Drug dosage in patients with renal failure optimized by immediate concurrent feedback.

OBJECTIVE: To examine the impact of immediate concurrent feedback on dose adjustment in patients with renal failure. DESIGN: Prospective 12-month study in patients with various degrees of renal failure, with comparison to a retrospective control group. SETTING: A 39-bed unit of a university hospital providing primary and tertiary care. PATIENTS: Patients with renal failure (estimated creatinine clearance < or = 50 mL/min) receiving at least 1 pharmacologically active drug. INTERVENTIONS: Education of physicians and immediate concurrent feedback on the ward giving estimated creatinine clearance and dose recommendations for renally eliminated drugs adjusted to individual renal function. MEASUREMENTS AND MAIN RESULTS: The percentage of dosage regimens adjusted to renal function and cost assessment of drug therapy were calculated. Overall, 17% of the patients had at least 1 estimated creatinine clearance < or = 50 mL/min. In the intervention group, the dose of 81% of renally eliminated drugs was adjusted to renal function, compared with 33% in the control group ( P <.001). The mean difference in cost between standard and adjusted dose of renally eliminated drugs in the intervention and control groups was 5.3 +/- 12.3 and 0.75 +/- 2.8 Swiss francs (approximately US$3.5 and US$0.5), respectively ( P <.001), accounting for 16.5% and 2.8%, respectively, of daily medication costs of all drugs. CONCLUSIONS: The proportion of doses of renally eliminated drugs adjusted to renal function can be substantially increased by immediate concurrent feedback. This saves drug costs and has the potential to prevent adverse drug reactions.

[Individualization of drug therapy in renal or liver insufficiency]. / Individualisierung der Arzneimitteltherapie bei Nieren- und Leberinsuffizienz.

Individualisation of drug dosage in patients with renal or hepatic failure may prevent excessive drug accumulation and thus potentially reduce adverse drug reactions and costs. In renal failure, renal function may be estimated by combined evaluation of serum creatinine values and patient characteristics. Then individual elimination capacity of a given drug in the individual patient may be calculated and dosage accordingly adjusted. In severe liver cirrhosis, after peroral administration of drugs with a high extraction ratio each single dose has to be reduced because of increased bioavailability and decreased clearance. After i.v. administration and dosing of drugs with a low extraction ratio maintenance dose should be reduced either by prolonging the dosing interval or by decreasing each single dose.

[Clinically relevant adverse drug interactions]. / Unerwünschte, klinisch relevante Arzneimittelinteraktionen.

Drug interactions may lead to adverse drug effects or therapeutic failure. Many clinically relevant unwanted interactions are caused by a change in the activity of cytochrome P450 isoenzymes or the activity of active drug transport systems (e.g. p-glycoprotein). Most drug interactions may be anticipated and prevented by dose modification or using alternative drugs.

[Anticonvulsant hypersensitivity syndrome. 2 case reports and an overview]. / Antikonvulsiva Hypersensitivitäts-Syndrom. Zwei Fallbeschreibungen und eine Ubersicht.

Anticonvulsants with aromatic ring structure such as phenytoine, carbamazepine, phenobarbital and lamotrigine can induce a drug hypersensitivity syndrome ("anticonvulsant hypersensitivity syndrome", AHS). Though the incidence of AHS is low, correct and early diagnosis are crucial to stop further progression by immediately withholding the causative drug. AHS usually starts within the first 2-8 weeks after initiation of therapy with fever, followed over the next 1-2 days by a cutaneous reaction and lymphadenopathy. The skin reaction is usually exanthematous but can also manifest itself as Stevens-Johnson or Lyell syndrome. AHS is commonly associated with symptomatic or asymptomatic internal organ involvement usually affecting the liver, although haematologic, renal or pulmonary impairment may also occur. We report two cases illustrating the clinical course and discuss theories about the potential pathogenesis and the treatment of AHS.

Solubilization and characterization of GABAB receptor binding sites from porcine brain synaptic membranes.

1. The characteristics of membrane bound GABAB receptors in pig brain are similar to those in rat brain as judged by in vitro binding experiments and sensitivity to GTP. The rank order of affinity of GABAB receptor ligands was CGP 54626 > GABA approximately (-)-baclofen >> CGP 35348 = CGP 36742 > (+)-baclofen in membranes from both species. 2. For solubilization of GABAB receptors from pig brain, washed membranes were preincubated with 5 mM MgSO4 and subsequently incubated with various detergents. 3-[(3-Cholamidopropyl)dimethyl-ammoniol]-1-propane sulphonate (CHAPS) (0.5%) proved to be the most successful, solubilizing 22.7 +/- 4.7% (mean +/- s.e. mean, n = 6) of GABAB receptors. 3. Binding of [3H]-GABA to GABAB receptors solubilized with 0.5% CHAPS exhibited similar characteristics to the binding at membrane bound receptors since, firstly, the Kd and Bmax values (around 30 nM and 450 fmol mg-1 protein, respectively) were comparable; secondly, stereospecific binding for baclofen was obtained in both forms; thirdly, the affinity for the agonists GABA and (-)-baclofen and the antagonists CGP 35348, CGP 36742 and CGP 54626 were the same; fourthly, comparable sensitivity to Ca2+ (2.5 mM) was observed and finally, a similar sensitivity to GTP was apparent. 4. Saturation experiments performed with the GABAB antagonist, [3H]-CGP 54626, indicated a higher Kd value and a lower Bmax value for solubilized (7.7 +/- 2.6 nM and 1033 +/- 41 fmol mg-1 protein, mean +/- s.e. mean, n = 3) than for membrane bound receptors (1.35 +/- 0.08 nM, 1171 +/- 20 fmol mg-1 protein, n = 3).

Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies.

Agonists at the benzodiazepine receptor (BZR) produce their effects through potentiation of the inhibitory alpha-aminobutyric acid-mediated neurotransmission in the central nervous system via positive allosteric modulation of the gamma-aminobutyric acidA receptor. Agonists with high intrinsic efficacy are anticonvulsant, anxiolytic, muscle relaxant and sedative, whereas agonists with low intrinsic efficacy (partial agonists) are predominantly anticonvulsant and anxiolytic, but antagonize muscle relaxant and sedative effects of full agonists. The four BZR ligands triazolam, diazepam, Ro 19-8022 (a benzoquinolizinone) and bretazenil (Ro 16-6028, an imidazobenzodiazepinone) were pharmacologically characterized in various neurological and behavioral paradigms in mice: two anticonvulsant tests (prevention of audiogenic and pentylenetetrazol-induced seizures), a conflict test which reveals both anxiolytic and sedative properties and two tests which mainly measure motor impairment (rotarod and horizontal wire test). Although triazolam and diazepam elicited an effect in all tests, Ro 19-8022 and bretazenil exhibited anticonvulsant and anxiolytic properties, but virtually failed to induce motor impairment and severe sedation. In separate experiments, fractional BZR occupancy in vivo was assessed by inhibition of [3H]flumazenil binding and correlated with the pharmacological effects. Although diazepam and triazolam produced effects beginning at low to intermediate fractional BZR occupancy, Ro 19-8022 and bretazenil required a higher BZR occupancy to do so, in accordance with their partial agonistic character. With the two full agonists, anticonvulsant and anticonflict activities were elicited at a lower fractional BZR occupancy than muscle relaxant and sedative effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between benzodiazepine receptor occupancy and potentiation of gamma-aminobutyric acid-stimulated chloride flux in vitro of four ligands of differing intrinsic efficacies.

Intrinsic efficacy is the inherent ability of a ligand to induce the conformational change of its receptor that is required to transduce the event of signal recognition into a physiologically relevant response. Relating fractional receptor occupancy to fractional effect is an indirect but reliable way to assess relative intrinsic efficacy. The receptor studied was the benzodiazepine receptor (BZR), a modulatory site on the gamma-aminobutyric acidA (GABAA) receptor-chloride channel. The relationship between fractional BZR occupancy, as assessed by inhibition of [3H]flumazenil binding, and potentiation of GABA-stimulated 36Cl- influx into membrane vesicles of rat cerebral cortex was evaluated for four ligands under identical experimental conditions. Triazolam and the quinolizinone Ro 19-8022 potentiated the effect of GABA maximally by nearly 50%, diazepam by about 40% and bretazenil by approximately 20%. Potentiation of GABA-stimulated 36Cl- flux by 25% was observed at about 35% BZR occupancy for diazepam, about 45% for triazolam and about 95% for Ro 19-8022. Bretazenil did not produce 25% potentiation even at receptor saturation. Although the curves relating fractional BZR occupancy to GABA potentiation were hyperbolic and nearly superimposable for triazolam and diazepam, those for Ro 19-8022 and bretazenil displayed parabolic characteristics by inducing an effect only at very high BZR occupancy, reflecting the partial agonistic profile of the latter two compounds. The rank order of relative intrinsic efficacy determined in this study was: triazolam congruent to diazepam much greater than Ro 19-8022 greater than bretazenil.

Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders.

The classic benzodiazepines produce anxiolytic, anticonvulsant, sedative and myorelaxant effects at overlapping dose ranges. Efforts to reduce the sedative/myorelaxant component of this profile has a long history. Two rational approaches might theoretically lead to the desired drugs. One is based on the combination of partial (low efficacy) agonists of the benzodiazepine receptor with different receptor reserves in neurons subversing various functions. The other approach is based on the existence of GABAA-benzodiazepine receptor polymorphism and assumes that distinct receptor variants may be more prevalent on neurons involved in various CNS functions. Results are presented that were obtained with the partial agonist bretazenil and three other ligands in vitro as well as in vivo. Curves relating fractional receptor occupancy and various effects (potentiation of GABA-induced chloride flux, anticonvulsant, anticonflict and sedative effects) are fully consistent with the view that the particular profile of activity of bretazenil is the result of partial agonism. Comparison of fractional receptor occupancy required for the various effects of both full and partial agonists confirm earlier suggestions that receptor reserves for the individual effects differ with the same order. Clinical aspects of partial benzodiazepine receptor agonists are discussed on the basis of the preliminary information available to date.