Mercury in traditional Tibetan medicine - panacea or problem?

UNLABELLED: Symptoms of mercury toxicity, biochemical changes, and blood/urine mercury levels were evaluated in a small group of patients. Six patients attending Delek Hospital, Dharamsala, India, taking mercury-containing traditional Tibetan medicine (TTM) (Group I), were compared with three patients taking non-mercury containing TTM (Group II) and healthy volunteers(Group II). Quantitative estimation of mercury ingestion based on chemical analysis was compared with US regulatory standards. RESULTS: Group I were significantly older (mean 55 years+/-SE 6.4) range 26-69 years, than Group II (26.7 years+/-SE 5) range 17-34 years and Group III (32.5 years +/-SE 0.5) range 33-34 years (P =0.05). Group I took TTM on average for 51 months and had a mean of 2.5 non-specific, mercury-related symptoms. Group I had higher mean diastolic pressures (85 mmHg) than Group II (73 mmHg) (P=0.06) and more loose teeth. Mean daily mercury intake for Group I was 674 microg, estimated as 10 microg/kg per day. (Established reference dose for chronic oral exposure: 0.3 microg/kg per day.) Blood mercury levels were non-detectable, but mean urinary mercury levels for Group I were 67 microg/L (EPA levels <20 microg/L). Renal and liver function tests were not significantly different between groups and within normal clinical range. CONCLUSIONS: Prolonged ingestion of mercury containing TTM is associated with absent blood levels, but relatively high urinary levels. Further studies are needed to evaluate toxicity and therapeutic potential.

Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn's disease.

BACKGROUND: Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter. AIM: : To determine the relative bioavailability of oral low-dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease. METHODS: Ten patients were randomized to receive their regular maintenance dose of methotrexate (15-25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC infinity ) were compared between the three routes. RESULTS: The geometric mean AUC infinity values (95% confidence intervals) were 360 nmol x h/L (301-430 nmol x h/L), 261 nmol x h/L (214-318 nmol x h/L) and 281 nmol x h/L (209-377 nmol x h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62-0.86) and 0.77 (0.60-0.99) for oral and oral with folic acid administration, respectively (difference not significant). CONCLUSIONS: In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.

Serious adverse events of mefloquine in relation to blood level and gender.

Mefloquine is widely used for prophylaxis in areas with chloroquine-resistant falciparum malaria. As the use of mefloquine has increased, so have the reports on its adverse effects. We sought to evaluate the possible association between serum levels of mefloquine and serious side effects caused by this drug by means of a case-control design study. The study population included 17 patients who presented to emergency rooms or travel clinics with symptoms suggesting serious adverse effects of mefloquine and 28 controls (healthy people, still taking mefloquine after travel). The mean age of the patients and the controls was 31.5 +/- 11.6 years and 34 +/- 12.2 years, respectively. The percentage of women among the patients was higher than in the control population (76% versus 40%, respectively; P = 0.03). Most of the complaints were related to the central nervous system (13 of 17); 5 patients interrupted their trip and 2 others were hospitalized. No difference in the level of mefloquine in the blood was found between the patients and the control groups. Also, no significant difference was found between mefloquine levels in the blood of men and women. These results suggest that blood levels of mefloquine do not correlate with its severe adverse events. Women tended to be more susceptible than men, despite having similar blood levels of the drug.

Interindividual variability in sensitivity to warfarin--Nature or nurture?

BACKGROUND: Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme (CYP2C9) (allelic variants 2C9*2 and 2C9*3 ) linked with impaired metabolism of the potent enantiomere S-warfarin. PATIENTS AND METHODS: We quantified the relative effects of age and of simultaneously determined CYP2C9 genotype, plasma warfarin and vitamin K concentrations, and concurrent medications on warfarin maintenance doses in 156 patients at optimized stable anticoagulation. RESULTS: Allele frequencies for CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 0.84, 0.10, and 0.06. Warfarin doses were 6.5 +/- 3.2, 5.2 +/- 2.4, and 3.3 +/- 2.0 mg/d in the 3 genotype groups (P < .0001). Warfarin doses decreased with age as follows: 7.7 +/- 3.7 versus 4.9 +/- 2.9 mg/d at < 50 years and >66 years (P < .001), mainly as a result of decreased plasma warfarin clearance (2.8 +/- 1.4 mL/min versus 1.9 +/- 0.8 mL/min; P < .001). Vitamin K (1.6 +/- 1.1 ng/mL) did not differ among the age or genotype groups. Patients >or=66 years old with the CYP2C9*3 allele required only 2.2 +/- 1.2 mg/d compared with 7.9 +/- 3.7 mg/d in those

Malaria antibodies and mefloquine levels among United Nations troops in Angola.

BACKGROUND: The United Nations deployed about 8,000 soldiers in a peacekeeping mission in Angola. Malaria is the most common disease there and consequently it was the major risk to the UN troops. Most of them are from malaria free areas. As a result of improper prophylactic measures there were many cases of malaria, including some deaths in 1995. In February-March 1996, an Israeli team was sent to Angola to evaluate the malaria situation among UN soldiers. This paper deals specifically with some aspects of chemoprophylaxis and diagnosis. The efforts were concentrated in one particular area where malaria incidence had been reported as the highest. METHODS: Blood samples were collected from nonimmune soldiers who were using mefloquine as a prophylactic drug and were exposed to malaria. The mefloquine and the antimalarial antibody plasma levels were monitored. RESULTS: While the local laboratory indicated that about 80% had a malaria episode, the serological results revealed that only 5 soldiers of the 56 (9%) examined had antimalarial antibodies, of which 3 were Angolans. Despite a controlled prophylactic regimen there was considerable variability in mefloquine plasma levels: 46% of the samples were below the required prophylactic level and 26% above it. All patients who were proven positive with malaria by both microscopic and serologic observation had a low level of mefloquine. CONCLUSIONS: In field conditions, a kit which identifies plasmodial antigens, is preferable, to a microscopic diagnostic method. Controlled mefloquine prophylaxis may not prevent malaria, especially when blood levels are low. The reason for the low mefloquine blood levels is not clear and needs further evaluation.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.

Prolonged furosemide treatment is associated with urinary loss of thiamine and thiamine deficiency in some patients with congestive heart failure and low dietary thiamine intake. In the rat, diuretic-induced thiamine urinary loss is solely dependent on increased diuresis and is unrelated to the type of diuretic used. We studied the effects of single intravenous doses of furosemide (1, 3, and 10 mg) and of normal saline infusion (750 mL) on urinary thiamine excretion in 6 volunteers. Over a 6-hour period, furosemide induced dose-dependent increases in urine flow and sodium excretion rates (mean +/- SD), from 51 +/- 17 mL/h at baseline to 89 +/- 29 mL/h, 110 +/- 38 mL/h, and 183 +/- 58 mL/h (F = 10.4, P < .002) and from 5.1 +/- 2.3 mmol/h to 9.4 +/- 6.8 mmol/h, 12.1 +/- 2.6 mmol/h, and 20.9 +/- 10.6 mmol/h (F = 6.3, P < .005) for the three doses, respectively (104 +/- 35 mL/h and 13.0 +/- 6.2 mmol/h for the saline infusion). During this period the thiamine excretion rate doubled from baseline levels (mean of four 24-hour periods before the diuretic interventions) of 6.4 +/- 5.1 nmol/h to 11.6 +/- 8.2 nmol/h (F = 5.03, P < .01, for all four interventions, no difference being found between them), then returning over the following 18 hours to 6.1 +/- 3.9 nmol/h. The thiamine excretion rate was correlated with the urine flow rate (r = 0.54, P < .001), with no further effect of the type of intervention or sodium excretion rate. These findings complement our previous results in animals and indicate that sustained diuresis of >100 mL/h induces a nonspecific but significant increase in urinary loss of thiamine in human subjects. Thiamine supplements should be considered in patients undergoing sustained diuresis, when dietary deficiency may be present.

Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% +/- 0.60% (mean +/- SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 microL/min. Fractional excretion of sodium (FE(Na)) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

Atropine pharmacokinetics and pharmacodynamics following endotracheal versus endobronchial administration in dogs.

Emergency endotracheal and endobronchial drug administration provide an effective alternative for intravenous drug delivery during cardiopulmonary resuscitation. The purpose of the present study was to determine the immediate pharmacokinetic and pharmacodynamic properties of atropine following administration by either of these routes. Atropine (0.02 mg/kg) was given to seven anaesthetized mongrel dogs. Each dog was studied twice: once when atropine was injected into the endotracheal tube, and on another day when atropine was given via a flexible catheter wedged into a peripheral bronchus. Plasma atropine concentrations and blood gases were measured during 60 min following drug administration. Both routes of atropine administration differed significantly in three measures: the maximal atropine concentration (Cmax) was significantly higher with the endobronchial administration 40.0 +/- 7.8 ng/ml compared to 23.9 +/- 5 ng/ml endotracheally (P = 0.008); atropine's elimination (t1/2beta) half-life was significantly longer with the endobronchial route (39.3 +/- 5.2 min vs. 28.0 +/- 7.9 min; P = 0.05); Endobronchial administration resulted in an increase of 16% in heart rate, beginning immediately after drug delivery and peaking after 5 min. Other pharmacokinetic parameters were not significantly different. We conclude that endobronchial administration of atropine has a clear advantage over the endotracheal route.

The pharmacokinetics of morphine and lidocaine in critically ill patients.

OBJECTIVE: To evaluate the pharmacokinetic parameters of morphine and lidocaine after a single intravenous dose in critically ill patients. DESIGN: Prospective, clinical study. SETTING: General intensive care unit (ICU) in a university hospital. PATIENTS: Patients admitted to the ICU with severe systemic inflammatory response syndrome of various etiologies. INTERVENTIONS: A single intravenous dose of morphine (0.025 mg/kg) and lidocaine (1.5 mg/kg) were given separately 12-36 h after admission, and arterial blood samples for serum drug levels were taken. MEASUREMENTS AND RESULTS: Morphine pharmacokinetics were studied in 30 patients. The clearance (Cl) was found to be 5.7+/-2.3 ml/kg per min, volume of distribution of the central compartment (Vc) 0.16+/-0.12 l/kg and volume of distribution at steady state (Vss) 1.08+/-0.69 l/kg. These values are lower then those described previously for healthy volunteers (33.5+/-9 ml/kg per min, 1.01+/-0.31 l/kg, and 5.16+/-1.4 l/kg, respectively), and similar to those described in trauma and burned patients. Lidocaine pharmacokinetics were tested in 24 subjects. The Cl was 6.9+/-3.8 ml/kg per min, Vc 0.25+/-0.1 l/kg and Vss 0.78+/-0.26 l/kg. These values are not different from parameters published previously for healthy volunteers (10 ml/kg per min, 0.53 l/min and 1.32 l/min, respectively). No correlation was found between clinical variables and pharmacokinetic parameters of both drugs (ANOVA). CONCLUSIONS: Both morphine and lidocaine have a reduced volume of distribution in critically ill patients. The normal lidocaine clearance indicates preserved hepatic blood flow and suggests that other mechanisms are involved in the reduced morphine clearance. These findings may have application for the treatment of ICU patients.

Prenatal lead exposure in Israel: an international comparison.

BACKGROUND: Prenatal lead exposure (umbilical cord blood lead concentration > 10 (micrograms/dl) may impair cognitive development. Childhood lead poisoning is infrequent in Israel, and there are no data on lead exposure in immigrants to Israel from the former Soviet Union. OBJECTIVES: To evaluate prenatal blood lead concentrations in Israeli newborns whose mothers were born in Israel and in those whose mothers recently immigrated from Russia, and to compare data of prenatal lead exposure in Israel with those reported from other countries. METHODS: We compared the UCBLC of 35 newborns of new immigrants from Russia with a group of 35 newborns whose mothers were born in Israel. Venous BLC was also measured in 50 mothers. Data are compared with similar reports on prenatal lead exposure internationally. RESULTS: The UCBLC in all 70 newborns (mean +/- SD) was 3.53 +/- 1.6 micrograms/dl, and mothers' BLC (mean +/- SD) was 3.90 +/- 1.39 micrograms/dl. UCBLC and BLC in the 50 mother-newborn pairs correlated (r = 0.36, P < 0.01). All newborns except one had UCBLC < 8.0 micrograms/dl. There was no significant difference between UCBLC in the two groups. CONCLUSIONS: Prenatal lead exposure among the study subjects in both groups was low. In this sample the newborns of mothers born in Israel and those whose mothers recently immigrated from Russia were not found to be at risk for lead poisoning. Prenatal lead exposure in this sample was low compared to that reported from various parts of the world.

The pharmacokinetics of morphine and lidocaine in nine severe trauma patients.

STUDY OBJECTIVE: To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients. DESIGN: Clinical case study. SETTING: Department of Anesthesiology and Intensive Care of a university hospital. PATIENTS: Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study. INTERVENTIONS: After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration. MEASUREMENTS AND MAIN RESULTS: Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively). CONCLUSION: Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

Ocular effects of hyoscine in double dose transdermal administration and its reversal by low dose pyridostigmine.

The potential of low dose (30 mg t.i.d) pyridostigmine to reduce the ocular side effects of double dose transdermal controlled release hyoscine was evaluated by the study of near visual acuity, accommodation amplitude and pupil diameter in a placebo controlled, double masked study. We studied 47 healthy men (age 18-21 yr) in 3 groups: 16 assigned to placebo hyoscine and placebo pyridostigmine, 15 assigned to double dose hyoscine and placebo pyridostigmine, and 16 to double dose hyoscine and pyridostigmine. Subjects were tested during 48 h of treatment and 48 h of washout period. Blood cholinesterase inhibition level and amount of hyoscine released from the patches were used as parameters of reliability. Difference between groups was assessed using change from baseline scores. Double dose hyoscine caused decrease in near visual acuity to a mean of 14/18. Accommodation amplitude was decreased in the double dose transdermal hyoscine group from 9.19 +/- 1.04 to 4.83 +/- 1.97 diopters of accommodation. This decrease was significant when compared to the placebo group (p < 0.05) and to the pyridostigmine-protected group (p < 0.05). Pyridostigmine, however, did not significantly change the hyoscine-induced mydriasis of 1.47 + 0.15 mm change from baseline (p < 0.05). These results suggest that pyridostigmine administration may be beneficial in shortening recovery time when near vision impairment is experienced following single and double dose transdermal hyoscine administration.

Interrelationships among measures of autonomic activity and cardiovascular risk factors during orthostasis and the oral glucose tolerance test.

Overstimulation of sympathetic nervous system activity is related to atherosclerotic cardiovascular disease risk, but the role of parasympathetic activity in this association is not clear. This study evaluated sympathetic and parasympathetic function by spectral analysis of heart rate variability and plasma levels of norepinephrine (NE) epinephrine (EPI), dihydroxyphenylglycol (DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC). It also examined the interrelationships among these parameters and established atherosclerotic cardiovascular disease risk factors in 53 men (mean age 59.5 years). During supine rest, low-frequency power correlated positively with high-frequency power (r = 0.58, p < 0.001), plasma NE correlated with plasma DHPG (r = 0.41, p < 0.001) and plasma DOPA with DOPAC (r = 0.47, p < 0.001) but neither low- nor high-frequency power was correlated with plasma levels of any catechol. Among risk factors, plasma NE correlated with fasting insulin and mean arterial blood pressure, and urine NE correlated with body mass index. Both low- and high-frequency power correlated positively with insulin levels. Orthostasis decreased high-frequency power and increased low-frequency power and plasma NE levels. During the oral glucose tolerance test, both high- and low-frequency power increased, plasma NE levels were unchanged, and plasma EPI levels decreased [88.5 +/- 18 (SEM) versus 52.5 +/- 12 pM, p = 0.001]. The results suggest that orthostasis decreases and the oral glucose tolerance test increases parasympathetic outflows, whereas both stimuli increase sympathetic outflows. Among all atherosclerotic cardiovascular disease risk factors, hyperinsulinaemia showed the strongest association with autonomic nervous system activity, especially parasympathetic activity. Estimates of sympathetic responses obtained from power spectral analysis of heart rate variability agree poorly with those from plasma levels of catechols, possibly because of a parasympathetic contribution to low-frequency power and independence of sympathoneural outflows to the arm and heart.

Insulin resistance and autonomic function in traumatic lower limb amputees.

This study examined plasma insulin response to oral glucose load and autonomic nervous system activity in male lower limb amputees (n = 52) aged 50-65 years, compared to matched controls (n = 53). The groups had similar body mass index, blood pressure and plasma lipid levels. The amputees had higher mean fasting plasma insulin levels (18.4 +/- 9.7 (SD) versus 13.7 +/- 5.1 mU/l, p = 0.005) and during an oral glucose tolerance test (OGTT) (1 h levels 88.1 +/- 45.3 versus 62.1 +/- 42.7, p = 0.016) with similar plasma glucose levels, indicating insulin resistance. At baseline with the subjects supine, there were no group differences in low- or high-frequency power of heart rate variability or in plasma levels of norepinephrine (NE) or epinephrine (EPI). In response to orthostasis, the groups had similarly increased plasma NE levels. During the OGTT, amputees had significantly larger increments in low-frequency power than did controls (2.2 +/- 1.3 versus 1.6 +/- 0.9 (beats/min)2 respectively, p < 0.01) and plasma NE levels increased significantly in amputees (1595 +/- 849 versus 1941 +/- 986 pM, p = 0.0008) but not in controls. At 1 h after glucose administration, plasma EPI levels were decreased significantly from baseline in both groups; at both 1 and 2 h after glucose administration, plasma EPI levels were higher in the amputees than controls. Amputees appear to have a combination of enhanced sympathoneural responsiveness and attenuated suppression of adrenomedullary secretion during glucose challenge. As catecholamines antagonize insulin effects, one possible explanation for insulin resistance in amputees is hyperglycaemia-induced sympathoneural activation and a failure of hyperglycaemia to decrease adrenomedullary secretion.

Evaluation of the decarbamylation process of cholinesterase during assay of enzyme activity.

The activity of carbamylated cholinesterase increases continuously during assay, suggesting that progressive decarbamylation takes place. The following effects of assay conditions on the observed decarbamylation were studied: the effect of the sulfhydryl group of nitrobenzoate produced in the course of Ellman assay, the effect of substrate and the effect of sample dilution during assay. This study indicates that sample dilution is the main trigger to the decarbamylation observed during assay of cholinesterase activity. The process was described as a first-order reaction during which the inhibited enzyme gives place to the active form. Kinetic constants for decarbamylation of human pseudocholinesterase (EC 3.1.1.8) at 30 degrees C were approximately 0.005 min-1 for dimethylcarbamates and 0.010 min-1 for monomethylcarbamates, when 1 mmol/l propionylthiocholine was used as substrate.

Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.

In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.

Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.

PURPOSE: We have previously found thiamine (vitamin B1) deficiency in patients with congestive heart failure (CHF) who had received long-term furosemide therapy. In the present study, we assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF) in patients with moderate to severe CHF who had received furosemide in doses of 80 mg/d or more for at least 3 months. PATIENTS AND METHODS: Thirty patients were randomized to 1 week of double-blind inpatient therapy with either i.v. thiamine 200 mg/d or placebo (n = 15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/d as outpatients for 6 weeks. Thiamine status was determined by the erythrocyte thiamine-pyrophosphate effect (TPPE). LVEF was determined by echocardiography. RESULTS: TPPE, diuresis, and LVEF were unchanged with i.v. placebo. After i.v. thiamine, TPPE decreased (11.7% +/- 6.5% to 5.4% +/- 3.2%; P < 0.01). LVEF increased (0.28 +/- 0.11 to 0.32 +/- 0.09; P < 0.05), as did diuresis (1,731 +/- 800 mL/d to 2,389 +/- 752 mL/d; P < 0.02), and sodium excretion (84 +/- 52 mEq/d to 116 +/- 83 mEq/d, P < 0.05). In the 27 patients completing the full 7-week intervention, LVEF rose by 22% (0.27 +/- 0.10 to 0.33 +/- 0.11, P < 0.01). CONCLUSIONS: Thiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving longterm furosemide therapy.

Omeprazole has no effect on acetaminophen kinetics in the rat.

We investigated in the rat the effect of the H+/H(+)-ATPase inhibitor, omeprazole, on the kinetics of acetaminophen. Two groups of rats were treated with either omeprazole 50 mg/kg/day or the vehicle for 7 days. On day seven, the pharmacokinetic parameters of acetaminophen clearance were determined in the conscious rat. Elimination rate constant, elimination half life time, clearance and volume of distribution of acetaminophen were not disturbed by omeprazole. It is concluded that in the rat, omeprazole does not affect acetaminophen kinetics and, therefore, will not increase susceptibility to acetaminophen toxicity.