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Biomedical subjects

M Grundmann

Publications and source records attributed to M Grundmann.

At least 19 recordsLinked to original sources
PubMed2006

Differences between prescribed daily doses and defined daily doses of antiepileptics--therapeutic drug monitoring as a marker of the quality of the treatment.

OBJECTIVE: Prescribed daily doses (PDDs) of antiepileptics (N03A ATC group) were recorded for drugs used in monotherapy or in combination therapy in the University Hospital in Ostrava, Czechia. Plasma levels were used as an indicator of the quality of treatment. METHOD: Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of PDDs and plasma levels. The study included 1,144 in-patients examined in the period 1993 - 2004. The differences in PDD were tested by Mann-Whitney-U-test. ATC/DDD index 2005 was used. Doses given in mono- and polytherapy were compared. RESULTS: Median PDDs in samples within the therapeutic range (in mg) in mono-/polytherapy were as follows (DDDs in parenthesis): carbamazepine 600/800 (1,000), clonazepam 2.0/2.0 (8), phenytoin 300/300 (300), ethosuximide -/1000 (1,250), lamotrigine 250/200 (300), phenobarbital -/200 (100), primidone 500/625 (1,250), topiramate -/300 (300), valproic acid 750/1,000 (1,500). Median PDDs in polytherapy with antiepileptics not analyzed for TDM were: gabapentin 900 (1,800), levetiracetam 1,500 (1,500), vigabatrin 1,500 (2,000). CONCLUSIONS: PDDs in monotherapy were similar or slightly lower than in combination therapy with an exception for lamotrigine, NS. The differences were significant in carbamazepine, p < 0.0001, and valproic acid, p < 0.001. Patients with plasma levels within the therapeutic range were usually treated with similar or slightly higher doses than the remainder. In polytherapy the PDDs were similar to DDDs in carbamazepine, ethosuximide, phenytoin, and topiramate in samples within the therapeutic range when difference +/- 20 per cent was considered as acceptable PDD of levetiracetam was also similar to actual DDD. In general plasma levels tended to be below the therapeutic range. The differences between PDD and DDD of antiepileptics have to be taken into account especially when utilization of different drugs is compared.

Adolescent↗
PubMed2006

[Consumption of antiepileptics in 1993-2004 using various methods].

Drug utilization expresses the exposition of a drug in the relationship with determined population, certain time period, and specific socioeconomic background. The aim of this study was to compare the antiepileptic drug utilization (N03A) in the Czech Republic (CR) and in Ostrava University Hospital (FNsP). The sources of the data were I) wholesale data (SUKL, CR), II) prescriptions (UZIS, CR), III) request forms (FNsP), IV) request forms for therapeutic drug monitoring (FNsP). The utilization was expressed in DDD/TID (I, II), or in DDD/100 BD in neurological departments (III) on 5th or 4th level, resp. ATC/DDD index 2001, for levetiracetam 2004. Carbamazepine had the highest utilization that was increasing in the CR, while remaining high and constant in FNsP. The utilization of valproic acid is increasing. The number of patients shows greater prescription than utilization in DDD. The utilization of phenytoin was high in the CR, but diminished in FNsP. The number of patients was lower than expected. The utilization of barbiturates was considerable in the CR, but below the average in FNsP. The utilization of clonazepam and N03AX was increasing. The most important substance there was lamotrigin. The outcomes are in agreement with current recommendations. The utilization in FNsP and CR follows the same trend with a faster shift to newer drugs in FNsP.

Anticonvulsants↗
PubMed2005

[Comparison of the consumption of antiepileptic drugs in the Czech Republic, Scandinavia, and Australia].

Long-term trends in utilization of antiepileptic drugs expressed in DDD/TID according to the 4th ATC level were studied. Wholesale data recorded from statistical yearbooks and the database of the State Institute for Drug Control (SUKL) were the source of data. The correlation between trends in the Czech Republic (CR) and the other countries was studied. The utilization was expressed in DDD/1000 inhabitants and day (DDD/TID). The lowest utilization of antiepileptics was in the Czech Republic, while highest in Norway (until 1994) and Finland (from 1995). The utilization of barbiturates is decreasing. The highest one was in Norway and CR. Hydantoins were the most widely utilized group in Australia, Sweden, and CR. Even though their utilization was lower in Finland and Norway, they were one of the most widely utilized groups there. The utilization of succnimide derivatives was very low and still decreases. Benzodiazepins were the most widely utilized group in Finland, until 1995 also in Australia, from 1996 in Norway. Their utilization increases. Even though the utilization of carboxamide derivatives was lower in CR and Australia, they belong to the second most widely utilized group there. Fatty acid derivatives were most widely utilized in Australia and Finland. Their utilization is lower, but increasing in CR. The utilization of N03AX has been increasing in the recent period in all countries. The utilization of antiepileptics in CR follows the trends in other countries, but on a lower level of DDD/TID.

Anticonvulsants↗
PubMed2004

Slow N-acetyltransferase 2 status leads to enhanced intrastriatal dopamine depletion in 6-hydroxydopamine-lesioned rats.

We previously reported an association between the N-acetyltransferase 2 (NAT2) slow acetylator status and Parkinson's disease (PD). We have now investigated the possible functional relevance of this association by treating Fischer 344 (F344) rapid and Wistar-Kyoto (WKY) slow NAT2 acetylator rat strains with the neurotoxin 6-hydroxydopamine (6-OHDA). Intrastriatal treatment with either 10 or 20 microg of 6-OHDA lead to a significantly greater reduction of striatal dopamine concentrations in the WKY slow acetylator rat strain than in the F344 rapid acetylator rat strain (P < 0.004), reflecting a more marked degree of dopaminergic denervation. Nigral dopaminergic cell counts were also lower in the WKY rats, but this difference failed to reach statistical significance, suggesting that slow acetylation is especially deleterious at the level of striatal nerve endings.

Animals↗
PubMed2002

[Determination of cyclosporine A using high-performance liquid chromatography].

Recent analytical possibilities of therapeutic drug monitoring (TDM) of cyclosporine A (CyA) both in solid organ transplanted patients and in patients with autoimmune diseases are described. The standard method for determination of CyA in blood is a validated HPLC method. HPLC methods were developed which make it possible to determine not only the parent drug, but also the main metabolites of CyA: AMI (M17), AM9 (M1), and AM4N (M21). Preparation of blood samples, their extractions and purifications are discussed. Chromatography is usually carried on C18 or CN columns by isocratic elution under high temperature (70 degrees C). CyD or CyC is used as the internal standard HPLC-MS method enables unambiguous identification of CyA metabolites after their separation on a chromatographic column and it is used mostly for research purposes only.

Chromatography, High Pressure Liquid↗
PubMed2002

[Immunoanalytical methods of cyclosporine A determination].

The standard method for determination of CyA in blood is a good validated HPLC method. HPLC methods were developed which make it possible to determine not only the parent drug, but also the main metabolites of CyA: AMI (M17), AM9 (M1), and AM4N (M21). HPLC methods for determination of CyA are very laborious and expensive. Most transplantation centres in the world use immunoanalytical methods for TDM of CyA. In recent years there has been an increase in the number of users of nonisotopic automated methods (Abbott TDx mono, AxSYM, Dade-Behring EMIT or Microgenic Cedia), which render instantaneous analysis possible. The analysis of the results of CyA in the blood in patients after transplantation shows that all immunoanalytical methods overestimate the concentration of CyA against HPLC results. The usually presented series of results is as follows: HPLC < RIA = EMIT < CEDIA < AxSYM < TDx. The differences are difficult to explain only by a different degree of cross reactivity for particular metabolites of CyA with the antibody used in the immunoanalytical method. The criterion of IFCC, which should be met by each immunoanalytical method in order to be used for TDM of CyA, should be redrawn, because it is not able to ensure sufficient specificity of the method. A suitable, cheap, and quick analytical method for TDM of CyA is still wanted. Some transplantation centres, including ours, carry out not only one method for effective TDM of CyA.

Chromatography, High Pressure Liquid↗
PubMed2002

[Therapeutic monitoring of cyclosporine A].

Cyclosporine A (CyA) is a drug with a specific influence on the immune system and it is used both to prevent tissue rejection of transplanted organs and to treat autoimmune diseases. The properties, metabolism, and methods of therapeutic drug monitoring (TDM) in patients under immunosuppressive therapy are described. TDM of CyA reflects the clinical condition of the patient during immunosuppression and may include pharmacokinetic and pharmacodynamic data obtained either from measuring CyA levels in blood, or from determining some other parameters, which are modulated by CyA (II-2). Although TDM is mainly based on analyzing trough levels of CyA, the determination of the whole biological exposition calculated as AUC enables better correlation with the clinical state of patients. Pharmacodynamic parameters have not been measured routinely yet.

Cyclosporine↗
PubMed2001

Evaluation and comparison of therapeutic monitoring of whole-blood levels of cyclosporin A and its metabolites in renal transplantation by HPLC and RIA methods.

BACKGROUND: The aim of the work was to evaluate the possibility to estimate the level of cyclosporin A (CyA) metabolites as the difference of radioimmunoassay (RIA) non-specific and RIA specific methods. METHODS: Blood samples of renal transplant patients were analyzed by three different methods: RIA specific method (CYCLO-Trac, DiaSorin, USA) (RIA(SP)), RIA non-specific method (Immunotech, Czech Republic) (RIA(NS)), and high performance liquid chromatography (HPLC) method. RESULTS: Although values obtained by RIA(SP) correlated well those obtained by HPLC (RIA(SP)=0.995.HPLC+9.68; r(2)=0.962, n=448), the results of HPLC methods were lower by 8%. The values obtained by RIA(NS) were 2.57 times higher than the values obtained by RIA(SP) (RIA(SP)=0.356RIA(NS); r(2)=0.713, n=448). The ratio (CyA+CyA metabolites)/(CyA) calculated as the ratio RIA(NS)/RIA(SP) values for 42 renal transplant patients was relatively stable for each particular patient. The sum of selected CyA metabolites (M1+M17+M21) measured by HPLC correlated well with that estimated from the difference of RIA(NS)-RIA(SP): HPLC(metab)=0.921.(RIA(NS)-RIA(SP))+21.3; (r(2)=0.746, n=448). CONCLUSION: The combination of both the specific and non-specific methods for the determination of CyA presents an improved means for the TDM of CyA and CyA metabolites in renal transplant patients. Moreover, a combination of both methods can help to elucidate some unexpected events, such as the persistence of high cyclosporin blood levels.

Blood Chemical Analysis↗
PubMed2001

Influence of P-glycoprotein on the transplacental passage of cyclosporine.

The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P-glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno-fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L-[(3)H]-glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L-[(3)H]-glucose, passage across the placenta. Our findings indicate that P-glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

High-performance liquid chromatographic method for therapeutic drug monitoring of cyclosporine A and its two metabolites in renal transplant patients.

A novel fast HPLC method was developed for the determination of cyclosporine A (CyA) and its two metabolites M17 (AM1) and M21 (AM4N) in blood. Whole blood was precipitated with zinc sulphate, extracted with diethyl ether, evaporated, dissolved in aqueous methanol and partitioned twice with n-hexane. Chromatography was carried out using a microbore RP-column under isocratic elution with acetonitrile-methanol-water (200:80:140, v/v/v) at 70 degrees C and a detector set at 205 nm. Linearity for all three compounds was tested in the range of 1-1000 ng/ml. Recovery was 97-109%, and a coefficient of variation was 1.6-8.8% depending on the particular compound and its concentration. The method was used for a group of renal transplant patients having an inadequate response to CyA therapy in order to evaluate the possible role of CyA and its metabolites on the occurrence of hypertension and other toxicological events.

Calibration↗