquamation or both during treatment with the cream. The similar incidence of skin reactions in both groups suggests that they were related to the cream base rather than the acyclovir.

Acyclovir↗
PubMed1985

Interaction of soluble pig heart glutamate-aspartate transaminase with various beta,gamma-unsaturated amino acids.

beta-Ethylidene-DL-aspartate (beta EA) and beta-methylene-DL-glutamate (beta MG) were synthesized and tested as potential suicide inhibitors of soluble pig heart glutamate-aspartate transaminase (sGAT). beta MG was found to be a) a substrate with a very low turnover number relative to glutamate and b) a competitive inhibitor with respect to aspartate (albeit with a large binding constant). At high concentrations beta MG inactivated the enzyme but only very slowly. beta EA was also found to be a substrate with a very low turnover number; it did not inactivate the enzyme (1 hr, 25 degrees C) even at a high concentration. However, beta EA was found to bind to the enzyme with an affinity comparable to that of aspartate and glutamate. beta-Methylene-DL-aspartate (beta MA) has been shown to rapidly inactivate glutamate-aspartate transaminase. Therefore, it appears that glutamate-aspartate transaminase can bind analogues of aspartate with alkene groups in the beta position. The conjugated carbonyl groups of beta MA and beta EA will enhance Michael addition in comparison with that expected for vinylglycine. On the other hand, the presence of the methyl groups should reduce the electrophilicity of the double bond of beta EA compared to beta MA. This deactivation and/or steric hindrance to Michael attack may account for the inability of beta EA to inactivate sGAT. Therefore, it may be possible to design selective suicide inhibitors of glutamate-aspartate++ transaminase with the following structure: HO2CC(= CHX)CH(CO2H)NH2, where X is an electron-withdrawing group. Ideally, X would increase the reactivity of the double bond while affording a minimum of steric hindrance to susceptible enzyme-bound bases.

Amino Acids↗
PubMed1977

Male intersexuality presenting at puberty.

A 15-year-old girl was referred to the Endocrine Unit because of a deep voice and the absence of menstruation. Secondary sex hair showed a male pattern of distribution and there was a phallic clitoris 4 cm long, with the urethral orifice posterior. Plasma testosterone was within the normal male range. The karyotype was 46XY. Gonadectomy and clitoridectomy were performed. Histology suggested a diagnosis of anatomical testicular failure, which, in view of the imperfect attempt at masculinization, was thought to be only partial. Possible causes are discussed.

Adolescent↗
PubMed1972

On the mechanism of action of vitamin B 12 . Model studies. Thermal rearrangement of methyl 3,3-dimethylglycidate to methyl levulinate.

The discovery that methyl 3,3-dimethylglycidate rearranges to methyl levulinate on heating is discussed in terms of its possible consequences for the mechanism of action of the coenzyme B(12)-dependent enzymes: methylmalonyl-CoA mutase (EC 5.4.99.2), glutamate mutase (EC 5.4.99.1), and a-methyleneglutarate mutase. It is also suggested that the proposed mechanism may provide a unifying link between the mechanism of action of the above enzymes and that of the coenzyme B(12)-dependent dioldehydrase and related enzymes.

Butyrates↗