Quality management system and accreditation of the in vivo monitoring laboratory at Karslruhe Institute of Technology.

The in vivo monitoring laboratory (IVM) at Karlsruhe Institute of Technology (KIT), with one whole body counter and three partial-body counters, is an approved lab for individual monitoring according to German regulation. These approved labs are required to prove their competencies by accreditation to ISO/IEC 17025:2005. In 2007 a quality management system (QMS), which was successfully audited and granted accreditation, was set up at the IVM. The system is based on the ISO 9001 certified QMS of the central safety department of the Research Centre Karlsruhe the IVM belonged to at that time. The system itself was set up to be flexible and could be adapted to the recent organisational changes (e.g. founding of KIT and an institute for radiation research) with only minor effort.

1H-nuclear magnetic resonance (NMR) studies on the inclusion complex of prostaglandin E1 (PGE1) with alpha-cyclodextrin.

Prostaglandin E1 is currently marketed as a freeze-dried injectable inclusion complex with alpha-cyclodextrin for the treatment of peripheral arterial diseases. alpha-Cyclodextrin is used as a stabilizing agent and to improve the dissolution characteristics of prostaglandin E1. Upon dilution with the infusion medium, the inclusion complex dissociates almost completely as shown by NMR chemical shift measurements of the complexed and uncomplexed prostaglandin E1. Nuclear Overhauser effect (NOE) measurements of the interacting atoms of alpha-cyclodextrin and prostaglandin E1 provide insight into the structure of the complex.

[Development of tolerance in continuous nitroglycerin infusion]. / Toleranzentwicklung unter kontinuierlicher Nitroglycerin-Infusion.

For treatment of unstable angina pectoris or recent myocardial infarction, intravenous NTG is frequently employed, beginning with doses of 3 mg/h or more; thereafter, dependent on the clinical course, in particular, if the blood pressure is lowered notably, the dose may be reduced to 1 or 2 mg/h. Reports published in recent years have documented to the development of tolerance to nitrates when given orally in higher doses three times daily or administered by the transdermal mode. Accordingly, we suspected that tolerance development would be the inevitable outcome during a continuous intravenous infusion of NTG. Consequently, this placebo-controlled study was undertaken to determine whether tolerance develops during a continuous 28-hour infusion of NTG and whether tolerance is reversible on interruption of the treatment with a twelve-hour infusion-free interval. The studies were performed in ten male patients ranging in age from 49 to 65 years, mean age 53 years. All patients had recovered from myocardial infarction (mean interval since infarction 42 days) and had reproducible, asymptomatic ST-segment depression of at least 0.2 mV during exercise testing after discontinuation of all antiischemic drugs with a washout period of three days. Exercise testing was performed at four hours after beginning the infusion of 1.5 mg/h NTG or placebo (2 p.m.), at 28 hours after beginning the infusion (2 p.m. on the second day) and, after having discontinued the infusion for a twelve-hour period (from 10 p.m. to 10 a.m.), at four hours after having re-started the infusion (2 p.m. on the third day).(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the gastrointestinal transit and in vivo drug release of isosorbide-5-nitrate pellets.

An oral formulation of controlled-release isosorbide-5-nitrate pellets has been used to investigate the location of pellets in the gastrointestinal (GI) tract and, in parallel, to measure the drug absorption from these locations. Using the method of gamma scintigraphy the transit times and spreading of pellets in the GI tract have been determined. The method of numeric deconvolution was applied to calculate the drug input into the systemic circulation. The results indicate that a well-absorbed substance such as isosorbide-5-nitrate is absorbed from the stomach and small intestinal in a manner that is controlled by the properties of the pellets. Drug absorption is reduced in the colon. The average transit time from mouth to colon is 6 to 8 hr, which represents the maximum acceptable time for drug release for this oral controlled-release preparation. Taking into account these relations an isosorbide-5-nitrate pellet formulation with a bioavailability of 84% has been developed that maintained the minimal therapeutic plasma level for more than 16 hr after application.

In vitro and in vivo-release of nitroglycerin from a new transdermal therapeutic system.

A new transdermal therapeutic system (TTS) for nitroglycerin is presented that controls release of the active substance by means of desorption and diffusion. The drug release, in the dosage range examined under sink conditions, is independent of electrolytes and pH of the aqueous acceptor medium, but it does depend on its temperature as expected. Batches obtained on a production scale were highly reproducible. The validity of an "in vitro" dissolution model is demonstrated by the good correlation between the amount of nitroglycerin liberated "in vitro" and "in vivo". The amount of nitroglycerin released in vivo is approximately 10 µg/cm(2)/h from 4 hours after application, and, it is controlled by the system.

Isosorbide-5-nitrate sustained-release pellets - an example of computer-supported drug development.

To achieve a fast onset and a sufficiently long duration of action in the long-term treatment of angina pectoris a composite dosage form was developed, consisting of a fast-release initial dose Di and a slow-release maintenance dose Dm. The product is designed to be given once daily in the morning to achieve sufficiently high blood levels for clinical response during day-time with declining blood levels during night-time to avoid tolerance. In view of its pharmacokinetic properties, the antianginal drug isosorbide-5-nitrate (IS-5-N) was selected as the model substance. To minimize the influence of physiological factors such as GI-transit time and pH on the in vivo releasing properties, pellets with a membrane-controlled drug release appeared to be suitable. To investigate the in vitro/in vivo correlations, three variants of of this dosage form, differing in the Di:Dm ratio and in the duration of the drug release, were prepared. The pharmacokinetics of these variants were tested in man, and their in vitro dissolution behaviour was characterized by their mean dissolution times (TDiss). The in vivo performance was characterized by the mean residence time (MRT), the bioavailability (ba) relative to standard tablets, and the in vivo absorption rate by the method of Wagner and Nelson. The linear correlation coefficients were: ba vs. MRT, r = - 0.845, p < 0.01; MRT vs. TDiss, r = 0.949, p < 0.001, and ba vs. TDiss, r = - 0.886, p < 0.05. With the known pharmakokinetic and dissolution parameters, a prediction of the time course of the plasma level was attempted.