Monitoring of patients in prophylactic lithium treatment. An assessment based on recent kidney studies.
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Biomedical subjects
Publications and source records attributed to P Vestergaard.
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Patients given long-term treatment with lithium often develop an impairment of renal water reabsorption which may lead to clinically significant adverse reactions. A convenient measure of this impairment may be obtained using the ratio of urine volume (V) divided by lithium clearance (CLi). When data from a large group of patients were recalculated, this ratio showed a statistically significant correlation with the serum lithium level. This finding supports the suggestion that patients might advantageously be maintained at lower serum levels than those commonly employed.
A quantitative gas chromatographic-mass spectrometric (GC-MS) assay was developed for the determination of benztropine in human urine and plasma. The assay utilizes selected ion focusing to monitor in a GC effluent a specific fragment ion of benztropine generated by electron-impact ionization. Benztropine-d3 was the internal standard. The assay can measure 5 ng/ml of benztropine/ml with about 6% precision. The curve relating the amounts of benztropine added versus the amounts found over a large range of benztropine concentrations was a straight line with a nearly zero intercept and a slope of 0.98 +/- 0.02. The method was used for the analysis of benztropine in urine and plasma of patients on therapeutic dose of the drug.
A method for the determination of urinary 17-oxogenic steroids in two fractions (11-deoxy-17-oxogenic and 11-oxy-17-oxogenic steroids) is described. The method is based on initial reduction with borohydride and on oxidation with sodium metaperidate, followed by the formation of dinitrophenylhydrazone derivatives and the separation of the derivatives on short columns of alumina eluted by amyl alcohol to toluene. The assay is robust, reliable, and suitable as a simple laboratory measurement of the integrated adrenocortical function over time. Such analysis should be useful in any situation where cortisol metabolism is changed. Some suggested areas of applicability are in cases of Cushing's syndrome and in the diagnosis and treatment of congenital adrenal hyperplasia.
The results of 160 consecutive fibre-optic endoscopic polypectomies in the gastrointestinal tract are reviewed. Of 22 polyps snared in the upper digestive tract, 16 could be retrieved. One gastric polyp showed early intramucosal carcinoma. Biopsies from a pedunculated duodenal polyp, which was lost after snaring, revealed adenoma with moderate atypia. Of 138 resected colonic polyps, 132 were retrieved. Of these, 104 (79%) were adenomas. Of 49 colonic adenomas smaller than 10 mm, 4 (8%) showed severe atypia (carcinoma in situ) but not invasive carcinoma. Of 36 adenomas sized 10--19 mm 8 (22%) showed severe atypia and one (3%) invasive carcinoma. Of 19 adenomas larger than 60 mm, 6 (32%) showed severe atypia and one (5%) invasive carcinoma. Of the colonic polyp patients, 87% had only one or two polyps. Synchronous adenomas and non-neoplastic polyps were found in 6 of 11 cases with 3 or more colonic polyps. It is concluded that endoscopic polypectomy, carefully and properly performed, is a valuable and promising procedure in the diagnosis and treatment of polyps in the gastrointestinal tract, especially in the large bowel.
Two years after a survey of the kidney function in 237 patients given long-term lithium treatment the patients were invited for reexamination. Of 184 patients who came for the reexamination 147 had continued lithium treatment; in 37 patients the treatment had been discontinued. The lithium-treated patients were compared with a group of 68 manic-depressive patients who were about to be given prophylactic lithium treatment but who had not yet started. Neither the patients who continued nor the patients who had discontinued lithium showed any deterioration of glomerular filtration rate as assessed through determination of the 24-h creatinine clearance and the serum creatinine concentration; mean values in the lithium-treated patients were the same as mean values in patients not yet given lithium. Impairment of renal water reabsorption, revealed by increased 24-h urine volume and decreased urine osmolality after DDAVP, had progressed in the patients who continued lithium treatment, and multiple regression analysis revealed the duration of treatment and the serum lithium level to be significant predictor variables. In the patients who had discontinued lithium the changes in renal water handling had decreased. The urine volume was the same as that found in the patients not yet given lithium; maximum urine osmolality had not become fully normalized. Side effects such as thirst, nycturia, tremor, diarrhoea, oedema, and weight gain were found with the same frequency at the second as at the first examination in the patients who had continued lithium. In the patients who had discontinued lithium they were infrequent or absent.
The serum lithium concentration was determined around the clock in patients treated with conventional tablets given once daily, in the evening, and in patients treated with slow-release tablets given twice daily, in the morning and in the evening. Curve shapes differed markedly in the two groups, with much wider variation of serum concentrations in the former than in the latter. The data were used to calculate for the two patient groups the ratio of the mean serum lithium concentration over the 24-h day to the serum lithium concentration in blood samples drawn 12 h after the last intake of lithium. Around-the-clock determinations of the patients' renal lithium clearance showed about 20% lower values during the night than during the day.
The findings of morphological changes in the kidneys of some patients given long-term treatment with lithium and indications that lithium intoxications frequently are preceded by alterations in water and electrolyte metabolism have generated new interest in the effect of long-term lithium treatment on kidney structure and function. Today it is not firmly established to which extent renal morphological changes are present in unselected groups of patients given long-term treatment with lithium. Neither is it clear what is the clinical significance of these changes and what are the relative roles played by lithium, concomitant and previous treatment with other psychotropic drugs, previous occurrence of lithium intoxications, and coexistence of somatic illness for their development. Studies on kidney function in long-term lithium-treated patients, however, have revealed that affection of GFR was either moderate or absent indicating that the risk of renal insufficiency and terminal azotemia is remote even when lithium is given for many years. A large number of patients have altered water excretion with polyuria or lowered urine concentrating ability or both. Due to the extra fluid loss these patients are apt to develop dehydration, and they may then be in danger of lithium intoxication. We hypothesize that lithium-induced changes of kidney function may become less frequent and less pronounced if patients are maintained at serum lithium levels somewhat lower (0.5-0.8 mmol/l) than those commonly employed. We recommend careful monitoring of serum lithium levels, regular control of kidney function, and extra caution when physical illness or additional drug treatment may lead to disturbance of fluid and electrolyte balance.
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A quantitative GLC-mass spectrometric assay was developed for the determination of maprotiline and its major metabolite, desmethylmaprotiline, in animal and human plasma. The assay utilizes selective-ion focusing to monitor, in a GLC effluent, the fragment ions and the base peaks of maprotiline and desmethylmaprotiline trifluoroacetamides generated by electron-impact ionization. Maprotiline-d3 was the internal standard. The assay can measure 2 ng of maprotiline (and the metabolite)/ml of plasma with approximately 5% precision. The curves relating the amounts of maprotiline and the metabolite added versus the amounts experimentally found over a large concentration range were linear with nearly zero intercepts and slopes of 0.99 +/- 0.01 and 0.98 +/- 0.02, respectively. The method was used to study the pharmacokinetic pattern of the drug in rabbits as well as to analyze intact maprotiline and the metabolite in patients maintained on therapeutic doses of maprotiline. Assay specificity was confirmed by complete consistency of the mass spectra of maprotiline and desmethylmaprotiline with those of the authentic materials.
A survey in given of current trends in the assay of urinary hormonal steroids. Both group assay methodology and assays for single urinary steroids are reviewed as are semi-automated and automated procedures and high-resolution and high-capacity techniques, as applied to the profile analysis of urinary steroid hormones.
In patients given long-term treatment with lithium maximum urine osmolality was measured after 26 h of dehydration and after intranasal administration of desamino-8-D-arginine vasopressin (DDAVP). A high correlation was found between the results of the two tests suggesting that the DDAVP test is a suitable method of assessing renal concentrating ability in lithium-treated patients.
Mean adrenaline concentration in cerebrospinal fluid measured by a sensitive and specific isotope-derivative assay was significantly lower in 15 depressed patients during illness compared with 18 control subjects. At the time of recovery cerebrospinal adrenaline levels had increased markedly to normal levels. Cerebrospinal fluid noradrenaline did not differ in patients compared with controls. The present findings suggest that adrenaline as a neurotransmitter may be involved in affective disorders.
A group fo 237 patients in a long-term lithium treatment were questioned specifically about five side effects commonly associated with lithium treatment and unspecifically about "other" complaints. About one tenth of the patients did not complain of side effects, two thirds had one or two complaints, and one fourth had three or more. About one half of the patients complained of hand tremor, two thirds of increase thirst, one fifth of weight gain exceeding 10kg, one fifth of diarrhea, and one tenth of edema of legs or face. A few patients had other complaints. For each side effect we analysed whether its presence was significantly associated with such patient and treatment variables as sex, age, duration of the lithium treatment, 12-h serum lithium concentration, type of lithium preparation, and additional medication. Men complained of tremor significantly more often than women. Diarrhea was significantly less frequent in patients given additional treatment with antidepressants. Weight gain was associated with increased thirst and fluid output and with significantly increased blood pressure. None of the other variables distinguished between patients with and without the various complaints. We nevertheless hypothesize that a moderate reduction of the serum lithium level may lead to a lowering of the frequency of some side effects.
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