ABSTRACT
BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).
Subject(s)
Drug-Related Side Effects and Adverse Reactions/epidemiology , Hospitalization/statistics & numerical data , Inappropriate Prescribing/statistics & numerical data , Potentially Inappropriate Medication List , Age Factors , Aged , Aged, 80 and over , Algorithms , Drug-Related Side Effects and Adverse Reactions/prevention & control , Female , Humans , Incidence , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Risk FactorsABSTRACT
OBJECTIVES: Package inserts are the most frequent source of patient information about medicines aside from doctors and pharmacists. MATERIALS AND METHODS: A representative selection of 271 German package inserts available in 2005 was investigated, using 152 validated quality criteria and by measuring 242 further values. RESULTS: A significant increase in package insert texts over recent years was found; standing at an average of 2,005 words. This is associated with the significant increase in complicated medical information being communicated; with on an average of 114.1 difficult words and 46.3 non quantifiable phrases per package insert. Only 60.1% of the package inserts offered all dosages as number of tablets or other amounts of the ready to use medicine, while just 29.5% listed the maximum daily dose for all users. 54.6% provided actions for all possible side effects and 24.2% the frequencies of side effects in numerical form. CONCLUSION: The significantly increased volume of medical information provided in package inserts does not meet the requirements of patients. Major efforts are required by pharmaceutical companies, authorities and legislative bodies in order to reduce information to that which is essential for patients and to ensure that this is provided in short, precise and easily comprehensible texts.
Subject(s)
Drug Labeling , Comprehension , Drug Information Services , Humans , Patient Education as TopicABSTRACT
OBJECTIVE: N-acetyltransferase 2 (NAT2) genotype-phenotype relation with sulfasalazine as probe drug by means of detailed genotype analysis and kinetic data evaluation. BACKGROUND: Though phenotype analysis of sulfasalazine metabolism has been described before, genotype investigations in this regard are scarce. The influence of different single point mutations on the metabolism of the sulfasalazine metabolite sulfapyridine (SP) should give more insight into the functionality of different alleles especially with those still under discussion. METHODS: In two bioavailability studies performed under comparable conditions with 24 healthy subjects of both genders equally distributed, plasma levels of SP and acetylsulfapyridine (Ac-SP) were determined after oral intake of enteric coated formulations of sulfasalazine (500 mg and 1,000 mg, respectively). The resulting metabolic ratios were calculated. NAT2 genotype was analyzed in parallel for all subjects deducing haplotype set as well as putative functional phenotype as (homozygous or heterozygous) rapid acetylator (RA) or slow acetylator (SA) and correlated with the PK results. RESULTS AND DISCUSSION: RA genotype in the overall study population was seen with 45.5% (including 6.8% homozygous wildtype *4/*4) and SA genotype with 54.5%. Compared to RA genotype, apparent terminal elimination half-life of SP as well as of Ac-SP was prolonged in the SA genotype population, C(max) and AUC values of SP were higher whereas average C(max) value of Ac-SP was lower (with AUC only some tendency to lower values). In general, phenotype-genotype correlation was good with only few exceptions. Strongest functional effect on enzyme activity was noticed in slow acetylators carrying the 341T > C mutation, followed by 590G > A mutation whereas the influence of 857G > A was considerably less pronounced. Homozygous 803A > G mutation (lysine > arginine shift) did not reveal enzyme activity reduction.
Subject(s)
Antirheumatic Agents/pharmacokinetics , Arylamine N-Acetyltransferase/genetics , Sulfasalazine/pharmacokinetics , Adolescent , Adult , Antirheumatic Agents/administration & dosage , Area Under Curve , Biological Availability , Clinical Trials as Topic , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Genotype , Half-Life , Humans , Male , Middle Aged , Pharmacogenetics , Phenotype , Point Mutation , Sulfapyridine/analogs & derivatives , Sulfapyridine/pharmacokinetics , Sulfasalazine/administration & dosage , Time Factors , Young AdultABSTRACT
OBJECTIVE: To analyze in a pilot study the association between the pharmacokinetics of chronomodulated administered oxaliplatin and non-hematological toxicity in patients with metastatic gastrointestinal cancer. METHODS: 16 patients received a 4-day chemotherapeutic regimen consisting of a 12-h chronomodulated infusion of oxaliplatin (25 mg/m2) followed by a 12-h chronomodulated infusion of 5-fluorouracil (750 mg/m2) and sodium folinate (150 mg/m2) daily. Plasma pharmacokinetics of oxaliplatin, measured as ultrafiltrable platinum, were determined. RESULTS: Pharmacokinetics and non-hematological adverse events could be assessed in all patients included in the study. Pharmacokinetic parameters showed moderate interpatient variability. The occurrence of nausea and vomiting, but not diarrhea, was significantly associated with the pharmacokinetics of ultrafiltrable platinum. Thus, increased AUC values were observed in patients who experienced nausea or vomiting. No differences in pharmacokinetic parameters were found between patients with and without oxaliplatin-induced neurotoxicity or the other selected non-hematological toxicities. CONCLUSION: The preliminary results in this pilot study suggest an association between pharmacokinetics of ultrafiltrable platinum and non-hematological toxicity such as nausea and vomiting. Furthermore, although the sample size is limited, systemic exposure to ultrafiltrable platinum appears to predict the risk of non-hematological toxicity in patients treated with chronomodulated oxaliplatin combined with 5-FU and FS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Chronotherapy , Gastrointestinal Neoplasms/drug therapy , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/pharmacokinetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Area Under Curve , Female , Fluorouracil/administration & dosage , Gastrointestinal Neoplasms/pathology , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Pilot ProjectsABSTRACT
OBJECTIVE: Package inserts have an important impact on patients compliance and thus on the effectiveness of drug use. Despite efforts of the European or national regulatory authorities and manufacturers to improve the readability and comprehensiveness of package inserts, they are still the subject of critical discussion. MATERIAL AND METHODS: 68 German package inserts were chosen for a detailed analysis of their quality and suitability based on a set of 104 quality criteria developed prior to the survey. RESULTS: In many cases package inserts available on the German drug market did not include important information or were difficult to read or understand. In 73.5% of cases, the daily maximum dose was missing and 63.2% gave no information on the measures to take for each of the interactions. 66.2% of package inserts provided no instructions about the correct storage and 58.8% gave no instructions on the appropriate storage temperature. In 13 cases, dosage instructions were provided only in milligrams of active substance instead of a number of tablets or volume of liquid. 98.5% of the 68 package inserts included non-quantifiable statements such as "high dosage" or "take 2 - 4 tablets, 1 - 3 times daily". 97.1% contained repetitious information, 83.8% included advertising elements and 8.8% contained contradictory information. CONCLUSION: Package inserts must be optimized and tested by selected groups of patients prior to approval of the drug. This will avoid misunderstandings and lack of information and ensure that use of the drug will give the best possible outcome and avoid safety risks.
Subject(s)
Drug Information Services/standards , Drug Labeling/standards , Comprehension , Drug Interactions , Drug Prescriptions , Drug Storage , Germany , Humans , Legislation, Drug , Nonprescription Drugs/adverse effects , Nonprescription Drugs/therapeutic use , Patient Education as Topic/methods , Risk AssessmentABSTRACT
OBJECTIVE: Several clinical trials have demonstrated that oxaliplatin is a useful agent in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of patients with colorectal carcinoma. The aims of this pilot study were to evaluate non-hematological toxicity and patient characteristics in gastrointestinal cancer patients treated with chronomodulated chemotherapy consisting of oxaliplatin, 5-FU and sodium folinate. METHODS: Patients with metastatic gastrointestinal cancer received a chronomodulated regimen with oxaliplatin (25 mg/m2), 5-FU (750 mg/m2) and sodium folinate (150 mg/m2). Non-hematological toxicities were evaluated and analyzed in relation to patient characteristics, i.e. age, sex, body weight, body mass index (BMI), body surface area and smoking status. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: The severity of non-hematological toxicity was generally moderate. Grade 4 toxicity was only found in 2 patients with diarrhea (12.5%). The most frequent common adverse events were nausea, Grades 1 - 2 in 13 patients (81.3%), followed by motor neuropathy, Grades 1 - 3 in 11 patients (68.9%). The analyses showed that patient characteristics such as BMI and smoking status were associated with mucositis/stomatitis, vomiting or mood alteration. Furthermore, there was a relationship between smoking status and the overall non-hematological toxicity. Smokers had significantly higher overall toxicity than non-smokers and body mass index correlated significant with overall toxicity. CONCLUSION: The results of this pilot investigation suggest that a chronomodulated regimen with oxaliplatin, 5-FU and sodium folinate has a manageable non-hematological toxicity profile and that toxicity of the chronomodulated schedule studied depends on the patient characteristics. In further investigations, risk factors determining chemotherapeutic toxicity should be considered. Because of the small number of patients in this pilot investigation, the findings need to be confirmed in a larger clinical study.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chronotherapy/methods , Gastrointestinal Neoplasms/drug therapy , Leucovorin/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Body Mass Index , Diarrhea/chemically induced , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Gastrointestinal Neoplasms/pathology , Humans , Infusions, Intravenous , Leucovorin/administration & dosage , Leucovorin/adverse effects , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Middle Aged , Motor Neurons/drug effects , Mucositis/chemically induced , Nausea/chemically induced , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Patient Selection , Pilot Projects , Risk Factors , Severity of Illness Index , Stomatitis/chemically induced , Vomiting/chemically inducedABSTRACT
The use of drugs is always accompanied by the risk of adverse drug reactions (ADRs). Particularly important among these are serious ADRs that require hospital admission. Such cases often include patients with gastrointestinal ADRs and many reports have been published on drug-induced gastrointestinal bleeding and ulcers. The objective of the project described here was to detect gastrointestinal ADRs by systematic screening of all medical files in three university departments of surgery, i.e. visceral surgery, vascular surgery and traumatic surgery in the University Hospital of Jena, Germany. The study was retrospective involving the analysis of patients records for the period January 1, 2000 to June 30, 2001. The evaluation concerned all the medical files of individual patients in surgery and in particular those with gastrointestinal disorders due to adverse drug reactions. Side effects were classified according to their severity, duration, symptomatology and pathogenesis and assessed according to frequency, age and sex of the patient and the surgical unit in which the side effect was being treated. Out of a total of 7,715 patients evaluated in the university surgical departments, 471 (6.1%) had gastrointestinal disorders, in 144 (1.9%) of these patients 202 adverse drug reactions were diagnosed and in 70 patients (49.3%) the adverse drug reactions affecting the gastrointestinal tract were classified as serious. Gastric ulcers were present in 86 patients (42.6%) and intestinal ulcerations in 62 patients (30.7%) with intestinal bleeding occurring in 21 (10.4%). In 33 patients (16.3%) the etiology of the gastrointestinal bleeding was uncertain. The average age of patients with gastrointestinal ADRs was 66.1 years in men and 74.4 years in women. Only 1.7% of our patients were aged below 40 years. In approximately 20% of patients analgetic drugs had been withdrawn because of side effects. It is known that there is a correlation between polypharmacy, multiple morbidity and advancing age. The relationship however is complex and the extent to which age is a causative factor in ADRs is difficult to determine. In addition, it is often difficult to obtain clear documentation on the drug history prior to admission to hospital. Physicians are usually unable to devote enough time for a thorough analysis of adverse drug effects and there is a need to correct this deficiency.
Subject(s)
Adverse Drug Reaction Reporting Systems , Drug-Related Side Effects and Adverse Reactions , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/epidemiology , Hospitals, University , Surgery Department, Hospital , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Aged , Drug Therapy/statistics & numerical data , Female , Germany , Hospitals, University/statistics & numerical data , Humans , Male , Retrospective Studies , Surgery Department, Hospital/statistics & numerical dataABSTRACT
The Department of Clinical Pharmacology in Jena is a pharmacovigilance center in a study on intensified spontaneous adverse drug reaction reporting. Physicians specialized in clinical pharmacology screen admissions to the Department of Internal Medicine for possible adverse drug reactions. Because of the collaboration between the Pharmacology Department and the nearby Poison Information Center (PIC) in Erfurt the question occurred whether the latter might contribute to adverse drug reaction monitoring. We compared the ADR registered by the intensified spontaneous reporting system in 1999 with those of the PIC during the same period. Each symptom observed was regarded as 1 case. Every suspected drug was also treated separately. The symptoms were classified using adverse reaction terminology. The drugs were classified according to the WHO Anatomical Therapeutic Chemical (ATC) classification index. The causality assessment was based upon bibliographic data and the method of Bégaud et al. [1985]. Only possible, probable or very probable ADR were compared. The PIC registered mainly psychiatric and nervous system disorders sedation and extrapyramidal disorders were the most frequent reactions - unlike the pharmacovigilance study which registered primarily gastrointestinal and heart rate disorders. The PIC registered mainly drugs used in the therapy of disorders of the central nervous system, i.e. mostly psycholeptics and drugs acting on the alimentary tract, mostly anticholinergics. Drugs for the therapy of sensory organs disorders were frequent owing to the systemic and local adverse drug effects of anticholinergic mydriatics. The PIC and pharmacovigilance centers can benefit from co-operation. The PIC provides easy access to qualified drug information and is thus a useful tool in ADR evaluation. Although the number of adverse reactions assessed was small, their evaluation revealed problems in drug usage which would not otherwise be reported. The evaluation has enlarged the pool of ADR data which is the basis for signal detection.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Poison Control Centers/statistics & numerical data , Evaluation Studies as Topic , Germany , Humans , Pharmaceutical Preparations/classificationABSTRACT
Drug-related illness is an important cause of admission to hospital. Little information is available regarding the frequency of ADRs caused by antilipidemic agents classified as HMG-CoA reductase inhibitors (statins). Treatment with statins has been associated with the occurrence of myopathy or liver toxicity in case reports. Recent lipid intervention studies have involved the implementation of lipid lowering therapy with HMG-CoA reductase inhibitors in cardiovascular risk management. Since January 1997 we have been involved in a study, the aim of which was to improve the spontaneous drug information reporting system in Germany. The study was supported by the German Federal Institute for Drugs and Medical Devices, the "Bundesinstitut für Arzneimittel und Medizinprodukte", Berlin BfArM. Between early 1997 and late 2000, as a result of this monitoring of ADRs, we analyzed all patient histories concerning therapy with statins. A total of 550 ADR patients were evaluated, (209 male, 341 female) with a mean age of 66.4 years. 27 (4.9%) of all patients had received statins (atorvastatin = 12, fluvastatin = 7, simvastatin as well as pravastatin = 3, lovastatin = 2). Only 2 of the 27 patients admitted to hospital for typical ADRs of statins such as skeletal muscle toxicity (e.g. myalgia, rhabdomyolysis) or disorders involving hepatic structure or function were receiving statins (atorvastatin). An increased risk of rhabdomyolysis has been reported in the case of several statins, following concomitant use with erythromycin, cyclosporine or itraconazole, all of which are potent inhibitors of CYP3A4 enzyme. But only 1 atorvastatin patient had received cyclosporine as a CYP3A4 inhibitor. After discontinuing medication, signs of intoxication disappeared. The antihyperlipidemic drugs available are generally safe and effective, and rate of ADRs is low if concomitant intake of other drugs and the differing pharmacokinetic profiles of the statins are considered.
Subject(s)
Adverse Drug Reaction Reporting Systems/organization & administration , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Aged , Female , Germany , Humans , MaleABSTRACT
OBJECTIVES: Cardiovascular drugs are the most often prescribed drug class in Germany. The objective of this study is to analyze the adverse drug reaction (ADR) profiles of these drugs and to identify some targets for prevention of ADR. METHOD: Since 1997 specially trained medical staff members of five Pharmacovigilance Centers in Germany prospectively screened all hospital admissions at the departments of internal medicine of five large teaching hospitals. ADR leading to hospital admission were registered and reported. Especially ADR caused by cardiovascular drugs and all factors, which could have been important for their occurrence were analyzed. RESULTS: 559 of 2270 (24.6%) registered ADR cases were related to cardiovascular drugs. The drugs most frequently related to ADR were angiotensin inhibitors (17.9%), digitalis (17.3%), calcium channel blockers (13.9%), beta blockers (12.8%), and diuretics (12.2%). The most often observed ADR were arrhythmias (27.1%), syncopes and blood pressure dysregulations (25.1%), gastrointestinal symptoms (12.4%), and metabolic disorders (10.2%). 72% of patients were older than 65 years. Older patients were on a significantly higher number of drugs (6.2 +/- 2.4 vs 5.5 +/- 3.2; p < 0.001) than the younger ones. Furthermore, they were hospitalized significantly longer (13.2 +/- 9.9 vs 15.3 +/- 9.3 days; p < 0.01). Eleven patients (2%) died because of ADR due to cardiovascular drugs. CONCLUSIONS: Cardiovascular drugs are frequently used. They are prescribed mainly to older patients. Often observed ADR can be prevented effectively by considering their indication, by a clear definition of the therapeutic target, by a dose adjustment to the individual clinical parameters of the patient and by regular control investigations. The large number of drug-induced rhythm disorders--in particular bradycardia--show that extraordinary attention should be paid to rhythm-affecting drugs. The detailed instruction of the patient about therapeutic aims, risks and a concrete guideline for the therapy/drug handling is generally necessary.
Subject(s)
Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/prevention & control , Cardiovascular Agents/adverse effects , Adrenergic beta-Antagonists/adverse effects , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/mortality , Calcium Channel Blockers/adverse effects , Cardiac Glycosides/adverse effects , Cardiovascular Agents/pharmacokinetics , Diuretics/adverse effects , Drug Interactions , Female , Germany/epidemiology , Humans , Incidence , Male , Retrospective Studies , Syncope/chemically inducedABSTRACT
Drug-related illness is an everlasting universal problem and also an important cause of admissions to hospitals. Adverse reactions are still grossly underreported by medical professions. Little information is available regarding the frequency or type of ADRs managed in hospitals. Since January 1997, we have taken part in a study, supported by the German Federal Institute for Drugs and Medical Device to improve the spontaneous drug information reporting system in Germany. Three German regionalized Departments of Clinical Pharmacology--Jena, Dresden, Rostock--serve as Pharmacovigilance Centers in collaboration with the Pharmacoepidemiology Research Group of the University of Munich. Since January 1997, the regional group in Jena has been monitoring the University Clinic of Internal Medicine for admissions caused by adverse drug reactions. All emergency cases and patients on intensive care units were checked for adverse drug reactions. We present our results, including clinical and demographic data, concerning intoxications and especially those involving digitoxin in 210 patients with ADR. Forty patients with digitoxin toxicity had an average age of 81 years (81.1+/-6.3), a low body weight (59.7+/-12.7 kg) and 3 out of 4 were women. 75% of all patients with digitoxin side effects had elevated serum digitoxin levels with concentrations higher than 25 microg/ml. The relatively high frequency of digitoxin intoxications in our hospital may reflect the advanced age and low body weight of patients. Patients received digitoxin regardless of age, weight and, sometimes, clinical indication. Physicians should be aware of drugs having a high risk when used in elderly patients. The use of digitoxin assays and keeping serum levels within or near the therapeutic range will diminish the incidence of overdoses.
Subject(s)
Adverse Drug Reaction Reporting Systems , Anti-Arrhythmia Agents/adverse effects , Digitoxin/adverse effects , Age Factors , Aged , Aged, 80 and over , Anti-Arrhythmia Agents/therapeutic use , Demography , Digitoxin/therapeutic use , Drug Overdose , Female , Germany , Hospitalization , Humans , Male , Risk FactorsABSTRACT
AIMS: An intensified monitoring system was set up to identify drug related hospital admissions and estimate population-based incidences for commonly prescribed medications. METHODS: Pharmacovigilance-centres systematically screened nonelective admissions to emergency rooms or departments of internal medicine for drug related hospitalizations (DRH). Clinical pharmacologists used standardized causality assessment. Service areas of each acute care hospital were defined by 5 digit postal codes that covered 60% of all admissions. Drug dispensing information was available through claims processed by regional pharmacy computing centres. Quarterly incidences were estimated by dividing the number of events by the number of treated patients. RESULTS: 435 DRHs were reported during five quarters. The incidence of ADRs leading to admissions varied for specific drug groups from 1.5/10 000 treated patients to 24/10 000. Quarterly variation of incidences was moderate except for insulin and calcium antagonists. 95% confidence intervals overlap for all quarters within each group. Incidences are sensitive to changes in the definition of the source population. CONCLUSIONS: Our pharmacovigilance monitoring system allows comparisons of population-based incidences of drug-related hospitalizations among drugs and over time. It provides important information for risk management and monitoring outcomes of pharmaceutical quality management programmes.
Subject(s)
Drug Monitoring , Drug-Related Side Effects and Adverse Reactions , Patient Admission/statistics & numerical data , Adverse Drug Reaction Reporting Systems , Community Health Planning , Humans , IncidenceABSTRACT
CASE REPORT: A case of a 73-year-old male with theophylline overdose complicated by rhabdomyolysis is reported. After uncontrolled self-medication with an unknown number of theophylline slow release 350 mg tablets and furosemide 40 mg tablets he was admitted with unspecific clinical signs like tachyarrhythmia, vomiting and restlessness. Maximum theophylline concentration was 66.5 mg/l, other abnormal laboratory findings included hypokalemia (2.8 mmol/l) and hyponatremia (123 mmol/l). The maximum creatinkinase level was measured after admission (32.29 mumol/s/l) accompanied by a serum myoglobin level of 3,789 micrograms/l. Immediate treatment with oral activated charcoal and continuous veno-venous hemodialysis (CVVH) was instituted, together with intravenous potassium and sodium chloride substitution, forced diuresis and continuous administration of intravenous metoprolol. The theophylline, creatinkinase and myoglobin levels decreased rapidly and there was no second rise in theophylline found. The patient survived without sequelae. CONCLUSION: Rhabdomyolysis is a rare complication of theophylline intoxication. In literature only a small number of cases are reported. Our results illustrate the necessity of a purposeful and fast management to successfully prevent renal failure or death. Some pathogenetic mechanisms of theophylline-induced rhabdomyolysis, epidemiologic data, risk factors and therapeutical principles will be demonstrated by a detailed literature survey.
Subject(s)
Rhabdomyolysis/chemically induced , Theophylline/poisoning , Aged , Creatine Kinase/blood , Delayed-Action Preparations , Furosemide/administration & dosage , Furosemide/adverse effects , Humans , Male , Myoglobin/blood , Rhabdomyolysis/diagnosis , Rhabdomyolysis/therapy , Self MedicationABSTRACT
Percutaneous absorption studies are performed in various in vitro models to determine the rate of drug absorption via the skin. We designed an phonophoretic drug delivery system to investigate the influence of ultrasound on transmembrane transport of different drugs. Phonophoresis is defined as the migration of drug molecules, contained in a contact agent, through the skin under the influence of ultrasound. We investigated the absorption of flufenamic acid in a buffer medium in dependence of ultrasound energy and application time. For evaluating membrane penetration of flufenamic acid, the concentration range of buffer solution was measured. Flufenamic acid was determined by using a fluorimetric method. Ultrasound energy was supplied for between 5 and 30 min at a range of intensities (0; 0.3; 0.6; 0.9; 1.2; 1.5 W/cm2). energy levels commonly used for therapeutic purpose. The pronounced effect of ultrasound on the transmembrane absorption of the drug was observed at all ultrasound energy level studied. The time of application was found to play an important role in delivery and transport of drug. Dependent on time, we observed an arise of temperature up to 4.5 degrees. It appears that there was no difference between an intensity of 0.3 and 1.5 W/cm2 and the measured drug concentrations in solution. The highest penetration was observed at an intensity of 1.0 W/cm2 after 30 min. These results were not significantly different from concentration in measurements after 30 min and 0.5 and 1.5 W/cm2. It seems that the arise of drug concentration is caused by effects of temperature and by variation of membrane delivery in dependence of temperature.
Subject(s)
Flufenamic Acid/pharmacokinetics , Membranes, Artificial , Phonophoresis/methods , Biological Transport , In Vitro Techniques , Temperature , Time FactorsABSTRACT
Although topical drugs are usually applied at a convenient site, the target for the drug interaction may be systemic. Phonophoresis is the use of ultrasound to enhance the delivery of topical applied drugs. The purposes of our study were to investigate the in vitro penetration and the in vivo transport of flufenamic acid in dependence of ultrasound. Percutaneous absorption studies are performed in various in vitro models to determine the rate of drug absorption via the skin. We designed a phonophoretic drug delivery system to investigate the influence of ultrasound on transmembrane transport of different drugs. We investigated the absorption of flufenamic acid in a buffer medium in dependence of ultrasound energy and application time. For evaluating membrane penetration of flufenamic acid, the concentration range of buffer solution was measured. Ultrasound energy was supplied for between 5 and 30 min at a range of intensities up to 1.5 W/cm2, energy levels commonly used for therapeutic purpose. The pronounced effect of ultrasound on the transmembrane absorption of the drug was observed at all ultrasound energy levels studied. The time of application was found to play an important role in delivery and transport of drug. Dependent on time, we observed a rise of temperature up to 4.5 degrees C. It appears that there was no difference between an intensity of 0.3 and 1.5 W/cm2 and the measured drug concentrations in solution. The highest penetration was observed at an intensity of 1.0 W/cm2 after 30 min. These results were not significantly different from concentration measurements after 30 min and 0.5 and 1.5 W/cm2. It seems that the arise of drug concentration is caused by effects of temperature and by variation of membrane delivery in dependence of temperature. Using this in vitro model we note it is possible to compare the transdermal penetration and absorption of commercial flufenamic ointment in volunteers.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Flufenamic Acid/pharmacokinetics , Phonophoresis , Skin Absorption , Administration, Topical , Adult , Biological Transport , Buffers , Drug Delivery Systems , Female , Flufenamic Acid/administration & dosage , Flufenamic Acid/blood , Humans , In Vitro Techniques , Knee , Lumbosacral Region , Male , Temperature , Time FactorsABSTRACT
OBJECTIVE: To investigate the influence of oral contraceptives on cytochrome P450 3A4 (P450NF) activity. METHODS: In 23 healthy women, the pharmacokinetics of nifedipine and its main metabolite dehydronifedipine in plasma were assessed after a single oral dose, prior to and after intake of one of two oral contraceptive formulations, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). RESULTS: While the intake of two oral contraceptives for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine, mean AUC0-23.5 h and the mean Cmax values of dehydronifedipine were significantly lower in both groups tested/(24% in group A and 25% in group B). This observation may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. The activation of the same or other metabolic degradation mechanism(s) could explain this result. CONCLUSION: The investigation presented demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing ability.
PIP: The influence of combined oral contraceptives (OCs) on cytochrome P450 3A4 activity was investigated in a study of 23 healthy women. The pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in plasma were measured after a single oral dose, before and after intake of 1 or 2 OC formulations. The first contained 2 mg of dienogest and 0.03 mg of ethinyl estradiol (group A); the second contained 0.125 mg of levonorgestrel and 0.03 mg of ethinyl estradiol (group B). OC use for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine. However, the mean area-under-curve values at 0-23.5 hours after nifedipine administration were significantly lower than baseline (by 24% in group A and 25% in group B). This finding may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. Activation of the same or other metabolic degradation mechanisms could explain this finding. Assessment of its clinical importance requires a longer period of nifedipine use. This study demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing activity.
Subject(s)
Calcium Channel Blockers/pharmacokinetics , Contraceptives, Oral, Hormonal/pharmacology , Nifedipine/pharmacokinetics , Adult , Area Under Curve , Calcium Channel Blockers/urine , Contraceptive Agents, Female/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Estradiol Congeners/pharmacology , Ethinyl Estradiol/pharmacology , Female , Half-Life , Humans , Levonorgestrel/pharmacology , Mixed Function Oxygenases/metabolism , Nandrolone/analogs & derivatives , Nandrolone/pharmacology , Nifedipine/urine , Pyridines/urineABSTRACT
The possible interference of simultaneously given dextromethorphan (10 mg dextromethorphan-HBr-H2O), coumarin (10 mg), and mephenytoin (100 mg (R/S)-mephenytoin) on oxidative routes of drug metabolism performed by different cytochrome P450 enzymes and the possibility to detect all of the three substances and their metabolites in urine were investigated in 12 healthy subjects. The concentrations of parent drugs and main metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorphan as calculated using hydroxylation index (HI) for mephenytoin and as seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their metabolites or of coumarin and mephenytoin with their metabolites in urine is possible. The combined HPLC separation of all parent compounds and metabolites, however, is not useful because of the necessity to treat the urine samples in very different ways. An overlapping of retention times of the substances in HPLC does not occur. With it a simultaneous administration of all three drugs is possible. A following collection of urine over a period of 8-12 h serves for characterizing activities of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activities of these cytochromes is easily definable without the disturbing influence of intraindividual variation of drug oxidation with time.
Subject(s)
Anticoagulants/pharmacokinetics , Anticonvulsants/pharmacokinetics , Antitussive Agents/pharmacokinetics , Coumarins/pharmacokinetics , Dextromethorphan/pharmacokinetics , Mephenytoin/pharmacokinetics , Administration, Oral , Adult , Anticoagulants/administration & dosage , Anticoagulants/urine , Anticonvulsants/administration & dosage , Anticonvulsants/urine , Antitussive Agents/administration & dosage , Antitussive Agents/urine , Coumarins/administration & dosage , Coumarins/urine , Dextromethorphan/administration & dosage , Dextromethorphan/urine , Drug Interactions , Humans , Liver Function Tests , Male , Mephenytoin/administration & dosage , Mephenytoin/urine , PhenotypeABSTRACT
Several clinical investigations have been published regarding the interaction of nifedipine and quinidine. The results of these studies are contradictory. In vitro studies indicate that the 3-hydroxylation and N-oxigenation of quinidine appear to involve the P4503A4 family, a form of cytochrome that predominantly catalyzes the aromatization of nifedipine, too. The aim of our study was to investigate the effect of oral intake of 200 mg quinidine on the kinetics of 20 mg nifedipine as a retarded formulation and vice versa. Twelve healthy male volunteers between 18 and 40 years were treated. Each subject was studied on three occasions each separated by a one week washout period. Drug administration consisted of one oral dose of nifedipine (Adalat retard 20 mg), one oral dose of quinidine (Chinidin sulfuricum "Buchler" 200 mg) or a combination of both (20 mg nifedipine and 200 mg quinidine) in a randomised 3 way crossover. Administration of the test drugs in combination slightly increased the bioavailability of both--nifedipine [N] to 18% and quinidine [Q] to 16%--and decreased the clearance of both drugs. The results were not statistically significant. Based on our data, the combination of nifedipine and quinidine seems to lack a clinically relevant interaction.
Subject(s)
Calcium Channel Blockers/pharmacokinetics , Nifedipine/pharmacokinetics , Quinidine/pharmacokinetics , Adult , Biotransformation , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/blood , Chromatography, High Pressure Liquid , Cross-Over Studies , Delayed-Action Preparations , Drug Interactions , Half-Life , Humans , Male , Nifedipine/administration & dosage , Nifedipine/blood , Quinidine/administration & dosage , Quinidine/bloodABSTRACT
The objective of this study was to investigate in a twoway randomized crossover whether repeated uptake of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h enhances bioavailability of a nifedipine (1) slow release formulation (20 mg) in ten healthy volunteers. Grapefruit juice increased the AUC and cmax of 1 statistically significantly by 103 (SD 73, range 48 to 265)% and 94 (SD 83, range -23 to 259)%, respectively. AUC of dehydronifedipine (2) was also higher during grapefruit phase, but to a lesser extent (mean increase 66, SD 106, range -30 to 236)%. Half lives of neither 1 nor 2 were altered by grapefruit juice. Because 2/1-ratio was not lowered by grapefruit juice in comparison to control, a selective inhibition of cytochrome P450 3A based on the presented in vivo data is not very likely. In the light of other reports concerning grapefruit juice induced increase in bioavailability our data contradict the assumption of a selective inhibition of only one cytochrome P450 subfamily. The observed effect could be clinically significant, especially if other factors affecting the elimination of 1 occur.