Biomedical subjects
Publications and source records attributed to J M Wright.
Five cases of squamous odontogenic tumorlike proliferations occurring in the walls of odontogenic cysts are presented. These lesions showed no more aggressive potential than the cysts, if taken alone, in which they occurred. The lesions showed no tendency to develop into solid tumors and, on the basis of this limited series of cases, conservative surgery appears to be the treatment of choice.
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We describe clinical and biochemical changes in seven patients with Huntington disease given isoniazid (INH) in dosages three to five greater than normally used in tuberculosis. Because INH inhibits the enzyme gamma-aminobutyric acid aminotransferase (GABA-T), and increases GABA content in the brains of experimental animals, it might correct the brain GABA deficiency characteristic of Huntington disease. Of six patients treated long enough to be clinically evaluated, one showed marked and two others showed signifciant improvement. High-dose INH therapy carries serious toxic risks, which are influenced by patients' acetylator phenotypes. Nevertheless, results are sufficiently promising to warrant further controlled trials of INH or other GABA-T inhibitors in Huntington disease.
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1. The 2',3'-dialdehyde derivative of ADP (oADP) at concentrations approaching the millimolar range induces human blood platelets to undergo the transition from discoid to globular morphology (the 'shape change') but is incapable of inducing aggregation. 2. When incubated with platelets for 1 min before addition of the agonist, oADP acts as a competitive inhibitor of shape change and aggregation induced by ADP. Under these conditions secretion and hence aggregation induced by low concentrations of collagen; and secretion and hence secondary aggregation induced by adrenaline, thrombin and vasopressin are also inhibited by this analogue. In addition, oADP stimulates the rate of primary aggregation induced by adrenaline and causes partial inhibition of primary aggregation induced by thrombin or vasopressin. When longer preincubation times are employed the extent of inhibition with respect to all agonists, except for high concentrations of collagen, is increased and the competitive character of the inhibition with respect to ADP is no longer apparent. 3. Incubation of human platelets with the 2',3'-dialdehyde derivative of ATP (oATP) causes effects similar to those described for oADP except that the analogue neither induces platelet shape change, nor stimulates the rate of primary aggregation induced by adrenaline. In addition oATP fails to cause significant inhibition of platelet shape change induced by serotonin. The extent and character of inhibition caused by addition of oATP is not a function of the time of incubation. 4. The 2',3'-dialcohol derivatives of ADP and ATP and orATP) effect the aggregation properties of human blood platelets in a manner generally resembling those observed for the 2',3'-dialdehyde analogues. However, orADP is only weakly effective in causing platelet shape change and stimulating the rate of primary aggregation induced by adrenaline and does not inhibit secretion induced by adrenaline, collagen, thrombin and vasopressin. The extent of inhibition by orADP increases only slightly with increased time of incubation. 5. The data suggest that oADP acts as a partial agonist, and oATP as an antagonist, at the platelet ADP receptor, but that platelet membrane stabilisation also results from interaction with these dialdehyde analogues. Such membrane stabilisation does not complicate the interaction of platelets with orADP, which appears to act as a classical antagonist for the ADP receptor.
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On 20 consecutive work days during four weeks, one technologist performed 24 microchromatographic determinations of hemoglobin A2 (Hb A2) by each of four methods: the Efremov procedure requiring Tris/HCl buffer, the original Huisman technique with use of glycine developer, and two commercial test kits in which a modified glycine developer is used. The bloood samples tested were obtained from 12 adults with no hematological abnormality and from 12 beta-thalassemia carriers previously diagnosed by familial and hematologic studies. Results by the first method and the two commercial kits (one from Helena Laboratories and one from Isolab, Inc.) did not differ significantly in precision for either the normal or beta-thalassemia trait samples. For both sample types, the second method yielded larger coefficients of variation than those obtained with the other methods. Moreover, the second method was the only one with which values overlapped for normal samples and samples with above-normal Hb A2 concentrations.
Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.
These experiments were designed to determine the site and mechanism of action of neomycin on cholinergic transmission. These agents depressed the response of rat diaphragm preparations to phrenic nerve stimulation and to injected acetylcholine (ACh); however, equi-effective neuromuscular blocking concentrations of neomycin (6 x 10(-4) M), streptomycin (1.2 x 10(-3) M) or d-tubocurarine (6.5 x 10(-7) M) reduced the muscle response to injected ACh to 54,27 and 15% of control, respectively, suggesting that neomycin and streptomycin have a presynaptic effect. This finding was confirmed by measuring ACh release from the diaphragm during phrenic nerve stimulation; neomycin (6x10(-4) M) and streptomycin (1.2 x 10(-4) M) depressed ACh release to 29 and 41% of control, respectively. In the cat superior cervical ganglion neomycin (2 x 10(-3) M) blocked ganglionic transmission, did not reduce the response of ganglion cells to injected nicotine and depressed ACh release during preganglionic nerve stimulation to 61% of control in normal Ca++ (2.5 mM) medium and to less than 10% of control in low Ca++ (0.5 mM) medium. The increased accululation of 45Ca induced in rat isolated ganglia by preganglionic nerve stimulation was not changed by d-tubocurarine (2 x 10(-4) M), but was abolished by neomycin (2 x10(-3) M). It is concluded that neomycin blocks ACh release by blocking the influx of Ca++ necessary for transmitter release. This conclusion suggested that neomycin should block noradrenaline release, and this was shown using the anococcygeus preparation from the rat.
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To compare the antihypertensive efficacy of methyldopa administered once at bedtime with the same total dose given three times daily, a double-blind crossover study was performed in 14 patients previously well controlled on methyldopa. Each patient received a total daily dose of 0.37 gm, 0.75 gm, or 1.5 gm of methyldopa, depending on the dose of drug that had previously been successful in that individual. The trial design included either 12 wk of methyldopa three times daily (TID) followed by 12 wk of single daily bedtime (HS) doses of methyldopa or administration of drug in the reverse order. Supine and erect blood pressures were recorded 4 times daily (8 a.m., 12 noon, 4 p.m., and 8 p.m.) every 4 wk throughout the study. Blood pressure control was excellent in all patients whether the drug was administered three times daily or at bedtime. Systolic pressures were slightly lower at 8 a.m., when methyldopa was given at bedtime than on doses three times daily, and systolic and diastolic pressures were slightly higher at 8 p.m. that at 8 a.m. on the bedtime regimen.
The site of neuromuscular blockade induced by polymyxin B and rolitetracycline was studied on isolated nerve and nerve-muscle preparations. Polymyxin B (1.8 X 10(-4) M) was equipotent to lidocaine as a local anaesthetic on a frog desheathed nerve preparation, while rolitetracycline (up to 3.6 X 10(-3)M) had no local anaesthetic effect. Polymyxin B (6 X 10(-5) M) and rolitetracycline (7 X 10(-4) M) blocked by 50% the response of rat diaphragm induced by phrenic nerve stimulation, but did not decrease the amount of acetylcholine (ACh) released from this preparation during nerve stimulation. Both antibiotics depressed the response of the rat diaphragm to inject ACh, and this response was more sensitive to inhibition by the drugs than was the response to nerve stimulation. With rolitetracycline, a concentration that blocked the response to nerve stimulation by 50% inhibited the response to injected ACh by 85%, and this relationship was similar to that with d-tubocurarine; however, polymyxin B was relatively more effective than d-tubocurarine in inhibiting the effect of ACh. Polymyxin B (1-1.5 X 10(-4) M) but not rolitetracycline (1 X 10(-3) M) depressed the response of the diaphragm to direct muscle stimulation. It is concluded that polymyxin B and rolitetracycline block neuromuscular transmission predominatly by an effect to depress the muscle's sensitivity to ACh; polymyxin B probably acts by an effect similar to that of local anaesthetics, while rolitetracycline probably acts by an effect similar to that of d-tubocurarine.
The site of neuromuscular blockade induced by clindamycin and lincomycin was studied on isolated nerve and nerve-muscle preparations. Clindamycin (3.6 X 10(-3) M) but not lincomycin (up to 1.5 X 10(-2) M) had a local anaesthetic effect on a frog desheathed nerve preparation. Clindamycin (8 X 10(-4) M) and lincomycin (4 X 10(-3) M) depressed the response of the rat diaphragm to nerve stimulation and to direct muscle stimulation in parallel. This indicated that the predominant neuromuscular blocking effect of these antibiotics was due to an effect on the muscle. Clindamycin was fivefold more potent than lincomycin in this effect, and the unionized form of both drugs was the active form. Lincomycin (4 X 10(-3) M) but not clindamycin (8 X 10(-4) M) also had some depressant effect on nerve-muscle transmission as indicated by the interaction of the effects of the antibiotics and d-tubocurarine. The significance of these findings is discussed in relation to the acute clinical toxicity of these antibiotics.
Some factors affecting the metabolism of the potent hepatotoxin, acetylhydrazine, were studied in rats. After ip administration of [14C]acetylhydrazine, 36% and 38% of the dose was recovered in the urine and as 14CO2, respectively. The major urinary metabolites were diacetylhydrazine and the pyruvic acid and alpha-oxoglutaric acid acetylhydrazones. The acetylation of acetylhydrazine to diacetylhydrazine was found to be dose-dependent and to be inhibited by coadministered isoniazid and p-aminosalicylic acid. Coadministered acetylisoniazid had no effect on acetylation. The proportion of acetylhydrazine recovered as 14CO2 presumably reflects the amount metabolized by the microsomal oxidation pathway, thought to be responsible for the toxicity, and also possibly by hydrolysis to acetate and hydrazine. This latter pathway could not be confirmed, as only a small proportion of hydrazine administered to rats was recovered. The inhibition of acetylation by p-aminosalicyclic acid, but not isoniazid, significantly increased the excretion of 14CO2, suggesting that isoniazid may also inhibit a pathway resulting in the production of 14CO2. These results indicate that the metabolism and hepatotoxicity of acetylhydrazine may be different when it is produced as a metabolite of isoniazid than when it is given alone.
The interaction of isoniazid with its hepatotoxic metabolite acetylhydrazine has been studied. In vitro, isoniazid at a concentration of 0.5 mM was found to inhibit the microsomal metabolism of acetylhydrazine to a reactive acylating species. In vivo, however, coadministered isoniazid inhibited the acetylation to diacetylhydrazine and concomitantly increased the microsomal metabolism of 14C-acetylhydrazine to a reactive intermediate which covalently bound to liver macromolecules. Comparison of urinary metabolites of isoniazid at two dose levels indicated that acetylation of acetylhydrazine produced as a metabolite may be inhibited by the parent drug.