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Biomedical subjects

D Holt

Publications and source records attributed to D Holt.

At least 73 records · Page 4Linked to original sources
PubMed1986

Intestinal uptake and retention of copper in the suckling rat, Rattus rattus--I. Distribution and binding.

The distribution of the heterogeneous copper (Cu)-complex in the intestine of the neonatal rat parallels that of total Cu and is maximal in the ileum. In the ileum the total Cu concentration exceeds 400 micrograms/g wet wt at 14 days of age and then falls to about 20 micrograms/g wet wt in the 20-day-old pup. The apoproteins (apopeptides) of the Cu-complex, which are absent from the late-foetal intestine, vary in number and proportion with postnatal age and nutritional status.

Aging↗
PubMed1986

Intestinal uptake and retention of copper in the suckling rat, Rattus rattus--II. Copper accumulation in the ileum and distal jejunum.

High concentrations of copper were demonstrated histochemically in the enterocytes lining the ileum and distal jejunum of suckling rats. Copper was not detected in cells from the duodenum or proximal jejunum of these rats or from any region of the small intestine of rats in which "closure" had taken place. X-Ray microanalysis demonstrated copper, in equi-atomic association with sulphur, within discrete vesicles in the supranuclear cytoplasm of the enterocytes. Despite the high concentrations of these two elements no biochemical evidence was found for the presence of significant amounts of copper-binding metallothionein. The highest concentrations of copper (226 +/- 48 mg atoms/kg dry wt: +/- SD) were found in vesicles adjacent to the nucleus, which did not accumulate particulate tracers, or calcium from the lumen of the intestine. These vesicles probably result from the coalescence of Golgi-derived primary lysosomes followed by fusion with endocytic vacuoles. They may provide a mechanism of copper excretion from the neonatal rat.

Acid Phosphatase↗
PubMed1986

Physiological zinc-binding proteins of medium molecular weight in the rat gut.

1. Gel filtration on Sephadex G 75 was used to separate the medium-molecular-weight zinc-binding proteins from the soluble fractions from the duodenal and jejuno-ileal segments of the rat gut at 30 min after the intragastric administration of a tracer dose of 65Zn. These proteins were resolved by ion-exchange chromatography on DEAE cellulose. 2. In both the duodenum and jejuno-ileal segment an appreciable fraction of the total soluble Zn was bound in a protein fraction that resembled metallothionein (MT) in its behaviour on gel filtration. These fractions, however, were not homogeneous, but contained several medium-molecular-weight Zn-binding proteins. In the duodenum, but not in the jejuno-ileal segment, two of these proteins appeared to be the isometallothioneins, ZnMT-I and ZnMT-II. 3. These results suggest a possible role for MT in the binding of newly-absorbed Zn in the duodenal mucosal cells. They also show that gel filtration alone is insufficient for the identification of MT in the intestine.

Animals↗
PubMed1985

The chronic toxicity of equine cadmium metallothionein in the rat.

The extensive renal tubular necrosis that results in male rats after the intravenous injection of a single, low dose of equine kidney cadmium (Cd), zinc(Zn)-metallothionein (MT) (0.2 mg MT-bound-Cd/kg body wt.) is followed within 72 h by active regeneration. With repeated administration of the same dose at 3- or 4-day intervals, lesion resolves although, at least initially, the kidney content of Cd increases progressively. At any time during treatment, about 40% of the accumulated Cd is bound as the endogenous (Cd, Cu)MT. The rate of increase in the renal Cd content is dependent on the ratio of Cd:Zn in the injected metalloprotein, and is appreciably less when the constant dose of protein-bound Cd is given as a (2.4 Cd:1 Zn)MT, than as a (3.0 Cd:1 Zn)MT. On repeated administration of the latter preparation, however, the concentration of Cd in the kidney does not attain a critical concentration, above which persistent tubular damage occurs, but reaches a maximum of about 150-160 micrograms Cd/g wet wt. (after 16 doses) and then declines. After 19 doses of the (2.4 Cd:1 Zn)MT under the same conditions, the renal Cd concentration is submaximal and is less (92 micrograms Cd/g wet wt.) than that after either 16 or 27 doses of the (3.0 Cd:1 Zn)MT. In animals that are dosed with either of the heterologous MT preparations, the first dose, although not innocuous, seems to protect the kidneys against further damage by subsequent doses. Repeated doses, however, lead to vascular changes, e.g. lymphoid infiltration, periarteriole oedema and dilation of the arcuate veins, and to dilation of the glomerular spaces.

Animals↗
PubMed1985

The acute toxicity and teratogenicity of nickel in pregnant rats.

The increase susceptibility of the pregnant rat to intraperitoneally administered nickel (Ni) is apparent at 12 and 19 days of pregnancy and cannot be due, therefore, to the increase in total body weight. Teratogenic malformations occur when Ni is administered during organogenesis and are maximal at dose levels that are toxic for the dam. The yolk sac and chorioallantoic placentas accumulate Ni, but this does not prevent the transport of the metal to the embryo or foetus. The Ni concentrations in the conceptuses decrease more slowly with time than those in the maternal organs. In the foetuses, the decrease in concentration is due to the increase in weight, since the content of Ni increases between 4 h and 24 h. Foetal uptake of [14C]thymidine, [3H]leucine and 65Zn is unaffected at 3 h after the injection of the dam with 4 mg Ni/kg body wt. Incorporation of [3H]leucine into foetal protein, but not the incorporation of [14C]-thymidine into DNA, is decreased at this time. A major effect of treatment with this teratogenic dose is an increase in the maternal plasma glucose concentration which, in turn, alters the supply of the sugar to the foetus. The possible relevance of temporary foetal hyperglycaemia to teratogenesis is discussed.

Abnormalities, Drug-Induced↗
PubMed1985

Digoxin and cimetidine: investigation of the potential for a drug interaction.

The potential for a pharmacokinetic interaction between digoxin and cimetidine was investigated in a series of studies. In a single-dose cross-over study in healthy volunteer subjects cimetidine increased the area under the plasma digoxin concentration curve and the peak plasma digoxin concentration. In a repeated-dose study in healthy volunteer subjects taking digoxin 0.25 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.15 ng/ml. In a repeated-dose study in healthy volunteer subjects taking digoxin 0.5 mg daily, co-administration of cimetidine resulted in an average increase in plasma digoxin concentration of 0.19 ng/ml. In a repeated-dose study in patients receiving long-term digoxin therapy for atrial fibrillation co-administration of cimetidine had no significant effect on plasma digoxin concentrations. We have shown that co-administration of cimetidine and digoxin in volunteer subjects causes a statistically significant but small increase in plasma digoxin concentration but no such increase was found in patients. We conclude that it is doubtful that this interaction is of any clinical significance.

Adult↗
PubMed1984

Dimethoxyethylphthalate metabolism: teratogenicity of the diester and its metabolites in the pregnant rat.

The rat foetus, in contrast with the maternal liver and placenta, has little or no ability to hydrolyse di-(2-methoxyethyl)-phthalate (DMEP) to mono-2-methoxyethyl)-phthalate (MMEP). At short times after the administration of DMEP to the dam on the 14th day of gestation, however, both the di- and mono-ester are present in the foetus. Clearance of total phthalate from the foetus and placenta, is rapid and the foetal burden is reduced by 96% between 45 min and 4 h. Although MMEP, when injected into the dam at the same molar dose level, crosses the placenta, its concentration in the foetus is lower than the after the injection of DMEP, MMEP (2.49 mmol kg-1), is no teratogenic when administered as an aqueous solution of the sodium salt on day 8, 10, 12 or 14 of gestation, in contrast with the same molar dose of the liquid DMEP. The alcohol, 2-methoxyethanol (ME), when administered as a single injection at this dose level (2.49 mmol kg-1), however, is highly teratogenic and its effects cannot be differentiated clearly from those of DMEP. These results, which indicate the possibility that ME, derived by metabolism of DMEP, may be the teratogenic agent, suggest that both the rate of hydrolysis to the monoester and the chemical properties of the liberated alcohol, could be important determinant factors in the teratogenic activities of different phthalate diesters.

Animals↗
PubMed1984

The teratogenicity of methoxyacetic acid in the rat.

Intraperitoneal (i.p.) administration of methoxyacetic acid (MAA) to rats on Day 8, 10, 12 or 14 of pregnancy was embryolethal and teratogenic. Skeletal anomalies, hydrocephalus and dilatation of the kidney pelvis were the most common malformations. Embryonic response to MAA varied with gestational age and with dosage (0.1 to 2.5 mmol/kg). These actions are similar to those previously reported for 2-methoxyethanol (ME) and dimethoxyethyl phthalate (DMEP). Embryos were also examined on Day 12, 48 h following i.p. administration of 2.5 mmol/kg MAA. Abnormalities were comparable to those previously observed following MAA treatment of rat conceptuses in culture. These data support the conclusion that MAA is the proximal teratogenic metabolite of ME and DMEP.

Abnormalities, Drug-Induced↗
PubMed1984

Pharmacokinetics and pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol.

Treatment of angina pectoris with beta-adrenoceptor antagonists and verapamil in combination is effective and increasingly common. The study reported here was designed to show whether the pharmacokinetics of verapamil are influenced by concurrent treatment with three different beta-adrenoceptor blockers, and whether there is any pharmacodynamic interaction between these drugs. Twelve healthy volunteers (eight men, four women) aged 21-25 years and weighing 48-82 kg consented to participate in the study. They received verapamil 50 mg three times daily for four 1-week periods, each separated by a 1 week 'washout' period. During three of the four treatment periods, the subjects took either atenolol 100 mg once daily, metoprolol 100 mg twice daily or propranolol 80 mg twice daily; in the remaining period they took verapamil alone. The concentration/time curve and plasma elimination half-life of verapamil and norverapamil, its major metabolite, were not influenced by 1 weeks co-administration atenolol, metoprolol or propranolol. As expected, co-administration of each of the beta-adrenoceptor blockers significantly reduced exercise heart rate when compared with verapamil alone.

Adrenergic beta-Antagonists↗
PubMed1983

The appropriate dosage regime for the transition from intravenous lignocaine to oral tocainide after acute myocardial infarction.

To define the appropriate regime for the transition from intravenous lignocaine to oral tocainide after uncomplicated acute myocardial infarction, 43 patients received lignocaine to steady state. Each patient then received a tocainide dosage schedule. Plasma concentration of lignocaine and tocainide was measured frequently until the third peak plasma tocainide level. Tocainide 400 mg 8 hourly starting 4 h before cessation of lignocaine and tocainide 400 mg 4 hourly starting at the end of the infusion produced therapeutic plasma tocainide concentration (3.5-9 mg/l) only after the second dose. Tocainide 600 mg 12 hourly starting 6 h before cessation of lignocaine and tocainide 600 mg 6 hourly starting at the end of the infusion quickly achieved therapeutic plasma tocainide concentration which declined to give subtherapeutic first dose troughs of 2.42 mg/l (+/- 0.28 SEM) and 2.79 mg/l (+/- 0.27 SEM) respectively. Consistently therapeutic plasma tocainide concentrations were achieved by both of these regimens after the second dose. The short plasma half-life of lignocaine which for these regimes was 3.71 h (+/- 0.25 SEM), resulted in subtherapeutic lignocaine concentrations before consistently therapeutic plasma tocainide concentrations had been achieved. On the basis of these results, the 600 mg 6 hourly tocainide dosage schedule was studied with cessation of lignocaine infusion either two or six h after the first tocainide dose. With the former regime only three of 5 patients had therapeutic lignocaine at the subtherapeutic tocainide trough.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1982

Plasma concentrations of lignocaine during fibreoptic bronchoscopy.

Peak plasma concentrations of lignocaine were recorded in 41 patients receiving topically applied lignocaine for fiberoptic bronchoscopy. Adequate anaesthesia was achieved in all patients with an average dose per unit weight of 9.3 +/- 0.5 mg/kg (SEM) giving a mean peak plasma concentration of 2.9 +/- 0.5 mg/l-1 (SEM) (+/- SEM 0.5). The plasma concentration exceeded toxic levels of 5.0 mg/l-1 in only two patients, and no complications were observed. Peak concentrations were influenced only by dose per unit weight administered and not by factors considered likely to influence mucosal absorption from the bronchial tree, such as sputum production, airflow obstruction, or cigarette smoking. A major proportion of the total dose of lignocaine was required to anaesthetise the nose, pharynx, and larynx, only a small proportion being needed for the bronchial tree. Lignocaine gel (2% w/v) was preferred by patients, and in a study of 10 volunteers, produced lower plasma concentrations when used as a topical anaesthetic than did lignocaine aerosol (10% w/v) or lignocaine solution (4% w/v).

Administration, Topical↗