Pharmacokinetics of lithium: elimination half-time, renal clearance and apparent volume of distribution in schizophrenia.

The elimination half-time and renal clearance of lithium was measured in 12 schizophrenic patients. Minimum plasma lithium concentrations during alternate dosage intervals in 5 patients increased rapidly during the first 2 to 3 days of treatment and reached a steady state level after 5 to 6 days. After the establishment of the remaining 7 patients on lithium the decline in plasma lithium concentration when treatment was stopped was monoexponential. Elimination half-times ranged from 19.3 to 41.3 hours (mean +/- SD = 28.9 +/- 7.9h) and were significantly correlated with renal creatinine clearance (p less than 0.01). Renal lithium clearances ranged from 13.5 to 36.8 ml/min (mean +/- SD = 24.4 +/- 8.0 ml/min) and the apparent volumes of distribution ranged from 0.39 to 1.39 L/kg (mean +/- SD = 0.79 +/- 0.34 L/kg). There was no evidence that the elimination parameters of lithium in schizophrenic patients were significantly different from those in healthy individuals or manic-depressive patients.

Displacement from protein binding of sulphormethoxine by phenylbutazone using in vivo dialysis in rats.

1. Displacement of the ultra-long-acting sulphonamide sulphormethoxine from binding to serum proteins by phenylbutazone has been demonstrated by in vivo dialysis in rats. The technique used involved the introduction of dialysis sacs into the peritoneal cavity. The regression line relating free to total sulphormethoxine was significantly displaced after addition of phenylbutazone to the regime although the mean level of free drug was not significantly raised. No significant effect was observed on the proportion of phenylbutazone in the free form. The range of concentrations employed corresponded to that encountered clinically.2. In vitro experiments with comparable concentrations of both drugs confirmed displacement of sulphormethoxine by phenylbutazone. Insignificant displacement of phenylbutazone from binding occurred. These experiments indicated the relationships between the relative affinities of sulphormethoxine and phenylbutazone for serum proteins and the extent to which mutual displacement from binding occurred.

Drug displacement from protein binding: isolation of a redistributional drug interaction in vivo.

1. The pharmacokinetic interaction between phenylbutazone and sulphadoxine has been studied in live sheep.2. Intravenous injection of phenylbutazone causes a rapid fall in the concentration of total sulphadoxine together with a simultaneous rise in the concentration of free sulphadoxine in plasma. Both processes are complete within 3 min of the injection of phenylbutazone.3. These reciprocal changes in the concentrations of total and free sulphadoxine in plasma do not depend on changes in the absorption, hepatic metabolism or renal excretion of sulphadoxine. By exclusion therefore, it is concluded that the effect of phenylbutazone in this interaction is solely to cause redistribution of the sulphadoxine.

The long term safety of hormonal steroid contraceptives.

PIP: The accumulated data on combined OC (oral contraceptive) use makes it possible to assess with accuracy the longterm risk associated with such use. The risks for young women are low. Risks rise with age and such factors as smoking, hypertension, diabetes, and hyperlipidemia. Women over 35, especially smokers, are at considerable risk of vascular disease. There are small risks of liver, endometrial, and cervical neoplasms, increasing with use and other risk factors. Diabetes may be accelerated. There is also a risk of depression in susceptible patients. For oral and injectable progestagen-only contraceptives, the risks are reasonably well documented in the short- but not the longterm. With progestagen-only minipills, the risks other than that of pregnancy are low. Injectable progestagen may cause anaphylaxis at the time of injection.^ieng

The effect of zinc and copper pretreatment on the binding of gold (I) to hepatic and renal metallothioneins.

In the first part of this study, single s.c. injections of gold (I) sodium thiomalate were given to male Wistar rats at various dose levels and sacrificed either at 48 hr or 4 days later. The results indicate that though metallothioneins play a significant role in the sequestration of renal gold, the ability of gold itself to induce synthesis of the metalloprotein was limited in the kidneys and practically insignificant in the liver. Pre-injection with zinc however, (4 mg/kg body wt), significantly (P less than 0.01) enhanced the uptake of gold into the metallothioneins both, in the liver as well as the kidneys. The pretreatment increased the proportion of cytosolic gold incorporated into the thioneins from 29% to 48% in the kidneys and from 22% to 47% in the liver. Concurrent increases in the uptake of zinc and copper into the thioneins was also observed. Pre-injection with copper induced a similar effect in the kidneys only. There was no significant difference in the overall uptake of gold into the cytosol itself between the control animals (injected with gold only) and those pretreated with either zinc or copper. This indicated that the increased uptake of gold into the thioneins in the pretreated animals were due to enhanced synthesis of metallothioneins and subsequent increased binding of gold to thioneins rather than increased levels of intracellular gold itself. It is suggested that increased protection against the deposition and possible toxicity of gold in the cell organelles of the liver and kidney tissues may be provided by an increased binding of gold to metallothioneins through pretreatment with zinc, and to a lesser extent copper.

Subcutaneous fluid administration in elderly subjects: validation of an under-used technique.

In a crossover study in six volunteers over the age of 65, absorption of 500 mL of normal saline given subcutaneously was compared with that given intravenously. Tritiated water and technetium pertechnetate were used as water tracers. Tritium radioisotope levels in the blood increased in a smooth curve during subcutaneous infusion, reaching equilibrium levels within 60 minutes. The area under the curve after subcutaneous infusion was almost identical to that after intravenous infusion in all subjects. Radioactivity could not be demonstrated at the subcutaneous site 1 hour after completion of the infusion. Subcutaneous infusion is an effective method of giving fluid to elderly people and deserves more widespread use.

Factors determining the aggregation of urinary mucoprotein.

The factors determining aggregation of Tamm-Horsfall urinary mucoprotein have been examined using the technique of light-scattering photometry, which has allowed the study to be performed at the concentrations of the mucoprotein in which it occurs in the urine in vivo. The tendency to formation of aggregates is enhanced by increases in concentration of the mucoprotein, by increases in electrolyte concentration within physiological limits, and by lowering of the pH within the physiological range. The effects of 1:2 and 2:1 electrolytes are somewhat different from those of 1:1 electrolytes. The data suggest that the isoelectric point of Tamm-Horsfall protein is higher than previously thought.

Immunofluorescent localization of Tamm-Horsfall mucoprotein in human kidney.

A fluorescein-labelled antiserum to human Tamm-Horsfall mucoprotein applied to frozen human kidney sections gave strong specific labelling, mainly of cells of tubules in the outer medulla. By comparison with adjacent serial sections stained for alkaline phosphatase and succinic dehydrogenase, it is suggested that material reacting immunologically as Tamm-Horsfall muco-protein is found particularly in the cells of the ascending limb of the loop of Henle and the macula densa segment of the distal tubule.

Noradrenaline release from slices of the thalamus of normal and morphine-dependent rats.

The effect of morphine on potassium-induced stimulation of (3H)-noradrenaline release from slices of the rat thalamus was investigated. The in vitro addition of morphine (10(-6)M) significantly depressed potassium-induced tritium overflow by 42% and this was prevented by the prior addition of naloxone (3 x 10(-6)M) to the medium. The stimulation-evoked overflow of tritium from slices of the thalamus of morphine-dependent rats was not significantly different from normal controls. Addition of naloxone (10(-5)M) 10 min before exposure of the tissues to 20 mM K+ significantly enhanced noradrenaline release from 'dependent' slices. The results suggest that the basic release mechanism may have adapted to the continuous presynaptic inhibition of release by morphine.

New Zealand Committee on Adverse Drug Reactions: eleventh annual report 1976.

Under the voluntary reporting scheme 499 cases of adverse drug reaction or reactions were reported. Noteworthy items included immediate hypersensitivity-type reactions to anaesthetic agents, a number of life-threatening reactions to anti-inflammatory drugs, paradoxical increase in blood pressure with high-dose pindolol and rebound hypertension after cessation of clonidine. A further 904 reactions were reported during an intensive survey in general practice and 342 from the ongoing hospital monitoring studies in units at the Auckland and Hutt hospitals. Data from numerous sources are now being channelled through the Committee's administrative centre. During the 11th year of operations 499 reports were received under the spontaneous reporting scheme. Additionally 342 reactions derived from the established hospital monitoring programmes at the Auckland Hospital and School of Medicine and the Hutt Hospital were notified to the Committee, and a further 904 reactions were received as a result of the intensive monitoring survey of drug reactions in general practice carried out in October and November 1975. The significance of each of these sets of data is substantially different and they will be discussed separately.

Non-steroidal anti-inflammatory drugs and platelet function.

The effect of some newer non steroidal inflammatory drugs on platelet function has been assessed using platelet malondialdehyde production as a measure of cyclooxygenase activity. After single doses of the short acting NSAID's diflunisal, naproxen and sulindac, platelet malondialdehyde production was substantially diminished at one and three hours. It had largely recovered by 24 hours and had returned to normal by 48 hours. After aspirin malondialdehyde production was markedly reduced and was still down at 72 hours. After the long acting NSAID piroxicam, in doses providing blood levels comparable with those in long term treatment, malondialdehyde production was still down at 72 hours.

Blood level estimation in phenytoin treatment of epilepsy.

Observations are presented on the monitoring of blood levels of phenytoin. Amongst blood samples from 453 adults and 136 children substantial numbers were either well below the therapeutically most effective range or within the potentially toxic range. The value of blood level monitoring in management of epilepsy with phenytoin is emphasised.

The antiemetic activity of tetrahydrocannabinol versus metoclopramide and thiethylperazine in patients undergoing cancer chemotherapy.

A double blind-cross-over randomised clinical trial has been conducted to compare the antiemetic effects of tetrahydrocannabinol, thiethylperazine and metoclopramide. There were no significant differences in the antiemetic effects of these drugs. The incidence of adverse reactions as recorded by both the staff and the patients was significantly higher in the tetrahydrocannabinol group than in either the metoclopramide or thiethylperazine groups. This trial has established that in the dosages used tetrahydrocannabinol given by mouth has an antiemetic effect of approximately the same order as thiethylperazine and metoclopramide. However, its adverse effects are sufficiently greater than those of the other agents to prevent is widespread usage for this purpose. Tetrahydrocannabinol taken by mouth is not recommended as a routine antiemetic agent in cancer chemotherapy.

Changes in red cell shape in healthy elderly subjects taking low dose fish oil: pilot study.

OBJECTS: to investigate the effects of low dose fish oil on red cell shape and blood pressure in healthy elderly subjects during a 16 week treatment and an eight week follow-up. METHODS: red cell shape analysis by scanning electron microscopy with data analysis by repeated measures analysis of variance. RESULTS: in the preoil blood samples the percentage of cells with surface changes was much higher than that of younger healthy subjects (24.0% vs 14.4%). While taking fish oil the percentage of cells with surface changes declined to a minimum at the end of the eighth week, steadily increased during the next eight weeks then declined during the eight week follow up. Mean blood pressures were not altered by the fish oil although that of five subjects taking different types of antihypertensive drugs tended to show greater fall in blood pressure than those not on drugs. CONCLUSION: that dietary supplementation with low dose fish oil was associated with changes in red cell shape. The observed changes are currently inexplicable.

Serial hexachlorophene blood levels in the premature infant.

The concentration of hexachlorophene was determined in serial blood samples taken from seven premature infants washed with pHisoHex. Results indicated that after a single wash with 5ml of pHisoHex, blood concentrations reached a maximum of 0.75-1.20mug/ml two to four days after application. The results obtained in this study confirm that the dermal absorption of hexachlorophene is greater in premature than in full-term infants. Use of hexachlorophene for infants. Use of hexachlorophene for infants of birth weight less than 2kg has now been discontinued at Queen Mary Hospital and the amount of pHisoHex used in the initial toileting of infants with birth weight more than 2kg has been limited to a single application of 5ml.