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Three novel single-chain bis(phosphocholines) bearing two lateral alkyl chains of variable length next to the headgroup have been synthesized as model lipids for naturally occurring archaeal membrane lipids. The synthesis was realized using the Cu-catalyzed Grignard bis-coupling reaction of a primary bromide as a side part and a 1,ω-dibromide as a centre part. We could show that the aggregation behaviour of the resulting bolalipids strongly depends on the length of the lateral alkyl chain: the C3-branched bolalipid self-assembles into lamellar sheets, whereas the C6- and C9-analogues form nanofibres. The lamella-forming bolalipids could be used in the future to prepare stable and tailored liposomes for oral drug delivery.

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The expression and function of the drug transporter P-glycoprotein are highly variable. Environmental and genetic factors contribute to this variation. We studied the disposition of digoxin, a frequently used probe drug for P-glycoprotein function in humans, in monozygotic (MZ) twins and found that digoxin pharmacokinetics after oral and intravenous administration are highly correlated within MZ twins, supporting the hypothesis of a robust contribution from genetic variance. Our study suggests that studies involving twins could be more widely applied to elucidate pharmacogenetics.

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We studied the efficacy of propafenone in preventing atrial tachyarrhythmias after cardiac surgery, and the possible relationships between CYP2D6 polymorphism and the efficacy, pharmacokinetics, and tolerability of propafenone. One hundred and sixty patients were randomized (double blind) to receive propafenone (n= 78) or placebo (n= 82) for 1 week after cardiac surgery. The patients who were assigned to the propafenone group received 1 mg/kg infused in 1 h, followed by a continuous infusion at a rate of 4 mg/kg/24 h until the following morning, and subsequently 450 mg/day orally until the sixth postoperative day. Thirty-seven patients completed the trial in the propafenone group and 45 in the placebo group. The frequency of occurrence of atrial tachyarrhythmia was lower in the propafenone group than in the placebo group (29.7% vs. 53.3%, P< 0.05; relative risk, 0.56). Plasma propafenone concentrations were markedly influenced by CYP2D6 genotype-derived phenotype.

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AIMS: To investigate the potential induction by rifampicin of intestinal CYP2C8, CYP2C9, CYP2D6 and CYP3A4 using preparations of human enterocytes. METHODS: Using a multilumen perfusion catheter shed human enterocytes were collected from 6 healthy subjects before and after 10 days of 600 mg day(-1) oral rifampicin administration. The protein expression of CYP2C8, CYP2C9, CYP2D6 and CYP3A4 as well as that of CYP3A4 mRNA was determined using Western blotting and RT-PCR, respectively. RESULTS: CYP3A4 mRNA expression in shed enterocytes increased from 74.6 +/- 44.2 to 143.2 +/- 68.4 a.u. (P < 0.05, 95% CI: 21.8-115.3). Expression of CYP2C8 and CYP2C9 increased from 5.1 +/- 0.9 to 10.4 +/- 2.3 pmol mg(-1) protein (P < 0.01, 95% CI: 2.8-7.7) and from 4.2 +/- 1.4 to 5.7 +/- 1.1 pmol mg(-1) protein (P < 0.01, 95% CI: 0.6-2.4), respectively. No significant difference in CYP2D6 expression before and during rifampicin intake was observed. Rifampicin administration also resulted in a significant induction of CYP3A4 protein (34.1 +/- 10.7 vs. 113.9 +/- 31.1 pmol mg(-1) protein (P < 0.001, 95% CI: 51.8-107.6)). Ex vivo incubation of enterocyte homogenates with verapamil resulted in a significantly increased production of the metabolites formed via CYP3A4 (D-617: 125.9 +/- 118.8 vs. 277.2 +/- 145.5 pmol min(-1) mg(-1) protein (P < 0.05, 95% CI: 30.1-272.5); norverapamil: 113.0 +/- 57.9 vs. 398.4 +/- 148.2 pmol min(-1) mg(-1) protein (P < 0.05, 95% CI: 47.2-523.6)). CONCLUSION: Our findings indicate that shed enterocytes are a useful tool to study the expression, regulation and function of drug metabolizing enzymes. Induction of intestinal CYP2C8 and CYP2C9 might contribute in part to rifampicin - mediated drug interactions, in addition to their hepatic counterparts and intestinal and hepatic CYP3A4.

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P-glycoprotein (PGP) is a membrane protein which determines drug disposition in humans (e.g. digoxin). It is also expressed in various leukocyte lineages with highest expression in CD56+ natural killer cells. Recently, a polymorphism in exon 26 (C3435T) of this gene was shown to correlate with intestinal PGP expression and function in humans. Carriers homozygous for this polymorphism (TT) showed more than two-fold lower PGP expression and higher digoxin plasma concentrations compared to the CC group. However, it is not known whether this mutation in the MDR1 gene is also associated with altered PGP function in peripheral blood cells. We therefore assessed efflux of the PGP-substrate rhodamine 123 from CD56+ natural killer cells. Leukocytes were isolated from whole blood of 10 CC, 10 CT and 11 TT healthy Caucasian individuals. Using flow cytometry, rhodamine fluorescence was determined in CD56+ cells. Moreover, MDRI mRNA was quantified in leukocytes by real-time polymerase chain reaction. Subjects with CC genotype revealed a significantly lower rhodamine fluorescence (i.e. higher PGP function) compared to individuals with TT genotype (51.1 +/- 11.4% versus 67.5 +/- 9.5%, p < 0.01). Heterozygous individuals had an intermediate rhodamine fluorescence (61.4 +/- 6.3%). MDR1 mRNA normalized for cyclophilin was lowest in the TT population (1.29 +/- 1.01), intermediate in heterozygous subjects (1.60 +/- 0.76) and highest in the CC group (1.91 +/- 0.94; not significant). In summary, subjects being homozygous for C in position 3435 of the MDR1 gene have a more pronounced efflux of rhodamine from CD56+ natural killer cells and a higher MDR1 mRNA expression in leukocytes than subjects with the TT genotype. Measurement of rhodamine efflux using flow-cytometry from peripheral blood cells allows assessment of genetically determined differences in P-glycoprotein function.

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BACKGROUND: Racemic (R /S)- verapamil is widely used in the management of chronic atrial fibrillation. The negative dromotropic effect is mainly mediated by the S -enantiomer, which is preferentially metabolized. Previous studies report an accumulation of R /S- verapamil during long-term oral treatment of patients with chronic atrial fibrillation. However, the specific disposition of S -verapamil and the pharmacologic effects were not assessed. Therefore uncertainties about the need for dose adjustments remain. METHODS: Using stable isotope technology and a stereospecific assay, we compared the pharmacokinetics and pharmacodynamics of intravenous (10 mg of d(7)-R /S -verapamil) and oral (240 mg of slow release (SR) d(0)-R /S -verapamil) R -verapamil and S -verapamil after the first dose (day 1) and after 3 weeks (day 21) of continuous oral therapy in 8 patients with long-term atrial fibrillation. On both study days, serum samples were obtained for the analysis of d(7)- and d(0)-R -verapamil and S -verapamil. Heart rate (HR) was monitored with electrocardiography (with each blood sample) and Holter electrocardiography (before the study, on day 1, and on day 21). RESULTS: Compared with day 1, clearance of oral R -verapamil and S -verapamil was significantly reduced on day 21 (1007 +/- 380 versus 651 +/- 253 mL/min [-35%] and 5481 +/- 2731 versus 2855 +/- 1097 mL/min [-48%], respectively; P <.05), whereas only a moderate decrease was observed for intravenous R -verapamil and S -verapamil (-23% and -14%, respectively, not significant). Mean HR (89 +/- 11 bpm before verapamil) was effectively reduced, with the same effects on day 1 (68 +/- 8 bpm) and day 21 (68 +/- 8 bpm). Compared with day 1, the HR reduction per ng/mL of S -verapamil (calculated by the area under the curve [from 0-24 hours] ratio of HR reduction and S -verapamil concentration) was significantly lower on day 21 (0.7 +/- 0.4 versus 1.2 +/- 0.7 [bpm]. [ng/mL](-1), for day 21 versus day 1; P <.01). CONCLUSIONS: In patients with chronic atrial fibrillation, clearance of oral, but not intravenous, S -verapamil and R -verapamil is significantly reduced with multiple doses compared with a single dose, thereby indicating predominant impairment of prehepatic rather than hepatic metabolism as the underlying mechanism. However, this kinetic change is clinically compensated by a decrease in the responsiveness to S -verapamil observed with regular dosing. The data suggest that despite accumulation of the drug individual verapamil doses can be maintained during long-term oral rate control therapy.

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The antiarrhythmic properties of adenosine, its ultra-short half-life and the absence of frequent serious side effects make it a front-line agent in arrhythmia management, especially in the treatment of atrioventricular nodal reentrant tachycardia. Due to a shortening of atrial refractoriness, adenosine can facilitate the induction of atrial fibrillation. Life threatening tachycardias may result from a potential rapid conduction of atrial fibrillation over an accessory pathway especially if the latter one has a short antegrade refractory period. We report a case of a 59 year old female patient in which intravenous administration of adenosine during typical atrioventricular nodal reentrant tachycardia was followed by atrial fibrillation with rapid conduction over a hitherto unknown accessory pathway. After intravenous administration of adenosine the tachycardia was terminated successfully within 38 s. After a short period of asystole, spontaneous atrial fibrillation developed unmasking an antegrade preexcitation with subsequent rapid ventricular response (210 b/min). The three-lead ECG showed a narrow QRS complex tachycardia. Because of spontaneous conversion to sinus rhythm and the absence of hemodynamic compromise there was no need for external cardioversion. During electrophysiological study an antidromic atrioventricular reentrant tachycardia was recorded over a left posteroseptal accessory pathway including antegrade conduction properties only. Because of its ultrashort half-life, serious side effects after adenosine administration are rare. The possibility of life threatening proarrhythmias after intravenous adenosine administration should be taken into consideration if the etiology of a paroxysmal supraventricular tachycardia is not clear and a concomitant Wolff-Parkinson-White syndrome cannot be excluded. As with application of all intravenous antiarrhythmic agents, the administration of adenosine should only be performed if continuous ECG monitoring and cardioversion facilities are available and possible.

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Basing on the concept of rooming-in as the joint hospitalisation of mentally ill mothers and their children, which was developed in gynaecology and paediatrics, the differential indication, setting variables and therapeutic strategies relevant for inpatient psychotherapy were described. Therefore, 15 cases treated in the Department of Psychiatry of the Medical University Luebeck were reviewed. It will be demonstrated that a differentiated treatment approach with mothers with severe non-psychotic disorders can be realised. The advantages of the rooming-in approach seem to be on the one hand more adequate possibilities in the diagnosis and treatment of problems of mother-child interaction involving the nursing group, and on the other hand the rooming-in approach allows to identify connections between specific biographical events and actual conflicts related to birth and bringing up of the children.

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The negative feedback control of thyrotropin production by the anterior pituitary involves local 5'-deiodination of L-thyroxine (L-T4) to the active thyroid hormone 3,3',5-triiodo-L-thyronine (T3) by two 5'-deiodinase isozymes which are distinctly regulated by thyroid hormone. T3 rapidly increased steady-state mRNA levels and activity of type I iodothyronine-5'-deiodinase (5'DI) in rat anterior pituitary and in reaggregate cultures of anterior pituitaries. Type II 5'-deiodinase activity determined in parallel with 3,3',5-triiodo-L-thyronine (rT3) as substrate was markedly lower than that of 5'DI. 5'DI mRNA levels and activity were higher in anterior pituitaries of female compared to male rats. Neither gender differences nor T3 stimulation of 5'DI activity were found in the posterior part. These data demonstrate a T3 dependent expression of 5'DI in euthyroid anterior pituitary and suggest that this isozyme serves a major function within the complex network of thyroid hormone homeostasis.

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From March 1990 to January 1991 52 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study with the combination of interferon alfa-2b and fluorouracil (5-FU). 5-FU 750 mg/m2 per day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as IV push injection starting on day 15. Interferon alfa-2b (Intron A, ESSEX Pharma) 9 x 10(6) units was given subcutaneously three times per week. Response to therapy was evaluated after 3 and 6 months. So far, data on response rates and toxicity are available in 32 patients: partial remission, 10 patients (31%); stable disease, nine patients (28%); progressive disease, 12 patients (37%); toxic deaths, two patients (6%). Projected median survival has not been reached after 11 months. In about one third of the patients severe side effects occurred with leukopenia grade 3 and 4, diarrhea, mucositis and septic complications being the clinically most important. We think that this combination is an effective but toxic regimen in advanced colorectal carcinoma. Further studies must reevaluate both the schedule and the doses of the drugs administered.

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Between February 1990 and April 1991, 59 previously untreated patients with progressive and/or symptomatic metastatic colorectal carcinoma were enrolled in a phase II study of 5-fluorouracil (5-FU) and interferon alfa-2b (IFN-alpha). 5-FU 750 mg/m2/day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as intravenous push injection starting on day 15. IFN-alpha 9 MU was given subcutaneously three times a week. Treatment was given for a maximum of 6 months. 55 patients are evaluable for response and 51 for toxicity. 17 patients (31%) achieved a partial remission, 15 (27%) had stable disease and 21 patients (38%) had progressive disease. Median duration of remission was 5 months and median survival for all patients 10 months. Toxicity was important with two treatment-related deaths and severe leukopenia, fever, diarrhoea and mucositis in about one third of the patients. In our opinion, this regimen is effective but rather toxic in metastatic colorectal carcinoma.

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Vasoactive intestinal polypeptide (VIP) was incubated in an adenylate cyclase assay with a particulate fraction of caudate-putamen (CP) tissue of the rat in order to examine the effect of the peptide on forskolin-activated adenylate cyclase in vitro. Forskolin induced an enhancement of cyclic AMP formation that was mediated by an effect on catalytic subunit and stimulatory guanine nucleotide regulatory protein (Ns). In our preparation, VIP did not influence basal adenylate cyclase activity or the stimulation by dopamine and sodium fluoride but, in the absence of guanylylimidodiphosphate (guanosine 5'-(beta, y-imido)-triphosphate) VIP inhibited the forskolin-stimulation of the enzyme in a noncompetitive manner. Met-encephalin, acting on a D-2 receptor-coupled putative inhibitory guanine nucleotide regulatory protein (Ni), inhibited the adenylate cyclase activity stimulated by forskolin to a slightly greater extent than VIP. When assayed together, these inhibition effects were additive, implying that the peptide receptors are not identical. The Ni-antagonist, MnCl2 completely blocked the inhibition of met-encephalin but had no significant effect on VIP-induced inhibition. In addition, pertussis toxin did not influence the effect of VIP on forskolin-stimulation in contrast to cholera toxin which did antagonize the VIP effect via the stimulatory guanine nucleotide regulatory protein (Ns). Furthermore, specific D-1 and D-2 dopaminergic receptor antagonists alpha(+)-flupentixol and spiperone had no effect on VIP-modulated forskolin-stimulated adenylate cyclase activity. These results suggest that the neuromodulatory effect of VIP is mediated by a Ns distinct from those involved in several adenylate cyclase pools sensitive to stimulation by dopamine and VIP in the rat striatum.

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