PKU patients on a relaxed diet may be at risk for micronutrient deficiencies.

OBJECTIVE: To investigate micronutrient supply in phenylketonuria (PKU) patients on a relaxed diet. SUBJECTS/METHODS: Sixty-seven patients (6-45 years) with a phenylalanine tolerance ≥ 600 mg/day were included in the study. From a 3-day diet record, protein supply as well as consumption of essential amino acids and several micronutrients were assessed and compared with the current recommendations and data for the healthy population. RESULTS: Protein supply and consumption of all essential amino acids were sufficient in all patients. Supply of micronutrients depended on dietary regime. Patients with a total protein supply of 120% or more of the recommended amount and at least 0.5 g protein per kg body weight from amino-acid mixture (AAM) were sufficiently supplied with all investigated micronutrients. All patients without AAM supplement showed severe micronutrient deficiencies in their diet records. CONCLUSION: PKU patients under a relaxed diet are at risk of an insufficient nutrient supply, if they have first no substitution with AAM, second a protein supply less than 0.5 g per kg body weight from AAM or third a total protein supply less than 120% of the recommendations. Therefore, close monitoring, specific dietary counseling and potential supplementation is mandatory to prevent micronutrient deficiencies in PKU patients.

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 4th communication: drops (without ethanol).

In a balanced two-period cross-over study with 12 (6 male, 6 female) healthy young subjects the pharmacokinetics and absolute bioavailability of tramadol (tramadol hydrochloride, CAS 36282-47-0) after oral administration of Tramal drops (without ethanol) were to be determined in comparison with a 30-min i.v. infusion. Each fasting volunteer received the two single doses of 50 mg tramadol-HCl each in the morning; the time interval between the administrations was one week. Serum and urine concentrations of tramadol were analysed by gas chromatography. The pharmacokinetic evaluation was carried out model-dependently after previous selection of the optimal model by means of the Akaike information criterion; solely the extent of bioavailability was calculated model-independently. The study population results were presented descriptively as geometric means with standard deviation [xg (SDg)] or as medians with range [x (min, max)]. Model-dependently and model-independently calculated areas under the serum concentration curves (AUC and AUC, resp.) differed only minimally. The extent of the absolute bioavailability (F) of tramadol in the drops, based on AUC data, was 70.6 (1.13)% with a 90% confidence interval of 65.9-75.6% (ANOVAlog). The p.o. serum concentration peaks were reached after tmax = 1.2 (0.74, 1.5) h and amounted to Cmax = 136 (1.33) ng/ml, the half-life of absorption was t1/2,ka = 0.23 (1.89) h and the lag time t0 = 0.23 (0.20, 0.49) h. The dose-normalised p.o. and i.v. results for all pharmacokinetic parameters agreed well with those of a previous study with ethanol-containing drops. In summary, it may be concluded that the active ingredient is rapidly absorbed after oral administration of the drops without ethanol. Rate and extent of the absolute bioavailability of tramadol in drops without ethanol were about the same as after administration of drops with ethanol. The results of this study gave no indication of a therapeutically relevant gender difference in the pharmacokinetics of tramadol.

Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion.

OBJECTIVES AND METHODS: The bioavailability of tramadol after i.m. injection of tramadol-HCl was determined from serum concentration data in a balanced two-period crossover study with 12 healthy male subjects in comparison to the 30-min i.v. infusion. Additionally, the tramadol concentrations in saliva and urine samples were measured. The subjects received single doses of 50 mg after an overnight fast, the washout period was one week. Serum, saliva and urine concentrations of tramadol were analyzed by gas chromatography, and pharmacokinetic (PK) evaluation was carried out model-independently. Descriptive statistical evaluation was performed by calculating geometric means with standard deviations (x(g) (SDg)) or medians with ranges (x (min, max)) and the extent of systemic availability (F) was tested for bioequivalence using the ANOVAlog-based 90% confidence interval (CI). RESULTS: Retrospective sparteine phenotyping revealed two of the subjects as poor metabolizers (PM). Nevertheless, all subjects were considered on statistical evaluation since the PM results were within the range of the extensive metabolizers (EM). The 90% CI of F = AUCi.m./AUCi.v. was 92.9 - 105.4% (x(g) = 99.0%) and was thus within the range of 80 - 125% generally accepted for a positive bioequivalence decision. After i.m. injection the serum concentration peaks were reached after t(max) = 0.75 (0.25, 1.50) h and amounted to c(max) = 166 (1.24) ng/ml; the corresponding results after i.v. infusion were t(max) = 0.50 (0.33, 1.50) h and c(max) = 293 (1.35) ng/ml. Thus, the results reflect the different invasion kinetics of the two modes of administration. However, the observed difference is not therapeutically relevant since in both cases minimal effective serum concentrations are already reached after a few minutes and are maintained for 9 - 10 h on the average. The i.v. results for all PK parameters agreed well with those of previous studies. Tramadol concentrations in saliva and urine were considerably higher than in serum. Therefore, saliva and urine samples are very suitable for the qualitative proof of tramadol intake in therapeutic drug monitoring and forensic toxicology. CONCLUSIONS: Tramadol is rapidly and almost completely absorbed after i.m. injection. The i.m. injection and the 30-min i.v. infusion are bioequivalent with respect to the extent of systemic availability. The differences in the times of onset and duration of action to be expected due to a slightly slower invasion after i.m. injection are small and probably therapeutically irrelevant.

Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol.

OBJECTIVE: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. METHODS: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O- and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. RESULTS AND CONCLUSION: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (rs = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.

Optimization of methods and models in clinical pharmacology.

Utilization of methods and models undoubtedly has its merits in the evaluation and interpretation of data in clinical pharmacology, but it is a process that ought to follow rigorous scientific rules and thoughts. For a discussion about optimization-a word concerning the quality of a procedure-the meaning and extent of the terms, methods, and models are defined, and different types of models are identified. In drug development, many steps can be improved, some within the pharmaceutical companies, some in the interaction with other organizations. This situation requires good organization and scientific sincerity. Some of the pitfalls encountered in daily work are described.

[Administrative divisions, population, and the social situation in the Russian Federation: selected problems in the development of Russia]. / Verwaltungsgliederung--Bevolkerung--soziale Situation in der Russischen Foderation: zu ausgewahlten Problemen der Entwicklung RuSSlands.

PIP: The author discusses various problems that arose or were exacerbated after the breakup of the Soviet Union. These include changes in the status of various geographical entities, the population decline caused by decreasing fertility and sharply elevated mortality, internal migration, and runaway inflation.^ieng

Radiofrequency ablation of idiopathic ventricular tachycardia.

BACKGROUND: Radiofrequency ablation (RFA) has been shown to be very effective in the treatment of supraventricular tachycardias and has replaced surgical ablation. Only a few reports of RFA for idiopathic ventricular tachycardia (VT) have appeared in the literature during the last two years. AIM: This paper presents our experience with RFA for idiopathic VT in 19 patients. MATERIAL: The age range of patients was 22-60, with a mean of 37.9 years. Twelve out of 19 were females, two patients had cardiac failure due to almost incessant VT while the rest had normal left ventricular function. Twelve patients had VT arising from the right ventricle (RV); of these, nine were from the outflow tract, two from the RV apex, and one from the mid-anterior RV. Seven patients had VT arising from the left ventricle (LV); of these, five were from the inferobasal portion of the septum and two were from the anterolateral area. METHODS: In all patients the diagnostic study and therapeutic RFA were combined in a single procedure. Pacemapping was used to guide the site of RFA in patients with VT arising from the RV. Local activation time (LAT), Purkinje potentials (PP) and pacemapping were used to guide RFA in those patients with LV septal tachycardias. RESULTS: A total of 21 RF procedures were performed in 19 patients and 15 out of 19 patients had successful VT ablation. Ten of the 12 patients with RV tachycardias and all five patients with LV septal (left axis, right bundle branch block) tachycardias were successfully ablated. One patient with mid anterior RV VT required two attempts for successful ablation. One patient with RV outflow tract (RVOT) VT could not be ablated despite two attempts. Two patients with LV tachycardias arising from the antero-lateral LV could also not be ablated. During a follow up period of two to 16 months none of the successful patients had recurrence of VT. The number of RF applications was one to 27, mean 10; fluoroscopy times were four to 75, mean 26.9 minutes. CONCLUSION: Idiopathic VT frequently arises from the RVOT and inferobasal portion of the LV septum. These tachycardias can be diagnosed on clinical and ECG grounds. RFA for idiopathic VT arising from these areas has a high success rate and this mode of treatment should be considered as a nonpharmacological curative treatment for symptomatic patients.

Pharmacokinetics and absolute bioavailability of lansoprazole.

OBJECTIVE: In a crossover study 12 healthy volunteers received lansoprazole 15 mg or 30 mg orally, or 15 mg intravenously in randomized order as a single dose. Blood samples were taken and plasma levels of lansoprazole were determined using an HPLC method. The volunteers were phenotyped for the debrisoquine/sparteine and mephenytoin polymorphisms. RESULTS: The total clearance was 517 ml.min-1, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in Cmax and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose.

Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase.

OBJECTIVE: To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. METHODS: This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. RESULTS: The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. CONCLUSIONS: u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.

Pharmacokinetics of saruplase, a recombinant unglycosylated human single-chain urokinase-type plasminogen activator and its effects on fibrinolytic and haemostatic parameters in healthy male subjects.

Pharmacokinetics of two doses of the recombinant single-chain urokinase-type plasminogen activator (r-scu-PA) saruplase (40 and 20 mg) and its effect on fibrinolytic and haemostatic parameters were studied in six healthy male subjects using a randomized, double-blind, placebo-controlled, cross-over study. Special precautions were taken to prevent artefactual in vitro effects on fibrinolytic activity. The clearance of saruplase ranged from 310 to 862 ml/min and the apparent volume of distribution of the central compartment was about 8 1. Both doses of saruplase caused alpha 2-antiplasmin consumption, indicating some systemic fibrinolytic activation. However, the 20 mg dose caused no detectable fibrinogen breakdown and only a small increase in total fibrin/fibrinogen degradation products (TDP) (from 0.16 microgram/ml [range 0.14 to 0.19] to 0.78 microgram/ml [range 0.56 to 1.26]), while the 40 mg dose produce a fibrinogen breakdown to an average value of 44% (range 19 to 60%) and TDP increased from 0.12 microgram/ml (range 0.11-0.12) to 2.29 micrograms/ml (range 0.45 to 5.55). The breakdown of fibrinogen was related to the quantity of saruplase converted to active two-chain u-PA (tcu-PA) in vivo (6 to 22% conversion). There were no important effects of saruplase on overall blood coagulation (activated partial thromboplastin time) and platelet function (collagen induced platelet aggregation, urinary [2,3-dinor]-thromboxane B2 excretion and plasminogen activator inhibitor 1 [PAI-1] release from platelets). Saruplase is cleared rapidly from the plasma and a variable amount is converted to tcu-PA. This two-chain form of u-PA probably causes the dose-dependent systemic fibrinolytic activation.

Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia: a report of 135 procedures.

BACKGROUND: Paroxysmal Supraventricular Tachycardia (PSVT) is a common condition which until recently has been treated with anti-arrhythmic drugs or surgery. Radiofrequency (RF) catheter ablation is a new mode of treatment which provides a cure of this condition. AIMS: To present our early experience of RF catheter ablation for PSVT. METHODS: One hundred and thirty-five procedures were performed in 117 patients. The diagnostic study and therapeutic catheter ablation were performed as a combined electrophysiological procedure in 74 patients (63%). In 58 patients (50%), PSVT was due to Atrio-ventricular junctional (nodal) re-entrant tachycardia (AVJRT). Twenty-five of the 58 patients underwent a fast pathway ablation while 33 had ablation of their slow pathway. The mean number of radiofrequency pulses delivered was ten for a mean duration of 25 seconds. Radiofrequency ablation of accessory pathways was attempted in 58 patients; pathways were left-sided in 29 patients, postero-septal in 21, midseptal in five, Mahaim connection in two, antero-septal in one and right free wall in one patient. One patient with incessant automatic atrial tachycardia also underwent a successful RF ablation. RESULTS: Using RF ablation cure of PSVT was achieved in 90% of patients. Cure of AVJRT was achieved in 95% (55/58) of patients using either fast or slow pathway ablation. Only one patient required permanent pacemaker implantation for Mobitz type I AV block following fast pathway ablation. The overall success rate for ablation of accessory pathways was 85%. There is an operator learning curve for this procedure suggested by the fact that the success rate for accessory pathway ablation at first attempt was 63% in the first 29 patients and 93% in the remaining 29. There was no significant morbidity or mortality during or after the procedure. In a mean follow-up of nine months in the patients with successful ablation only two patients with AVJRT had a recurrence of documented PSVT. Both these patients had successful repeat RF ablation. Catheter ablation using radiofrequency energy is an effective and safe therapeutic option for patients with symptomatic PSVT.

Choice of method for identifying germplasm with superior alleles : 1. Theoretical results.

Elite, adapted germplasm is not likely to contain all the favorable alleles available in a species. Three statistics were evaluated for screening populations for their ability to contribute favorable dominant alleles not available in an elite single cross: (1) a statistic proposed by Dudley (SD)=[(P x I1-I1)(I1 x I2-I2)-(P x I2-I2) (I1 x I2-I1)]/[2(I1-I2)]; (2) the upper bound minimum (P x I1-I1, P x I2-I2) ; and (3) the testcross to the single cross [TC(SC)]=P x (I1 x I2), where P is the population to be evaluated and I1 and I2 are homozygous parents of the elite single cross I1×I2. A superiority measure for a population was defined as the product of frequencies of favorable alleles and effects summed over loci where I1×I2 is homozygous unfavorable. Of the statistics considered, TC (SC) should have the highest genetic correlation with the superiority measure under the assumptions made, require the fewest testing resources and have the smallest standard error. Methods considered for screening inbreds were: (1) SDI proposed by Dudley=[(I1 x IW)+(I2 x IW)-I1-I2-IW-(I1 x I2)]/4 ; (2) TC(SC)=IW x (I1 xI2); and (3) UBND=minimum where Iw is the inbred to be evaluated. The superiority measure of an inbred Iw was defined as the relative number of loci where I1 and I2 are unfavorable and Iw is favorable. The genetic correlation with the superiority measure should be highest for SDI. The larger number of measurements used in calculation, the necessity of evaluating potentially unadapted inbreds and larger testing resources required for SDI suggest further research should be done to evaluate these statistics.

Choice of method for identifying germplasm with superior alleles : 2. Computer simulation results.

An accurate and efficient method of screening the many germplasm sources available for their ability to improve elite, adapted germplasm is needed. The superiority measure (SX) of a population (P) was defined as the product of the frequency and relative superiority of the alleles in P that are more favorable than the best in an elite, adapted reference single cross I1×I2. A computer simulation was done to determine the correlations between various screening methods and the SX. The genetic model used included multiple alleles, no linkage, two types of non-epistatic gene action (additive and complete dominance) and two types of epistatic gene action (complementary and duplicate). Genetic variances in the populations and a statistic proposed by Dudley (SD={[P x I1-I1] [I1 xI2-I2]- [P x I2-I2]-[P x I2-I2] [I1 x I2-I1]}/{2[I1-I2]{) were inconsistently correlated with the SX over all types of gene action on the basis of rank correlations. The testcross to the single cross (TC[SC]=P x [I1 x I2]) and the upper bound on the SX (UBND=minimum [P x I1-I1, P x I2-I2]) were both consistently highly genetically correlated with the SX. In the set of populations simulated, there were positive correlations between products of allelic frequencies and effects at different classes of loci. The UBND usually had a higher rank correlation coefficient with the SX than did the TC(SC). The differences between their correlation coefficients were often insignificant. Although the TC(SC) gives no indication as to which inbred the population is more closely related, its ease of use and expected lowers standard error compared with the UBND indicate that it would be an appropriate choice of screening method for identifying superior populations in the sense defined.

Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility.

In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.

Nifedipine: kinetics and dynamics after single oral doses.

Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

Assessment of cardiac risk 10 days after uncomplicated myocardial infarction.

A total of 188 patients with uncomplicated acute myocardial infarction (long-term Norris prognostic index 3.2) were rapidly mobilised, underwent a symptom-limited exercise test around the day of discharge from hospital (day 10), and returned to work at a median of six weeks after the acute event. The incidence of cardiac death six months, one year, and three years after infarction was 2.7%, 4.5%, and 7.3% respectively, and the corresponding figures for recurrent heart attacks were 3.4%, 8.2%, and 18.5% respectively. The risk of recurrence of heart attack was predicted by three variables assessed at discharge--namely, a history of classical effort angina (p less than 0.01), radiological heart failure (p less than 0.05), and angina induced by the exercise test (p less than 0.05). The presence of any of these risk factors defined a group of patients with a sevenfold risk of recurrent heart attacks within six months of the initial acute infarct. It is concluded that these risk factors identify a group of patients with a high risk of recurrence early after infarction, in whom vigorous secondary prophylaxis is desirable.

[Therapy of a refractory idiopathic thrombocytopenic purpura by vinblastine-loaded thrombocytes (author's transl)]. / Therapie einer refraktären idiopathisch-thrombozytopenischen Purpura mit Vinblastin-beladenen Thrombozyten.

A 15-year-old patient with ITP which was refractory to corticosteroids, splenectomy, and immunosuppressive therapy with vincristine was twice treated with platelets loaded with vinblastine. Five days after the application of the platelets vinblastine complex the platelets began to rise up to 600 X 10(9)/l. The remission has lasted until now for more than 15 weeks. The therapy showed no major side effects except for a transient granulocytopenia.