Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: A phase I–II,open-label trial

Background: Fampridine (4-aminopyridine) is a potassium channel-blocking agent that has been reported to have therapeutic potential for improving walking and mobility in patients with multiple sclerosis (MS). A sustained-release (SR) formulation of fampridine was developed to improve the agent's pharmacokinetic profile by extending its t_½ relative to that of immediaterelease fampridine.Objectives: The primary study objective was to examine the pharmacokinetics of fampridine SR tablets after single escalating doses in patients with MS. Tolerability was evaluated as a secondary end point.Methods: This multicenter, Phase I–II, open-label trial evaluated the dose proportionality and tolerability of 4 single doses of fampridine SR (5, 10, 15, and 20 mg) in patients with MS. There was a 4-day washout between doses. Blood samples were collected immediately before drug administration, hourly for the first 8 hours after administration, and at 10, 12, 14, 18, and 24 hours after administration. The pharmacokinetic parameters evaluated included C_max, T_max, AUC, elimination rate constant, apparent elimination t_½, and apparent CL/F. Twelve-lead ECGs were obtained at baseline (0.5 hour before dosing) and at 1, 4, 12, and 24 hours after drug administration to evaluate potential effects on the QTc interval. All adverse events, abnormal laboratory values, and ECG abnormalities were recorded and evaluated for clinical relevance. Adverse-event data were monitored for 24 hours after the last dose, and patients were instructed to report any adverse events for 14 days after the conclusion of the study.Results: Twenty-four white patients were enrolled (58% female; mean [SD] age, 45.4 [7.3] years; weight range, 47.8–87.1 kg), and 23 completed the study. Mean plasma concentrations and AUC values were dose proportional. T_max occurred at 3.36 to 3.92 hours after dosing; the apparent elimination t_½ was 5.47 hours. Both sex and weight affected the pharmacokinetic parameters of fampridine SR. Eleven treamentrelated adverse events were reported in 10 patients, with dizziness being the most common (7 incidents reported by 6 patients [1 at 10 mg, 3 at 15 mg, and 3 at 20 mg]). Other adverse events included amblyopia, asthenia, headache, and ataxia. All treatmentrelated adverse events were mild to moderate in severity, with the exception of 1 case of dizziness (20 mg) that was considered severe. No serious adverse events were reported, and no clinically significant changes in corrected QT intervals were observed. No patients with-drew due to treatment-related adverse events.Conclusion: In these patients with MS, fampridine SR (5–20 mg) had a potentially advantageous pharmacokinetic profile relative to that associated with immediate-release fampridine and was generally well tolerated.     

Fibreoptic tracheal intubation after placement of the laryngeal tube

Background. The laryngeal tube is a new alternative for securingthe airway. After adequate oxygenation, insertion of a trachealtube is still required in many situations. In such circumstances,fibreoptic placement of a tube exchange catheter after placementof the laryngeal tube is possible before tracheal intubation.Throughout the procedure, oxygen administration can continuevia the laryngeal tube, the tube exchange catheter and the trachealtube. Methods. The feasibility of this technique was tested in 10patients scheduled for elective surgery. Results. The laryngeal tube was placed at the first attemptwith adequate ventilation in all patients. The tube exchangemanoeuvre was performed successfully in all but one patient. Conclusion. This technique is an important alternative for airwaymanagement and provides a significant degree of patient safety. Br J Anaesth 2002; 89: 733–8     

Fulminant radiation-induced necrosis after stereotactic radiation therapy to the posterior fossa. Case report and review of the literature

The problem of radiation-induced necrosis of normal brain surrounding the target area has been a major catalyst for the development of stereotactically focused radiation therapy. According to current opinion, the effects of stereotactic irradiation are confined to the region targeted. The authors present a case in which the administration of a conventional dose of stereotactically focused irradiation for treatment of a pilocytic astrocytoma produced fulminant necrosis that necessitated a combination of intensive surgical and medical management, after which the patient improved over the course of 1 year. Concomitant with his improvement, the initially remarkable findings on magnetic resonance imaging gradually resolved. In this presentation the authors emphasize the need to evaluate alternatives carefully before a decision is made to administer therapeutic irradiation. Furthermore, they explore the roles that target, host, and dosage factors play in hypersensitivity to radiation injury, the detection of these factors before treatment, and the administration of radioprotective agents. With the growing use of stereotactically focused irradiation as a primary treatment modality for a variety of neurosurgical conditions, it is important to be cognizant of its uncommon but potentially lethal side effects. A cooperative multicenter database in which the outcomes and morbidity following stereotactic irradiation are recorded is essential to the detection of relatively uncommon but severe complications such as those observed in this case.     

Zur Hemmwirkung von Herzglykosiden auf die86Rb-Aufnahme der Erythrocyten

Zusammenfassung Für serienmäßige Aktivitäts- und Konzentrationsbestimmungen von Herzglykosiden eignet sich die Messung der Hemmung der⁸⁶Rb-Aufnahme in Erythrocyten. Die Einflüsse verschiedener Parameter auf die glykosidbedingte⁸⁶Rb-Aufnahmehemmung der Erythrocyten wurden untersucht. Eine optimierte Methode wird beschrieben. Die Bestimmungsmethode hat gegenüber den übrigen Verfahren den Vorteil relativ geringen Zeitbedarfs, einfacher Handhabung und größter Empfindlichkeit. Die erzielten Ergebnisse waren gut reproduzierbar.

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The inhibitory effect of cardiac glycosides on⁸⁶Rb-up-take of erythrocytes. I. Investigations on the determination of cymarin (k-strophantin-) and digitoxin

Summary The measurement of inhibition of⁸⁶Rb uptake in human erythrocytes is a suitable method for determination of activities and concentrations of cardiac glycosides in series. The influences of various parameters upon this glycoside induced inhibitory effect were studied. In comparison with other methods the described one has the advantages of consuming less time, and to be very sensitive and easy to handle.