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The presence of diclofenac in the aquatic environment and the risks for aquatic wildlife, especially fish, have been raised in several studies. One way to manage risks without enforcing improved wastewater treatment would be to substitute diclofenac (when suitable from a clinical perspective) with another non-steroidal anti-inflammatory drug (NSAID) associated with less environmental risk. While there are many ecotoxicity-studies of different NSAIDs, they vary extensively in set-up, species studied, endpoints and reporting format, making direct comparisons difficult. We previously published a comprehensive study on the effects of diclofenac in the three-spined stickleback (Gasterosteus aculeatus). Our present aim was to generate relevant effect data for another NSAID (naproxen) using a very similar setup, which also allowed direct comparisons with diclofenac regarding hazards and risks. Sticklebacks were therefore exposed to naproxen in flow-through systems for 27 days. Triplicate aquaria with 20 fish per aquarium were used for each concentration (0, 18, 70, 299 or 1232 μg/L). We investigated bioconcentration, hepatic gene expression, jaw lesions, kidney and liver histology. On day 21, mortalities in the highest exposure concentration group unexpectedly reached ≥ 25 % in all three replicate aquaria, leading us to terminate and sample that group the same day. On the last day (day 27), the mortality was also significantly increased in the second highest exposure concentration group. Increased renal hematopoietic hyperplasia was observed in fish exposed to 299 and 1232 μg/L. This represents considerably higher concentrations than those expected in surface waters as a result of naproxen use. Such effects were observed already at 4.6 μg/L in the experiment with diclofenac (lowest tested concentration). Similar to the responses to diclofenac, a concentration-dependent increase in both relative hepatic gene expression of c7 (complement component 7) and jaw lesions were observed, again at concentrations considerably higher than expected in surface waters. Naproxen bioconcentrated less than diclofenac, in line with the observed effect data. An analysis of recent sales data and reported concentrations in treated sewage effluent in Sweden suggest that despite higher dosages used for naproxen, a complete substitution would only be expected to double naproxen emissions. In summary, naproxen and diclofenac produce highly similar effects in fish but the environmental hazards and risks are clearly lower for naproxen. Hence, if there are concerns for environmental risks to fish with diclofenac, a substitution would be advisable when naproxen presents an adequate alternative from a clinical point-of-view., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score., Methods and Results: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m 2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration., Conclusions: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m 2 , but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: It has been proposed that diabetic patients are more sensitive to the nephrotoxicity of cadmium (Cd) compared to non-diabetics, but few studies have examined this in humans, and results are inconsistent., Aim: To test the hypothesis that women with type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) have higher risk of kidney damage from cadmium compared to women with normal glucose tolerance (NGT)., Methods: All 64-year-old women in Gothenburg, Sweden, were invited to a screening examination including repeated oral glucose tolerance tests. Random samples of women with DM, IGT, and NGT were recruited for further clinical examinations. Serum creatinine was measured and used to calculate estimated glomerular filtration rate (eGFR). Albumin (Alb) and retinol-binding protein (RBP) were analyzed in a 12h urine sample. Cadmium in blood (B-Cd) and urine (U-Cd) was determined using inductively coupled plasma mass spectrometry. Associations between markers of kidney function (eGFR, Alb, and RBP) and quartiles of B-Cd and U-Cd were evaluated in models, including also blood pressure and smoking habits., Results: The mean B-Cd (n=590) was 0.53 µg/L (median 0.34 µg/L). In multivariable models, a significant interaction was seen between high B-Cd (upper quartile, >0.56 µg/L) and DM (point estimate +0.40 mg Alb/12h, P=0.04). In stratified analyzes, the effect of high B-Cd on Alb excretion was significant in women with DM (53% higher Alb/12h, P=0.03), but not in women with IGT or NGT. Models with urinary albumin adjusted for creatinine showed similar results. In women with DM, the multivariable odds ratio (OR) for microalbuminuria (>15 mg/12h) was increased in the highest quartile of B-Cd vs. B-Cd quartiles 1-3 in women with DM (OR 4.2, 95% confidence interval 1.1-12). No such effect was found in women with IGT or NGT. There were no associations between B-Cd and eGFR or excretion of RBP, and no differences between women with DM, IGT, or NGT regarding effect of B-Cd on eGFR or RBP., Conclusion: The present study provides support for the hypothesis that women with DM have higher risk of renal glomerular damage from cadmium exposure compared to women without DM., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Cadmium (Cd) can cause renal damage and osteoporosis after high-level exposure. Recently such effects, including increased urinary excretion of calcium, have been shown also at low-level exposure, as measured by Cd in blood or urine. However, associations with kidney Cd have not been examined. The aim of this study was to explore the relation between kidney Cd and urinary calcium excretion, or bone mineral density., Methods: Cd was determined in kidney cortex biopsies from 109 living kidney donors. Serum was analyzed for ionized calcium, parathyroid hormone and vitamin D. Calcium was analyzed in overnight and 24-hour urine samples. Bone mineral density was measured in a subgroup of 67 donors. Associations between single variables were assessed by Spearman and Pearson correlation coefficients. Differences between independent groups were compared using Student's t-test. For related samples, paired t-test was applied. Associations between urinary calcium and kidney Cd, ionized serum calcium, serum parathyroid hormone, inactive and active vitamin D and background variables were assessed using multiple linear regression and logistic regression., Results: In spite of relatively low kidney Cd levels (median 13 μg/g, range 1.5-55 μg/g) kidney Cd and urinary calcium were positively associated, mainly caused by an association in women. Donors with kidney Cd above the median (subgroup mean 23 μg/g) had significantly higher excretion of urinary calcium normalized for creatinine than those below the median (subgroup mean 7.3 μg/g). In women, also the excretion of Ca per hour was higher in those with high kidney Cd (24 hour sample mean 0.21 vs. 0.15 mmol/h; overnight sample 0.16 vs. 0.11 mmol/h). There were negative associations between kidney Cd and bone mineral density, most of which, however, disappeared in multivariate analyses., Conclusions: This study provides support for an association between kidney Cd levels and urinary calcium excretion in women, but not in men. The results strengthen the case for preventive measures against Cd pollution.

Objective: The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN). Its protein functionally binds to 5'-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN., Materials and Methods: Three cohorts including T1D with and without DN (n=1139) of European descents from the GoKinD study, Swedish T1D with and without DN (n=303) and Czech control subjects without diabetes, T1D, T2D with and without DN (n=1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot., Results: An association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P=0.037, OR=0.69 95% CI 0.49-0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and DN in male patients with T1D was still significant (P=0.030, OR=0.73, 95% CI 0.54-0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P=0.038, OR=0.67 95% CI 0.46-0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P=0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5weeks but not at 26 weeks., Conclusions: The present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians., Methods: Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg)., Results: The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete., Conclusions: Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.

The initial sign of cadmium (Cd)-induced renal effects is tubular damage, followed by glomerular damage. For the prevention of Cd-induced renal effects, it is essential to establish the reference exposure below which the risk of adverse health effects is low. In earlier Japanese studies, the estimated reference exposure of creatinine (cre)-adjusted urinary cadmium for renal tubular effect ranged from 1.6 to 4.0 microg/g cre in men and 2.3 to 4.6 microg/g cre in women. The benchmark dose (BMD) is defined as the exposure that corresponds to a certain response change from the background. The lower 95% confidence limit of the BMD (BMDL) can be used in risk assessment as a replacement for the no observed adverse effect level. This is a review of all relevant BMDL of Cd exposure for renal effects estimated so far. Based on studies in Japan, the best estimate is considered to be 1.5-3.2 microg/g cre for urinary Cd, 0.09-0.13 mg/kg for rice Cd concentration, and 0.9-1.4 g Cd for lifetime Cd intake. These BMDLs for renal effects were generally lower than the reference exposure expected from earlier studies, indicating the importance of further discussion regarding comprehensive measures to decrease the Cd exposure in the general population., (2010 Elsevier Ireland Ltd. All rights reserved.)

The gene and protein expression and the cellular localization of the ABC transport proteins breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance-associated protein 2 (MRP2) have been examined in the intestines, liver and kidney in horse. High gene and protein expression of BCRP and MRP2 were found in the small intestines, with cellular localization in the apical membranes of the enterocytes. In the liver, MRP2 was present in the bile canalicular membranes of the hepatocytes, whereas BCRP was localized in the cytoplasm of hepatocytes in the peripheral parts of the liver lobuli. In the kidney both BCRP and MRP2 were predominantly present in the distal tubuli and in the loops of Henle. In most tissues, the gene and protein expression of MRP1 were much lower than for BCRP and MRP2. Immunostaining of MRP1 was detectable only in the intestines and with localization in the cytoplasm of enterocytes in the caecum and colon and in the cells of serous acini of Brunner's glands in the duodenum and the upper jejunum. The latter cells were also stained for BCRP, but not for MRP2. Many drugs used in horse are substrates for one or more of the ABC transport proteins. These transporters may therefore have important functions for oral bioavailability, distribution and excretion of substrate compounds in horse.

In this study we show for the first time that lead poisoning from ammunition is a significant mortality factor for white-tailed sea eagle (WSE) (Haliaeetus albicilla) in Sweden. We analyzed 118 WSEs collected between 1981 and 2004 from which both liver and kidney samples could be taken. A total of 22% of all eagles examined had elevated (>6 microg/gd.w.) lead concentrations, indicating exposure to leaded ammunition, and 14% of the individuals had either liver or kidney lead concentrations diagnostic of lethal lead poisoning (>20 microg/gd.w.). Lead concentrations in liver and kidney were significantly correlated. In individuals with lead levels <6 microg/g, concentrations were significantly higher in kidney than in liver; in individuals with lead levels >20 microg/g, concentrations were significantly higher in liver. The lead isotope ratios indicate that the source of lead in individuals with lethal concentrations is different from that of individuals exhibiting background concentrations of lead (<6 microg/gd.w.) There were no significant sex or age differences in lead concentrations. A study from the Baltic reported in principle no biomagnification of lead, but background lead concentrations in WSE liver in this study were still four to >10 times higher than concentrations reported for Baltic fish from the same time period. In contrast to other biota there was no decrease in lead concentrations in WSE over the study period. The proportion of lead poisoned WSE remained unchanged over the study period, including two years after a partial ban of lead shot was enforced in 2002 for shallow wetlands. The use of lead in ammunition poses a threat to all raptors potentially feeding on shot game or offal. The removal of offal from shot game and alternatives to leaded ammunition needs to be implemented in order to prevent mortality from lead in raptors and scavengers.

In the northern hemisphere moose has been found to be suitable as a monitoring animal for the presence of cadmium in the environment. The metal accumulates mainly in the kidney and the liver, with the rate of accumulation dependent on age and possibly also on gender. Collection of tissue material often results in sample selections with disparate age and gender composition, which makes comparison between different regions and different studies difficult. A previous large scale investigation of metals in kidney and liver from moose in Sweden provided Cd data (n = 3,817 and 3,802, respectively) to further explore the relation between Cd accumulation and age/gender. Based on local averages, the individual deviations were analysed with respect to the factors age and gender resulting in an 'ageing function' for each gender and organ. In addition, estimates of the pure individual variations were obtained; the standard deviations correspond to a factor 1.7-1.9 for the Cd concentration, which indicates that 25-30 samples are needed to give a representative mean value (with RSD approximately 10%). In order to be able to compare results from different studies, all individual results can be transformed to represent a 'standard moose' with respect to age and gender. A comparison along these lines was undertaken between Cd levels in Alaska and Sweden. Finally, a relationship between the Cd levels in kidney and liver was derived, providing at least rough estimates for kidney from liver values (or vice versa).

Objective: Fibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease., Design: Serum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70-80 years were randomly selected from the population., Methods: Intact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D3 were measured. Association studies were performed using linear univariate and multivariate regression analyses., Results: The median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (r=-0.21; P<0.00001) and log PTH (r=0.13; P<0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (beta=0.082; P<0.05) and eGFR (beta=-0.090; P<0.05) were associated with log FGF23 in subjects with eGFR>60 ml/min. Only eGFR (beta=-0.35; P<0.0001) remained as a predictor of log FGF23 in subjects with eGFR<60 ml/min., Conclusions: Serum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi.

The Swedish variant of moist oral smokeless tobacco (snus) is popular in Sweden and Norway, banned from sale within the European Union and is currently being introduced in USA. The aim of the present study was to determine if snus is carcinogenic to the stomach, particularly in Helicobacter pylori (H.P.)-infected hosts at increased risk for gastric cancer development. Snus (Generaltrade mark; Swedish Match, Sweden) was mixed with powdered standard mouse chow at a concentration of 5-9% (wt/wt) and given to wild-type (WT, FVB) and gastrin transgenic (INS-GAS, FVB) mice for 6 months with or without H.P. (strain 67:21, CagA+, VacA+) infection. At necropsy, pathological evaluation of stomachs from uninfected snus-treated WT mice showed mild morphological changes, whereas 50% snus-treated INS-GAS mice developed carcinoma in situ (CIS), compared with 25% not exposed to snus. When snus was given to H.P.-infected mice, 9 of 17 WT mice developed CIS with intramucosal invasion, and the remaining 8 of 17 WT mice developed high-grade dysplasia (score >1.5) that was associated with increased gastritis, epithelial defects, oxyntic atrophy, hyperplasia and intestinal metaplasia. Twelve of 12 H.P.-infected INS-GAS mice developed CIS with intramucosal invasion and submucosal herniation. We suggest that snus is a potential gastric carcinogen in mice. The development of CIS was associated with increased rates of the epithelial cell proliferation and apoptosis, common features of gastric carcinogenesis.

A circumpolar survey of heavy metals in willow ptarmigan liver and kidney revealed considerable variations in Cd content in Canada and Scandinavia. The Cd content in central Canada was comparable with that in Scandinavia and Russia, at least for kidney. However, in both liver and kidney the median for Canada as a whole was much higher than in the other countries. Some Canadian locations had exceptionally high levels, several birds having >50 mg kg(-1) in liver and >400 mg kg(-1) in kidney. In Norway, the Cd content was highest in central mountain areas in south Norway and inland locations in the two northernmost counties. Five locations in central and north Norway showed mean Cd levels in kidney above 100 mg kg(-1). It is difficult to evaluate regional differences in Sweden, but most locations had the same Cd level as moderately contaminated locations in Norway. Cd levels in Russia were comparable to moderately contaminated locations in the other countries. Due to a high intake of willow, naturally rich in Cd, direct comparison of the Cd level in willow ptarmigan from different locations cannot reveal the effects of long-range pollution. The Pb concentration in willow ptarmigan kidney and liver varied significantly in Norway and Canada, but not in Sweden and Russia. Levels in Sweden and Russia were comparable to those in Canada and low levels in Norway. The highest median value from all locations within countries was found in Norway, both in liver and kidney. The highest Pb content was found in south Norway, indicating an effect of long-range pollution in willow ptarmigan. The level in western Canada was significantly higher than in central Canada. The Hg content in liver varied significantly from one location to another in all the countries and in kidney everywhere except Sweden. In Scandinavia, there is no distinct regional pattern. Canada had a significantly higher Hg level in central than western regions in both tissues the opposite of that found for Cd and Pb. Cu and Zn showed significant variations from one location to another in liver and kidney in Canada and Norway, but only in kidney in samples from Sweden. Comparison between western and central Canada revealed a significant difference for Cu in liver, samples from central Canada having more. There are no significant differences from one country to another, but some localities in Canada seem to have higher Cu concentrations in kidney than are found in Scandinavia and Russia.

Background: The aim of the study was to evaluate whether cadmium concentrations in kidney (K-Cd), blood (B-Cd) or urine (U-Cd) could reveal previous occupational cadmium exposure at a metal smelter., Methods: The study included 90 smelters and 35 controls (B-Cd and U-Cd determination). In a subgroup (N = 33), K-Cd was also determined., Results: B-Cd (median 4.6; range 0.5-53 nmol/L), U-Cd (0. 29; 0.04-1.9 micromol/mol creatinine) and K-Cd (14; 3-61 microg/g wet weight) were similar to reported concentrations in the general Swedish population. In the subgroup, significant associations (P<0. 001) were obtained between B-Cd and K-Cd (r = 0.70), U-Cd and K-Cd (r = 0.60) and between U-Cd and B-Cd (r = 0.62). Multiple regression analyses revealed smoking as the major predictor of K-Cd, B-Cd, and U-Cd. B-Cd and U-Cd were both associated with the duration of employment at the smelter., Conclusions: There was no statistically significant evidence of previous occupational exposure at the smelter from measurement of K-Cd., (Copyright 2001 Wiley-Liss, Inc.)

Tissue concentrations of antimony in lung, liver, and kidney tissue from a group of deceased smelter workers from northern Sweden have been compared with those of a group of persons without occupational exposure from a nearby area. Neutron activation analysis was used to determine the antimony concentration of lung tissue from exposed workers; these concentrations were 12-fold higher than those of referents (p less than 0.001). For lung tissue there was no tendency towards decreased antimony concentrations with time (up to 20 a) after the cessation of exposure, and this result indicates a long biological half-time. The highest values were found for workers who had worked for many years at the roasters and in the arsenic and selenium departments. There was no significant difference between the antimony concentration of the lung tissue from workers who had died of lung cancer and those of persons who died of other malignancies, cardiovascular disease, or other causes. This finding does not however rule out the possibility of a role for antimony in the etiology of lung cancer among smelter workers since multiple factors may have been operating. The antimony concentration of the liver tissue and the kidney cortex did not differ from the corresponding values of the reference group; this finding indicates either a short biological half-time or insignificance for the systemic distribution of antimony.

Therapy for severe beta-blocker poisoning should be based upon careful supportive therapy. In most cases of poisoning, elimination techniques cannot be expected to remove significant amounts of the drug. Inotropic drugs such as isoproterenol, prenalterol and glucagon in adequate (i.e. large) doses may be necessary to counteract cardiac failure.

The hardness of drinking water (i.e., the sum of calcium and magnesium concentrations) has been related to cadmium concentration in kidney cortex and to microscopic signs of arteriosclerosis and focal myocardial fibrosis in 50 Swedish horses slaughtered for meat production. A significant negative correlation was found between water hardness and cadmium concentrations in kidney cortex. This indicates that horses living in soft water areas are more inclined to accumulate cadmium from the general environment. Microscopic changes in the aorta and myocardium were approximately 2 times as frequent in horses that drank soft water compared to horses that drank hard water. The differences were, however, not statistically significant. It is concluded that horses are well suited for studies of the "water factor".

Outpatient prescriptions dispensed to 17,000 individuals in the county of Jämtland, Sweden, have been analyzed with regard to doses and dosage schedules. Two groups of drugs were studied; one group with marked interindividual variability in metabolism (antidepressants, beta receptor blockers, and phenytoin), the other group excreted unchanged in the urine (digoxin, nitrofurantoin, sulfonamides, and tetracycline). A 25-fold-15-fold variability in daily doses was found for amitriptyline and nortiptyline, respectively. Four-fifths of the prescriptions were for doses between 30 and 75 mg, making the mean dose remarkably low-58 and 48 mg, respectively. The variability in doses was higher for the beta receptor blockers propranolol and alprenolol. Daily doses of phenytoin varied between 0.1 and 0.6 gm, 93% of the doses falling between 0.2 and 0.4 gm. Generally, doses of sulfonamides and nitrofurantoin prescribed to children were correctly reduced. In the elderly the doses of these drugs and tetracycline and digoxin were only moderately reduced in discrepancy with the physiologic impairment of kidney function. The clinical significance of these findings has not been evaluated. The effect of drug information programs on dosage intervals prescribed for procainamide, phenytoin, and beta receptor blocking drugs is demonstrated. It is suggested that more emphasis be given to general pharmacokinetic principles in drug information programs.