Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate.

Elevated homocysteine concentrations are a risk factor for atherosclerotic disease. Recently it was reported that lipid lowering with fibrates increases homocysteine by up to 40%. Since elevated homocysteine concentrations can readily be lowered by vitamin supplementation, a randomized, double-blind crossover study was performed to investigate the effect of fenofibrate plus folic acid, vitamin B6 and B12 versus fenofibrate plus placebo in hyperlipidemic men. The crossover study comprised a run-in period of 6 weeks, a first treatment phase of 6 weeks, a washout phase of 8 weeks and a second treatment phase of 6 weeks. Vitamins were given at doses of 650 microg folic acid, 50 microg vitamin B12 and 5 mg vitamin B6 per day for a period of 6 weeks. After fenofibrate plus placebo the increase in homocysteine concentration was 44+/-47%. After fenofibrate plus vitamins it was 13+/-25%, being significantly lower than without vitamins. The increase in homocysteine in response to fenofibrate may counteract the cardioprotective effect of lipid lowering. The addition of vitamins involved in homocysteine metabolism can prevent most of the homocysteine increase seen after fenofibrate plus placebo. Addition of these vitamins to fenofibrate may therefore be warranted for routine use.

Population pharmacokinetics of 2% topical dorzolamide in the aqueous humor of humans.

PURPOSE: To evaluate the concentration and kinetics of dorzolamide in the aqueous humor after its topical application. METHODS: Samples of aqueous humor were collected at the beginning of routine cataract surgery at defined intervals after topical application of a 2% solution of dorzolamide. After deep-frozen storage of the samples, drug extraction was achieved with a mixture of solvents. Quantification was carried out by high-performance liquid chromatography on a reversed-phase column. RESULTS: Peak concentrations of dorzolamide in aqueous humor were reached approximately 2 hours after application with 1000 ng/ml. Average values were approximately 1000 to 700 ng/ml after 4 to 6 hours and approximately 200 ng/ml after 12 hours. Mean half-life of absorption was 1.2 hours and for elimination 3.0 hours. CONCLUSIONS: Pharmacokinetics of dorzolamide in the aqueous humor of humans are in comparable dimensions as previously reported in experimental trials in pigmented rabbits. There is a clear linear absorption and elimination kinetic, which is demonstrated using the Bateman function. A better knowledge of the distribution and kinetics of dorzolamide will help to explain its reported effects on intraocular hemodynamics, distinct from its intraocular pressure lowering effect.

Absorption kinetics of paracetamol are not influenced by high anxiety levels in preoperative patients.

OBJECTIVE: If the absorption kinetics of orally administered drugs in preoperative patients are influenced by high anxiety levels as maintained by Simpson and Stakes [1987], then this aspect would have to be taken into consideration in the preparation for surgery and would make dose adjustments necessary in such patients. METHODS: We differentiated and quantified the anxiety level in 40 patients, 4 - 5 hours prior to an operation, using the State-Trait Anxiety Inventory (STAI). Subsequently, all patients were given 1000 mg of paracetamol and serum levels were analyzed by means of HPLC. RESULTS: Over the first 3 hours after application there were no significant differences in the parameters C(max) and t(max) between patients with high levels of anxiety and patients with low levels of anxiety. However, AUC (area under curve) values were slightly higher in patients with high levels of anxiety. CONCLUSIONS: No clinically relevant differences in absorption parameters were observed in patients with high and low levels of anxiety.

Rapid and simple method for detection of fenofibric acid in human serum by high-performance liquid chromatography.

A sensitive HPLC method for the determination of fenofibric acid (FA), the active form of fenofibrate in serum is described. FA from human serum samples was isolated by an easy one-step extraction procedure with a mixture of n-hexane and ethylacetate (90:10, v/v). The recovery was 84.8% of the total Fa in serum. The compound was separated isocratically on a reversed phase with acetonitrile and 0.02 M phosphoric acid (55:45, v/v) at a flow-rate of 1.0 ml/min. Absorbance at 287 nm was recorded for quantification. Validation presents a detection limit of 0.03 microgram/ml and a quantification limit of 0.1 microgram/ml (relative standard deviation at 0.1 microgram/ml = 7.1%). For an extensive validation of this method we determined the serum levels of FA in one young male volunteer and examined the pharmacokinetics of standard, mikronized and slow release formulation of fenofibrate after oral intake. This method is a rapid and reliable tool for quantitative determination of fenofibric acid in pharmacokinetic investigations.

[Biologic availability of caffeine in subjects with regard to the variability of the elimination half life]. / Zur Bioverfügbarkeit von Coffein bei Probanden unter Berücksichtigung der Variabilität der Eliminationshalbwertszeiten.

400 mg of caffeine and sodium salicylate (= 220 mg of caffeine) were given orally and intravenously (at an interval of one week) to six test persons. The serum levels were determined; and certain pharmacokinetic parameters were measured, using an open one-compartment model. Finally, the absolute bioavailability was calculated. With one of the test persons this experiment was repeated ten times to evaluate the extent of the intra-individual variability of the half-life period and its repercussions on bioavailability.

Determination of orotic acid in serum by high-performance liquid chromatography.

A simple method for the determination of orotic acid in serum is described. The analyses were carried out using a strong anion-exchange column. Orotic acid was separated isocratically with 0.8 M formic acid (pH 2.8, adjusted with 10 M NaOH)-methanol (65:35, v/v) at a flow-rate of 1.0 ml/min. Absorbance at 275 nm was recorded for quantification. Validation yielded a detection limit of 0.07 micrograms/ml and a quantification limit of 0.25 micrograms/ml. The maximum within-day and day-to-day coefficients of variation were less than 6%. The method has the advantage that samples can be easily prepared.

Validation of the analysis of carbamazepine and its 10,11-epoxide metabolite by high-performance liquid chromatography from plasma: comparison with gas chromatography and the enzyme-multiplied immunoassay technique.

An improved procedure for the determination of carbamazepine (CBZ) and its main active metabolite carbamazepine-10,11-epoxide (CBZ-e) in serum is described. The validation of this procedure shows that the limits of detection are lower than 80 ng/ml for CBZ and 7 ng/ml for CBZ-e. The relative standard deviation does not exceed 4.7% for both compounds in an inter-day precision test. In the intra-day precision test the relative standard deviations are 1.9% for CBZ-e and 1.1% for CBZ. A comparison of the described procedure with gas chromatography and the enzyme-multiplied immunoassay technique shows good agreement, but gas chromatography seems to have a relative poor reliability.

Simultaneous determination of midazolam and its metabolites 1-hydroxymidazolam and 4-hydroxymidazolam in human serum using gas chromatography-mass spectrometry.

A method for the quantitation of midazolam and its metabolites 1-hydroxymidazolam and 4-hydroxymidazolam from human serum capable of monitoring concentrations achieved under therapeutic conditions is presented. The substances were extracted under basic conditions with toluene and the hydroxy metabolites transformed to their tert-butyldimethylsilyl derivatives with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide. The samples were measured by gas chromatography-mass spectrometry. The limits of detection are 0.2 ng ml(-1) for midazolam and 0.1 ng ml(-1) for 1-hydroxy- and 4-hydroxymidazolam. The coefficients of variation are 3.9% at 5 ng ml(-1) for midazolam, 6.7% at 2 ng ml(-1) for 1-hydroxymidazolam and 8.8% (22.2%) at 0.5 (0.2) ng ml(-1) for 4-hydroxymidazolam.

Validated method for the therapeutic drug monitoring of flunitrazepam in human serum using liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry with an ion trap detector.

An HPLC-MS-MS method for the quantitative analysis of flunitrazepam in human serum was established. The method features a very simple liquid-liquid extraction, the use of a standard 4-mm HPLC column, isocratic elution using a buffer-free solvent, short retention times in connection with good peak resolution and the sensitivity and selectivity of an ion trap MS-MS detector. The procedure enables unambiguous identification of analytes by their product ion spectra, as well as sensitive quantitation (limit of quantitation for flunitrazepam=0.5 ng/ml). This feature was used for the confirmation of HPLC-UV results for nitrazepam.

[The bioequivalence of two nifedipine sustained-release formulations after single administration in steady state]. / Untersuchungen zur Bioäquivalenz von zwei Nifedipin-Retardformulierungen nach einmaliger Applikation und im Steady-State.

Investigations into the Bioequivalence of Two Nifedipine Controlled-release Formulations after Single Application and in Steady State. The bioequivalence of nifedipine (CAS 21829-25-4) in controlled-release formulation (Corinfar retard dragees) was tested versus a reference preparation in 22 subjects in a cross-over design after the first dose and in steady state. Compared to the reference, the preparations tested were found to have a relative bioavailability of 0.86 and 0.95, respectively. The bioavailability parameters of the preparations tested did not differ from each other. In particular, the fluctuation indices were noted to be highly similar. In view of the marked prolonged-action effect, a twice-per-day application is possible for the majority of the patients.

[Determination of hepatic metabolic capacity: antipyrine pharmacokinetics in circulatory liver damage due to cardiac insufficiency]. / Die Bestimmung der hepatischen metabolischen Kapazität: Untersuchungen zur Antipyrin-Pharmakokinetik bei zirkulatorischer Leberschädigung infolge Herzinsuffizienz.

As it was demonstrated in a study, antipyrin halftime and clearance totalis are prolonged resp. reduced in patients with circulatory liver damage due to cardiac failure in myocardial infraction (group H) and in patients with chronic congested liver due to diseases of the heart valves (group V). group H: t50,2 +/- 11,7 h, Cltot 27 +/- 13,3 ml. min-1; group V: t50 19,3 +/- 6,3 h, Cltot 21,9 +/- 8,6 ml. min-1. Those patients with acute myocardial infarction and normal liver condition had a prolonged half-time as well though the clearance was decreased just insignificantly (t50 12 +/- 4,9 h, Cltot 42,6 +/- 15,8 ml. min-1). In the three groups we obtained the expected biochemical results. There was only a slight correlation of both the antipyrin half-time and the clearance totalis to biochemical parameters, Conclusions: In chronic inflammatory liver diseases and other forms of hepatic malfunctions as well as in circulatory liver damages the antipyrin half-time is influenced. Because of this reason, reduction of metabolic capacity should be expected. It is referred to necessary adaptation of the drug doses if capacity limiting medicaments are administered to patients with circulatory liver damage.

[Significance of caffeine values in serum, saliva and urine--determination of pharmacokinetic data by non-invasive methods in psychopharmacologic studies]. / Aussagefähigkeit von Coffeinwerten in Serum, Speichel und Urin--Ermittlung von pharmakokinetischen Daten durch non-invasive Methoden bei psychopharmakologischen Untersuchungen.

For psychopharmacological studies with caffeine two reliable non-invasive methods are available in order to determine pharmacokinetic parameters simultaneously with psychometric tests, without any appreciable impairment of the experimental subject. The investigation were performed in 13 healthy volunteers. Caffeine was determined in serum, saliva and urine. The caffeine level in saliva was about 70% of that in serum, corresponding to the percentage freely dissolved in serum. A good correlation was found to exist between elimination half-lives for serum and saliva levels (r = 0.9702) as well as serum and urine values (r = 0.8784). The amount of caffeine excreted in urine in its unmetabolized form was 1.1 +/- 0.2% of the dose administered. Furthermore, the saliva level was seen to represent the serum level on a broad scale. Sixty minutes after oral uptake, saliva levels were falsified due to adsorption of caffeine to the buccal mucosa. The special pattern of the saliva level during the phases of absorption and distribution is discussed.

[Lidocaine elimination and dose adjustment in acute heart infarct and heart insufficiency]. / Die Lidocain-Elimination und -Dosisanpassung bei akutem Herzinfarkt und Herzinsuffizienz.

In 40 patients with an acute myocardial infarction a prolonged lidocaine infusion was indicated. The dosage of lidocain was done according to the body-weight. Patients suffering from a heart insufficiency received the anti-arrhythmic drug with a reduced dose referring to the degree of severity. The lidocaine-plasma content was determined by means of a gas-chromatographic method. Furthermore, the half-value time, the clearance and the distribution coefficient were computed. Despite the reduction of the dose the plasma contents were highest in patients with manifest heart insufficiency. As we expected, the half-value time was shorter in the patients with infarction without heart insufficiency than in the patients with manifest heart insufficiency. The behaviour of the total clearance was analogous in the adequate groups of patients. The lidocain dosage performed which referred to more recent investigations of the behaviour of the half-value time after prolonged infusion is regarded as more precisely in comparison to the previous proposals. Corresponding to the findings got, a dosage scheme is given for patients with myocardial infarction and heart insufficiency, which should allow a secure and effective treatment.

Sensitive and specific determination of clindamycin in human serum and bone tissue applying liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry.

A method for the quantification of clindamycin in human serum and in human bone tissue samples applying high-performance liquid chromatography with atmospheric pressure chemical ionization-mass spectrometry (APCI-MS) is presented. Lincomycin is used as the internal standard. Serum samples are prepared only by protein precipitation with acetonitrile. Bone tissue samples have to be crushed and homogenized in extraction buffer prior to analysis. The chromatographic separation is achieved on an RP-18 stationary phase with 0.02% trifluoroacetic acid in water 60%/ acetonitrile 40% v/v as mobile phase. The limits of quantification are 0.1 microg/ml for serum samples and 0.1 microg/g for bone tissue samples. The coefficients of variation for the assays are 4.48 and 8.41% at the limit of quantification for serum and bone tissue samples, respectively. Bone tissue samples as small as 50 mg can be used.

[Side effects of nifedipine in healthy probands within the scope of a discontinued bioavailability study]. / Nebenwirkungen von Nifedipin bei gesunden Probanden im Rahmen einer abgebrochenen Bioverfügbarkeitsstudie.

In a prematurely discontinued bioavailability study of 40 mg nifidepine retard dragees, it was shown in four subjects that cardiovascular side effects may occur at nifedipine levels equal to or higher than some 80 ng/ml serum. These cases were suggestive of a relationship between the areas under the concentration vs. time curves in the range of side effects, AUC (tC80), and the so-called side effects scores which were derived from the number and the duration of undesirable side effects.

Determination of nifedipine in human serum by gas chromatography-mass spectrometry: validation of the method and its use in bioavailability studies.

A procedure for the determination of nifedipine in human serum is described. The light-sensitive substance is isolated from serum by liquid-liquid extraction and analyzed using capillary gas chromatography with a mass-selective detector. The validation of the method shows that the extraction recovery is ca. 85%, the limit of detection is 2 ng/ml and the standard deviations of the intra-day precision test range from 5.8 to 7.4% with respect to the concentration. The procedure is highly selective and sensitive. It is especially suited for bioavailability studies because of its stability and high sampling rate.

Lamotrigine concentrations in human serum, brain tissue, and tumor tissue.

PURPOSE: Although lamotrigine (LTG) has been used for years as an antiepilepic drug (AED), there are no data on penetration into the brain with the exception of a single case report. It was our aim to determine the LTG content in the brain and the tumor tissue and to bring the same into relation to the serum concentration and protein binding in neurosurgically operated patients. METHODS: Neurosurgical intervention was performed on 11 patients with brain tumors. Tumor tissue was removed, and LTG kinetics was carried out for 12 h. LTG was determined by means of (HPLC) and the protein binding by means of ultrafiltration. RESULTS: At the time of the section of the tumor, the LTG concentrations in the serum were an average of 3.7 microg/ml (range, 1.1-9.8); in the brain, an average of 6.8 microg/g (range, 1.0-14.9); and in the tumor, an average of 4.4 microg/g (range, 2.0-8.3). Brain/serum and tumor/serum ratios of 2.8 and 1.9, respectively, result from these data. The protein binding was on average 68% (range, 46-96). CONCLUSIONS: LTG is a lipophile AED with a moderate protein binding that penetrates brain tissue well and can be proven even in the tumor tissue.

[Effect of histamine H2 receptor blockers on hepatic elimination of drugs]. / Der Einfluss von Histamin-H2-Rezeptorenblocker auf die hepatische Elimination von Arzneimitteln.

In an investigation is proved that already after a treatment with the histamine-H2-receptor blocker Cimetidine (Altramet) lasting 14 days the elimination of Antipyrine is significantly delayed. In 14 male patients suffering from peptic ulcer the half-life period of Antipyrine (t50) was 8.6 +/- 0.6 h, whereas in the second test after 14 days it was 13 +/- 0.8 h. The systemic clearance (Cltot) was estimated with 78 +/- 11.3 ml X min-1 before treatment and with 40.8 +/- 3.6 ml X min-1 after treatment. It is pointed out that under a therapy with Cimetidine preparations and simultaneous application of medicaments which were eliminated by the so-called phase-I-reaction a hepatic interaction may occur.