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Biomedical subjects

J R McLean

Publications and source records attributed to J R McLean.

At least 37 records · Page 2Linked to original sources

The radiation dose to cells in vitro from intracellular indium-111.

Most of the radionuclides used in nuclear medicine emit low energy Auger electrons following radioactive decay. These emissions, if intracellular, could irreparably damage the radiosensitive structures of the cell. The resulting radiation dose, which is a measure of biological damage in the affected cell, could be many times the average radiation dose to the associated organ. In this series of experiments, the radiation dose to the nucleus of a chinese hamster V79 cell was determined for the intracellular radiopharmaceutical 111indium-oxine. Assuming the cell nucleus to be the radiosensitive volume, the radiation dose would be primarily due to the low energy Auger electrons. A much smaller dose would be absorbed from the penetrating X- and gamma-rays and internal conversion electrons released from other radiolabelled cells in the culture. The radiation dose to the cell from the intranuclear decay of 111In was empirically established from cell survival studies to be 3.5 mGy/decay, using cobalt-60 as a reference radiation. The average dose to V79 cells from extracellular 111In (i.e., from 111In located outside the target cell) was calculated to be 5.8 pGy/decay. This suggests that for an intracellular radiopharmaceutical, the radiation dose of consequence would be delivered by the low energy Auger electrons. In contrast, Auger electrons from an extracellular radiopharmaceutical could not directly damage the cell nucleus and therefore would not contribute to the radiation dose.

Animals↗

The Auger electron dosimetry of indium-111 in mammalian cells in vitro.

Most of the radionuclides used in the formulation of radiopharmaceuticals emit Auger electrons when they undergo radioactive decay. The release of these low-energy electrons at extracellular sites produces little direct damage to intracellular structures. However, many radiopharmaceuticals, or their metabolites, can be transported into the cell where the Auger electrons have the potential to damage nearby intracellular macromolecules, including DNA. In this preliminary study, chromosome damage, expressed as 60Co equivalent doses, and the effects on cell division following treatment with intracellular and extracellular 111In were measured in Chinese hamster V79 cells. The chromosome aberration yield in cells irradiated by intracellular 111In indicated that damage was induced at a rate of 7.2 X 10(-4) Gy/decay for levels of activity up to 0.075 Bq/cell and 4.5 X 10(4) and 2.9 X 10(4) Gy/decay for intermediate (0.204 Bq/cell) and high (0.389 Bq/cell) levels, respectively. Extracellular 111In-chloride produced damage at a rate of about 6.1 X 10(-12) Gy/decay. As little as 4.4 mBq/cell (about 4.4 X 10(3) Bq/ml of culture) of intracellular 111In was able to affect cell division, whereas extracellular 111In at 1.150 MBq/ml of culture had little effect. These data indicate that the Medical Internal Radiation Dose and International Committee on Radiation Units methods for organ dosimetry may underestimate the potential of intracellular Auger electron emitters to produce radiation damage.

Animals↗

A cavitation and free radical dosimeter for ultrasound.

A simple and sensitive method is described for measuring the number of hydroxyl radicals (.OH) produced in aqueous solution by high intensity ultrasound (US). The method is based on the conversion of nonfluorescent terephthalic acid (TA) to highly fluorescent hydroxyterephthalate (HTA). The spectrofluorimeter is calibrated by use of a TA solution which has been exposed to a reference dose of cobalt-60. This allows fluorescence readings produced by ultrasound to be read directly in equivalent centiGrays (cGy). The limit of detection for OH is about 1.3 X 10(-9) M (equivalent to an exposure of about 0.5 cGy of cobalt-60). The threshold for transient cavitation (TC) in an air-saturated aqueous solution was found at 0.7 watts per cm2. Cavitation was consistently produced when TA was exposed in a soft vinyl chamber and only when the chamber was being rotated about an axis which was perpendicular to the US beam. The use of TA as a quantitative indicator of transient cavitation should be of value to the study of ultrasonic biological effects and dosimetry.

Equipment Design↗

Cancer risk from inorganics.

Inorganic metals and minerals for which there is evidence of carcinogenicity are identified. The risk of cancer from contact with them in the work place, the general environment, and under conditions of clinical (medical) exposure is discussed. The evidence indicates that minerals and metals most often influence cancer development through their action as cocarcinogens. The relationship between the physical form of mineral fibers, smoking and carcinogenic risk is emphasized. Metals are categorized as established (As, Be, Cr, Ni), suspected (Cd, Pb) and possible carcinogens (Table 6), based on the existing in vitro, animal experimental and human epidemiological data. Cancer risk and possible modes of action of elements in each class are discussed. Views on mechanisms that may be responsible for the carcinogenicity of metals are updated and analysed. Some specific examples of cancer risks associated with the clinical use of potentially carcinogenic metals and from radioactive pharmaceuticals used in therapy and diagnosis are presented. Questions are raised as to the effectiveness of conventional dosimetry in accurately measuring risk from radiopharmaceuticals.

Animals↗

Neuropharmacology of zonisamide, a new antiepileptic drug.

Zonisamide readily crosses the blood-brain barrier and is readily absorbed after oral administration with a Tmax of about 3 hr. The half-life of ZNA in epileptic patients is about 28 hr. Zonisamide has a broader therapeutic range than other antiepileptic drugs. Neurotoxic, hemapoietic, renal, and liver effects have been minimal in patients participating in controlled clinical studies. It is effective in several experimental models of epilepsy and in initial clinical trials has been shown to be effective in generalized tonic-clonic, simple, and complex partial seizures.

Animals↗

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy.

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.

Adolescent↗

An in vitro study of the pharmacological and electrophysiological properties and the adrenergic innervation of small pulmonary arteries from children with pulmonary hypertension.

A study was made of the pharmacological and electrophysiological properties of pieces of small intrapulmonary arteries (100-450 micron I.D.) taken from children with cardiac defects that caused the pulmonary circulation to be exposed to an abnormally high perfusion pressure. The sensitivity of the arterial smooth muscle to the constrictor agonists acetylcholine and 5-hydroxytryptamine was similar to that reported for adult pulmonary arteries. Norepinephrine or histamine caused little or no constriction, although both these substances have been reported to be powerful constrictors of adult pulmonary arteries. The electrophysiological properties were similar to those of the smooth muscle of systemic arteries. The mean resting membrane potential was -6.12 mV +/- 1.29 (SEM n = 16). Stimulation of the perivascular nerves produced excitatory junction potentials, but no smooth muscle action potentials were recorded. Histochemical investigation revealed catecholamine containing nerve fibres around all intrapulmonary arteries down to 40 micron I.D.

Acetylcholine↗

Catecholamine-containing neurons and lymphoid cells in a lacrimal gland of the pigeon.

The Harderian gland of birds, a major lacrimal gland, contains a large population of lymphoid cells that produce IgA, a significant component of tears. Using histochemical techniques, we have examined the innervation of the gland. There was an extensive acetylcholine-esterase positive fiber network throughout the gland. However, catecholamine positive fibers were seen mainly associated with peripheral blood vessels and the lymphoid cell population which contained autofluorescent plasma cells. Ultrastructural examination showed that vesicle filled nerve varicosities were often seen near plasma cells and that some of these varicosities reacted positively for catecholamines. These anatomical data suggest that the lymphoid cell population may be affected by the autonomic nervous system.

Acetylcholinesterase↗

The adrenergic innervation of pulmonary vasculature in the normal and pulmonary hypertensive rat.

It would appear that susceptibility to chronic proliferative pulmonary hypertension in response to chronic alveolar hypoxia is most severe in species in which adrenergic innervation of pulmonary arteries is reduced or lacking. Intrapulmonary arteries of the rat have been reported to lack adrenergic innervation by some workers but not others. Since the rat develops severe proliferative pulmonary hypertension in response to prolonged alveolar hypoxia, the different divisions of the lung vasculature of Sprague-Dawley rats were thoroughly examined to determine the presence or absence of an adrenergic innervation. The degree of innervation in normal rats was compared with that of rats developing pulmonary hypertension. Both in normal and experimental pulmonary hypertensive rats the pulmonary arteries, all their branches and the small pulmonary veins with a smooth muscle media were found to be devoid of adrenergic innervation. In contrast, the cardiac-like muscle in the media of large pulmonary veins, the bronchial arteries and the vasa vasorum of larger vessels were richly innervated by adrenergic nerves. Thus the increase in medial smooth muscle which occurs in pulmonary arteries during chronic alveolar hypoxia is independent of a pre-existing adrenergic innervation or of such an innervation newly derived from that of adjacent vessels or structures. This is in contrast to systemic vessels where it has been suggested that increased adrenergic activity and density of innervation may augment hypertrophy of the media in hypertensive animals. Adrenergic nerves are suggested to have a protective action on pulmonary vessels.

Adrenergic Fibers↗

The effect of tin chloride on the structure and function of DNA in human white blood cells.

Tin compounds are being used increasingly in the home, in industry and in medicine. There have been relatively few studies on the long term biological effects of this metal, although acute effects have been documented. In this report we describe experiments which show that tin(II), as stannous chloride, is readily taken up by human white blood cells (WBC) and can cause damage to DNA. Damage was detected in WBC after exposure to 10-50 microM tin(II) for 30 min at either 0 degree or 37 degrees C. The amount of damage observed was more extensive than that produced by exposure of cells to equimolar amounts of chromium(VI), a known carcinogen and DNA damaging agent. Additional indication of cellular damage is that exposure of human lymphocytes or mouse splenocytes to tin(II) interfered with their ability to be stimulated by the polyvalent mitogen concanavalin A (Con A). By contrast, tin(IV) was not taken up by cells, did not cause DNA damage nor did it inhibit stimulation of DNA synthesis in cells that were exposed to Con A.

Biological Transport↗

The effect of stannous and stannic (tin) chloride on DNA in Chinese hamster ovary cells.

Tin(II) at concentrations up to 500 microM stannous chloride (SnCl2), produced extensive DNA damage, as detected by alkaline sucrose gradient (ASG) analysis in Chinese hamster ovary (CHO) cells treated for 1 h at 37 degrees C in serum-free minimal essential medium (MEM). However treatment of cells with tin(IV), as stannic chloride (SnCl4), produced no such DNA damage. There was no loss in colony formation 6 days after either treatment suggesting that the DNA damage induced by the tin(II) was rapidly repaired and/or that DNA synthesis proceeded on the damaged templates permitting cell division to occur. Alternatively, the type of DNA damage caused by tin(II) may not lead to a reduction in colony-forming ability. Tin(II) produced about 200 times more ASG detectable DNA damage on an equi-molar basis than did Cr(VI), a known human carcinogen. This study indicates that tin(II) may be potentially genotoxic.

Animals↗

On the mechanism of the pharmacologic activity of meclofenamate sodium.

N-(2,6-Dichloro-m-tolyl)anthranilic acid, sodium salt (meclofenamate sodium, Meclomen), the sodium salt of meclofenamic acid, has anti-inflammatory activity both in animal models and in clinical use. This activity is believed to be due in large part to the ability of the drug to inhibit the synthesis of prostaglandins by inhibiting arachidonic acid cyclo-oxygenase. Further, there is evidence that meclofenamic acid directly antagonizes the actions of prostaglandins at receptor sites. In addition, meclofenamic acid may also inhibit arachidonic acid lipoxygenase, resulting in decreased synthesis of leukotrienes, known mediators involved in the inflammatory process.

Animals↗

Rapid assay for total unbound Tc-99m in preparations of Tc-99m in macroaggregated albumin: concise communication.

A rapid economic filter-paper assay for determining total unbound Tc-99m in preparations of Tc-99m macroaggregated albumin (Tc-99m MAA) is described. The procedure uses Whatman 542 filter-papter discs and aqueous 0.009% NaCl as wash solution. The principal radiochemical impurities found in Tc-99m MAA kits are not significantly adsorbed to the filter matrix. The procedure can be completed in 1--2 min and gives results comparable to those obtained by the centrifuge assay (USP XIX).

Albumins↗