Volume 42, No. 9/2004(September)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Adverse drug reactions
Can St. John’s wort trigger psychoses?
Abstract
C. Stevinson and E. Ernst
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK
Background: St. John’s wort (SJW) is a popular herbal remedy often self-prescribed for depressed mood. It has recently been associated with psychotic events. Aim: To systematically review the clinical evidence associating SJW with psychotic events. Methods: Five electronic databases were searched for all relevant reports. Data were extracted according to predefined criteria. Results: Seventeen case reports associated the use of SJW with psychotic events. In 12 instances, the diagnosis was mania or hypomania. Causality is in most cases possible. In no case was a positive rechallenge reported. Conclusion: These case reports raise the possibility that SJW may trigger episodes of mania in vulnerable patients. Clinicians should be aware of this possibility and researchers should attempt to ascertain whether the association is causal.
Correspondence to:
Prof. E. Ernst
Complementary Medicine
Peninsula Medical School
Universities of Exeter and Plymouth
25 Victoria Park Road
Exeter, EX2 4NT, UK
Email: Edzard.Ernst@pms.ac.uk
Adverse drug reactions
Effects of acetylsalicylic acid on ascorbic acid concentrations in plasma, gastric mucosa, gastric juice and urine – a double-blind study in healthy subjects
Abstract
H.-U. Schulz1, M. Schürer1, S. Krupp1, H.-G. Dammann2, J. Timm3 and U. Gessner4
1LAFAA Laboratory for Contract Research in Clinical Pharmacology and Biopharmaceutical Analytics GmbH, Bad Schwartau, 2Clinical Investigations, Scientific Institute, Hamburg, 3Institute for Statistics, University of Bremen, and 4Business Unit Consumer Care, Bayer Vital GmbH, Leverkusen, Germany
Objective: This study investigated concentrations of ascorbic acid (ASC) in gastric mucosa, gastric juice, urine and plasma in healthy subjects under steady state and fasted conditions with and without concomitant administration of acetylsalicylic acid (ASA). Material and methods: This was a prospective, randomized, double-blind, parallel-group study in healthy subjects. It has assessed the effects of a 6-day administration of 0.8 g ASA or 0.48 g ASC, 3 times daily and the combination of both on concentrations of ASC in gastric mucosa, gastric juice, urine and plasma. Treatments were switched after 6 days without any washout for assessment of compartment sensitivity to changes in study medication resulting in an overall 14-day study period. Each of the 3 treatment groups consisted of 15 subjects. Results: ASC concentrations were highest in the gastric mucosa (251 ± 11 mg/g), followed by gastric juice (29 ± 6 mg/ml), plasma (10 ± 0.2 mg/ml), and urine (5 ± 1 mg/ml). On day 7, ASC concentrations in gastric mucosa, plasma and urine had increased in those groups receiving ASC and decreased in the group receiving ASA only. All differences were statistically significant and indicate an interaction with ASA. In gastric juice, differences in ASC concentrations between the treatment groups were not statistically significant between baseline and day 7. ASC concentrations in plasma were strongly correlated with corresponding ASC concentrations in gastric mucosa (r = 0.34) and urine (r = 0.83), as were ASC concentrations in gastric mucosa with ASC in urine (r = 0.28). Conclusions: The gastric mucosa is the largest depot of ASC in the human body with ASC concentrations 25 times higher than in plasma. In healthy subjects, clinically relevant doses of ASA reduced ASC concentrations in gastric mucosa by about 10% within 6 days resulting from antioxidative defense mechanisms. In patients with long-term ASA treatment or conditions with additional risks such as elderly subjects with unfavorable dietary conditions and impaired antioxidative protection, a protective adjunct administration of ASC appears to be beneficial.
Correspondence to:
Prof. Dr. H.-U. Schulz
LAFAA Laboratory for Contract Research
in Clinical Pharmacology and Biopharmaceutical Analytics GmbH
P.O. Box 1322
D-23602 Bad Schwartau, Germany
Email: lafaa_gmbh@t-online.de
Review
Inhibition of human liver and duodenum sulfotransferases by drugs and dietary chemicals: a review of the literature
Abstract
G.M. Pacifici
Department of Neurosciences, Section of Pharmacology, Medical School, Pisa, Italy
Sulfotransferase catalyzes the transfer of sulfate, donated by 3’-phosphoadenosine-5’-phosphosulfate, to an acceptor substrate that may be a hydroxy group or an amine group. Man is exposed daily to drugs and dietary chemicals that can inhibit sulfotransferase activity. The aim of this study was to review the literature concerning the inhibition of sulfotransferases by drugs and dietary chemicals in the human liver and duodenum. The IC50 value of mefenamic acid for human liver phenol sulfotransferase (SULT1A1) was 0.02 mM and for human liver catechol sulfotransferase (SULT1A3) 76 mM with a SULT1A3/SULT1A1 ratio for the IC50 of 3,800. Mefenamic acid is therefore a potent and selective inhibitor of human liver SULT1A1. The IC50 values of mefenamic acid for the sulfation rates of (–)-salbutamol and (–)-apomorphine were 4 orders of magnitude greater in the human duodenum than in the liver. Salicylic acid inhibited the sulfation of (–)-apomorphine in human liver with an IC50 of 54 mM but did not inhibit the sulfation of (–)-apomorphine in human duodenum. Quercetin, a flavonoid present in edible fruit, vegetable and wine, was a potent inhibitor of human liver SULT1A1 and estrogen sulfotransferase (EST) activities and the sulfation of resveratrol. Quercetin inhibited the sulfation of dopamine, (–)-salbutamol, minoxidil and paracetamol and the IC50 values were 1 – 2 orders of magnitude greater in human duodenum than in the liver. In conclusion, mefenamic acid, salicylic acid and quercetin inhibit SULT1A1 whereas SULT1A3 is relatively resistant to the inhibition by these compounds. Under particular circumstances, human duodenum sulfotransferase is more resistant than liver sulfotransferase to the inhibition by mefenamic acid, salicylic acid and quercetin.
Correspondence to:
Dr. G.M. Pacifici
Associate Professor in Pharmacology
Department of Neurosciences
Section of Pharmacology, Medical School
Via Roma 55
I-56126 Pisa, Italy
Email: pacifici@biomed.unipi.it
Pharmacogenetics
The MDR1 3435 polymorphism in patients with rheumatoid arthritis
Abstract
A. Pawlik, J. Wrzesniewska, I. Fiedorowicz-Fabrycy and B. Gawronska-Szklarz
1Department of Pharmacokinetics and Therapeutic Drug Monitoring, and 2Department of Rheumatology, Pomeranian Medical University, Szczecin, Poland
Objective: Rheumatoid arthritis (RA) is a multifactorial disease, the pathogenesis of which involves immunological, genetic and environmental factors. P-glycoprotein (P-gp) encoded by the MDR1 gene, is an important transporter for many drugs, xenobiotics and cytokines and may be associated with many immunological processes and apoptosis. The activity of P-gp is genetically determined. Naturally occurring MDR1 polymorphisms have been described and correlated with potential clinical effects. Several mutations in the MDR1 gene have been recognized, but only some of them are associated with P-gp expression. The C3435T polymorphism was found to correlate with the activity of P-glycoprotein. The aim of the study was to evaluate the C3435T MDR1 polymorphism in patients with rheumatoid arthritis and to investigate a possible correlation with disease susceptibility, activity and severity. Methods: The study was carried out in 92 patients with rheumatoid arthritis and 97 healthy subjects as a control group. The C3435T polymorphism was determined using the PCR-RFLP method. Results: The distribution of C3435TT MDR1 genotypes in RA patients did not differ significantly from that in a control group and was as follows: 3435CC in 25 (26.9%) subjects, 3435CT in 50 (53.8%) and 3435TT in 17 (18.3%). The probability of remission of RA symptoms after therapy with methotrexate and glucocorticosteroids however, was 2.89-fold greater in patients with the 3435TT genotype compared to patients with the genotypes 3435CC and 3435CT. The risk of having an active form of rheumatoid arthritis resistant to therapy with disease-modifying antirheumatic drugs in patients with 3435CC and 3435CT genotypes was 2.89 times greater than in homozygous 3435TT subjects. Conclusion: We suggest that the C3435T MDR1 polymorphism is not an important genetic risk factor for RA susceptibility, but that this polymorphism may have an influence on the activity of the disease and its response to therapy with disease-modifying antirheumatic drugs.Correspondence to:
Dr. A. Pawlik
Department of Pharmacokinetics and Therapeutic Drug Monitoring
Pomeranian Medical University
ul. Powstanców Wielkopolskich 72,
PL-70-111 Szczecin, Poland
Email: pawand@poczta.onet.pl
Pharmacokinetics
Population pharmacokinetics of methylprednisolone in accident victims with spinal cord injury
Abstract
J. Barth1,2, J. Winkler3, R. Schumann2, N.V. Nagaraja3, R. Madabushi3, S. Balbach3, H. Derendorf3, H. Möllmann2 and G. Möllenhoff2
1Medical Clinic Bergmannstrost, Halle, 2Medical Clinic Bergmannsheil,
University of Bochum, Germany, and 3Department of Pharmaceutics,
University of Florida, Gainesville, FL, USA
Objective: High-dose methylprednisolone (MP) is used to treat acute spinal cord injury (ASCI). The objective of the present study was to determine the pharmacokinetics of the pro-drug methylprednisolone hemisuccinate (MPHS) and MP in accident victims with ASCI. Methods: The patients (n = 26) were treated with a bolus intravenous loading dose of 30 mg/kg MPHS within 2 h after injury and this was followed by a maintenance infusion of 5.4 mg/kg/h up to 24 h. Blood, CSF and saliva samples were collected up to 48 h after the initial dose and the samples were analyzed by HPLC. Concentration-time data of MPHS and MP were analyzed using population pharmacokinetic analysis with NONMEM software. Results: MPHS and MP could be monitored in plasma and CSF. MP but not MPHS was present in saliva. High variability was seen in the MPHS levels in CSF. The pharmacokinetics of the pro-drug and the metabolite were adequately described by a 2-compartment model with exponential distribution models assigned to the interindividual and the residual variability. At steady state, the average measured MP concentration in plasma was 12.3 ± 7.0 mg/ml and 1.74 ± 0.85 mg/ml in CSF. The CSF levels of MP could be modeled as a part of the peripheral compartment. Conclusion: This study demonstrated that CSF concentrations of MP were sufficiently high after i.v. administration and reflected the concentrations of unbound drug in plasma. Salivary levels of MP were about 32% of the plasma level and may serve as an easily accessible body fluid for drug level monitoring.
Correspondence to:
PD Dr. J. Barth
BG-Kliniken Bergmannstrost
Merseburger Straße 165
D-06112 Halle/Saale, Germany
Email: juergen.Barth@Bergmannstrost.com
Drug interactions
Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil
Abstract
L. Reyderman, T. Kosoglou, P. Statkevich, L. Pember, T. Boutros, S.E. Maxwell, M. Affrime and V. Batra
1Department of Drug Metabolism and Pharmacokinetics, and 2Department of Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, NJ, USA
Objective: Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between ezetimibe and gemfibrozil. Methods: This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of ³ 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of ezetimibe and gemfibrozil. The oral bioavailability of ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model. Results: Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC0-12 of gemfibrozil was 74.7 and 74.1 mg h/ml with and without ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (CI) = 92 – 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of ezetimibe and total ezetimibe (i.e. ezetimibe plus ezetimibe-glucuronide). Exposure to ezetimibe and total ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 – 173% for ezetimibe and 142 – 190% for total ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated. Conclusions: The coadministration of ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.Correspondence to:
Dr. L. Reyderman
Department of Drug Metabolism and Pharmacokinetics
Schering-Plough Research Institute
2015 Galloping Hill Road
Kenilworth, NJ 07033-1300, USA
Email: larisa.reyderman@spcorp.com
Bioavailability section
Bioequivalence of a prednisolone tablet administered as a single oral dose in healthy male volunteers
Abstract
H.J. Lee, J.Y. Yoo, Y.G. Kim, S.B. Han and K.R. Lee
1Department of Pharmacokinetics, Seoul Medical Science Institutes, Seoul, and 2Department of Pharmacology, College of Medicine, Dankook University, Choungnam, Republic of Korea
Objective: A bioequivalence study of prednisolone as Nisolone (test) tablets versus Delta-Cortef (reference) tablets was conducted. Patients and methods: Eighteen healthy male Korean volunteers received both 20 mg formulations of prednisolone in this 2 × 2 crossover study with a 1-week washout period between the doses. Plasma concentrations of prednisolone were monitored over a period of 12 hours after the administration using high-performance liquid chromatography. The AUC (area under the plasma concentration-time curve from time zero to infinity) and AUCt (area under the plasma concentration-time curve from time zero to the last sampling time) were calculated using the trapezoidal rule-extrapolation method. The Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC, AUCt and Cmax and untransformed tmax. Results: The geometric mean of AUCt was 1,786 ng/ml × h (test medication) and 1,787 ng/ml ×h (reference medication). A Cmax of 409 ng/ml and 404 ng/ml was achieved for the test and the reference medication, respectively. Point estimates and 90% confidence intervals for AUCt (parametric) and Cmax (parametric) were 0.989 (0.942 ~ 1.039) and 1.013 (0.934 ~ 1.100), respectively. These results satisfy the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of tmax was –0.221 (–0.415 ~ 0.000). Conclusion: The 2 medications of prednisolone examined are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
Dr. H.J. Lee
Department of Pharmacokinetics
Seoul Medical Science Institutes
Heasan Bldg. 108-1, Yangjea-Dong,
Seocho-Gu, Seoul 137-130, Korea
Email: hjlee@scllab.co.kr
Book review
Tobacco or Health?
Book review
Erratum
