Influence of single-stranded DNA-binding protein on recA induction in Escherichia coli.

Two ssb mutants of Escherichia coli, which carry a lesion in the single-strand DNA-binding protein (SSB), are sensitive to UV-irradiation. We have investigated the influence of SSB on the "SOS" repair pathway by examining the levels of recA protein synthesis. These strains fail to induce normal levels of recA protein after treatment with nalidixic acid or ultraviolet light. The level of recA protein synthesis in wild-type cells is about three times greater than ssb cells. This deficiency in ssb mutants occurs in all strains and at all temperatures tested (30-41.5 degrees). In contrast, the ssb-1 mutation has no effect on temperature-induced recA induction in a recA441 (tif-1) strain. Cells carrying ssb+ plasmids and overproducing normal DNA-binding protein surprisingly are moderately UV-sensitive and have reduced levels of recA protein synthesis. Together these results establish that single-strand DNA-binding protein is involved in the induction of recA, and accounts, at least in part, for the UV sensitivity of ssb mutants. Three possible mechanisms to explain the role of SSB are discussed.

Drug release in vitro--an aid in clinical trials?

The topic of this article is biopharmacy. Using delayed release tablets with the active ingredient theophylline as a practical example, it was demonstrated that prior to clinical trials, galenical preparations can be characterized according to drug release in vitro and, that profiles of in vitro drug release can be compared with each other (LEVY-plot). Drug release from the retard tablets was examined following the Cube Root Law which describes the dependency of release rate on surface and agitation. Comparing profiles of in vitro release to a hypothetical or even known profile of in vivo release, produce results that are open to interpretation (LEVY-plot). A postulated correlation between the nonanalogous parameters, relative bioavailability and the mean in vitro dissolution time was confirmed. Due to established in vitro/in vivo correlations, we can in our case, predict the hypothetical in vivo release profiles for tablets showing more or less retarded release profiles in vitro and the relative bioavailability can be estimated. In addition, prediction of blood level is possible. In vitro/in vivo correlations can also provide information about residence times of the delayed release tablets in components of the gastrointestinal tract (stomach, small bowel and large bowel). Thus, using these methods, delayed release tablets (with the active ingredient theophylline) can be optimized for their use in clinical trials.

Practical application of the concept of mean times in biopharmaceutics.

The "concept of mean times" (1) in combination with the "method of moments" (3, 4) provides a practical basis for handling biopharmaceutical problems. This holds for in vitro, in vitro/in vivo and in vivo situations. Using several examples, it was demonstrated that questions concerning the comparability of in vitro dissolution models and their in vivo relevance can be answered, and that the rate of bioavailability can be evaluated exactly.

In vitro--in vivo correlation of dissolution, a time scaling problem? Transformation of in vitro results to the in vivo situation, using theophylline as a practical example.

Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.

Surgical clipping of difficult intracranial aneurysms using deep hypothermia and total circulatory arrest.

Intracranial aneurysms often present a challenging problem for the neurosurgeon. A variety of techniques have been developed to deal with these lesions. Several subspecialists are frequently involved in such treatment. We present our experience in a community hospital using a previously described technique of hypothermic cardiac arrest and barbiturate cerebral protection.

Pharmacokinetics of an extended-release dosage form of molsidomine in patients with coronary heart disease.

Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3-5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.

[Release, absorption and elimination of theophylline from fast and slowly released oral formulations]. / Untersuchungen zur Liberation, Absorption und Elimination von Theophyllin bei rasch und verzögert freisetzenden oralen Arzneiformen.

Each 2 tablets of four tablet formulations with 150 mg theophylline were administered to 6 and 5 volunteers, respectively, as single oral dose. 8 volunteers received 256 mg theophylline as a solution and as a sustained released formulation, as well as 176 mg theophylline as short intravenous bolus infusion. The elimination was independent of the examined formulations, but differences occurred between the experiments with the different groups of volunteers. The invasion parameters (t1/2i) of the four fast released tablet formulations corresponded to the values (t1/2a) of the oral theophylline solution. Furthermore, no difference existed concerning the mean times (Tsys). The mean time (theophylline) for the body model, Tvss, is 9.9 h; the mean time, which is attributed to the absorption process (Tabs) is 0.7 h; the mean in vivo dissolution time (Tdiss-vivo) for the sustained release formulation is 6.3 h. The mean time after oral administration of the theophylline solution (Tbiol) is 10.6 h. General conditions for a comparison between the in vitro and the in vivo release data are reported.