Hiding solutions in random satisfiability problems: a statistical mechanics approach.

A major problem in evaluating stochastic local search algorithms for NP-complete problems is the need for a systematic generation of hard test instances having previously known properties of the optimal solutions. On the basis of statistical mechanics results, we propose random generators of hard and satisfiable instances for the 3-satisfiability problem. The design of the hardest problem instances is based on the existence of a first order ferromagnetic phase transition and the glassy nature of excited states. The analytical predictions are corroborated by numerical results obtained from complete as well as stochastic local algorithms.

Bioequivalence of allopurinol-containing tablet preparations.

AIM: The study was undertaken to prove the bioequivalence of two allopurinol tablet preparations. SUBJECTS, MATERIALS AND METHODS: The relative bioavailability of allopurinol from two tablet preparations (Uribenz vs. Zyloric 300) was estimated on 18 volunteers of both sexes in an open randomized study by administering one tablet of each preparation at an interval of 2 weeks. The plasma concentrations of allopurinol and its active metabolite oxypurinol were measured over a time-period of 72h by HPLC. RESULTS: While the mean AUC(0-72) values of allopurinol and oxypurinol after the test and reference preparations are entirely identical (5.33 vs. 5.21 and 137.95 vs. 137.96 microg h ml(-1), respectively), the C(max) values of oxypurinol unlike those of allopurinol show small differences (4.59 vs. 4.78 and 1.91 vs. 193 microg/ml, respectively). According to the parametric and non-parametric analysis, the quotients AUC(T)/AUC(R) and C(maxT)/C(maxR) lie within the confidence intervals 0.8 to 1.2 and 0.7 to 1.3 respectively With regard to the t(max) of allopurinol, the differences of test and reference preparations are between 0.10 to 0.05h and of oxypurinol between -0.10 to 0.87h (parametric analysis). Both, Uribenz 300 and Zyloric 300 caused a maximum decrease of the uric acid concentration in the volunteers by 18% after 10 and 24h, respectively. CONCLUSION: Thus the bioequivalence of the allopurinol tablet preparations is demonstrated.

Effects of a supersulfated low molecular weight heparin (IK-SSH) on different hemostatic parameters.

In a phase I trial effects of a new supersulfated low molecular weight heparin (IK-SSH) on different hemostatic parameters were investigated in healthy volunteers. Parameters studied were activated partial thromboplastin time (aPTT), thrombin time, Heptest, anti-activated factor II (anti-FIIa) and anti-activated factor X (anti-FXa) activity, platelet adhesion, platelet count, platelet-induced thrombin generation time (PITT), bleeding time, antithrombin III, fibrinogen and several safety parameters. After single intravenous (i.v.) injections of IK-SSH (0.14, 0.33 and 0.66 mg/kg) aPTT, Heptest and PITT were strongly and dose-dependently prolonged. After ascending subcutaneous (s.c.) doses of IK-SSH (0.33, 0.66 and 1 mg/kg) aPTT, Heptest and PITT were prolonged in a dose-dependent manner. Repeat s.c. injections of 1 mg/kg IK-SSH for 5 days markedly prolonged aPTT, Heptest and PITT. No cumulative effects were observed. Anti-FIIa and anti-FXa activity were not or only slightly increased. Bleeding time, thrombin time and platelet adhesion were not significantly changed after i.v. and s.c. injections of IK-SSH. However, tissue factor pathway inhibitor (TFPI) concentration was markedly increased after each injection of IK-SSH and returned to the preinjection value 24 h later. IK-SSH prolongs aPTT, Heptest and PITT in a similar manner as other low molecular weight heparins but without significantly affecting thrombin time, FIIa and FXa activity. The release of TFPI may well be responsible for the prolongation of aPTT, Heptest and PITT. IK-SSH may be further developed as an antithrombotic agent.

Bioequivalence of tolbutamide-containing tablet preparations.

The present crossover study was undertaken to investigate in 22 volunteers (15 males, 7 females, aged 22-28 years) whether the 2 tolbutamide preparations (tolbutamide R.A.N. vs. rastinon Hoechst) are bioequivalent. After administering a single dose of one 1 g tablet of each preparation the plasma tolbutamide concentration was measured by HPLC over a time-period of 48 hours. The mean AUC0-48 values are nearly identical (998.42 vs. 997.73 micrograms x h x ml-1), while the Cmax values (51.1 vs. 58.8 micrograms/ml) and the tmax values (4.55 vs. 3.82 h) show slight differences. The Westlake intervals claimed to prove bioequivalence lies in the 95% confidence interval between the limits 0.972 and 1.046 (AUC), 0.896 and 0.978 (Cmax), and 0.056 and 1.346 (tmax). For example, this is the result of the parametric analysis considering the randomization. In the case of the parameters of the multiplicative model (AUC and Cmax) the probability of correctly concluding bioequivalence (power) between the 2 preparations reaches 2.0. Regarding maintenance therapy it is of minor importance that the maximum plasma tolbutamide concentrations is 0.7 h later observed with the test preparation than with the standard. The results of this study allow the conclusion that the 2 tablet preparations are bioequivalent.

Cost-benefit analysis--a prerequisite of a rational pharmacotherapy in cardiovascular diseases. Timely thrombolysis in the acute myocardial infarction.

The worldwide increase in the expenses of the National Health Services compels the legislation of some countries to take economizing regulatory measures. In Germany the existent and planned activities are an essential part of the German Structural Health Act of 1993. In the last years methods have been developed to estimate the cost-benefit relationship of special therapeutic interventions giving the physician an aid to avoid the application of those of low cost-efficiency. The cost-effectiveness and the cost-utility analyses are the recently most usual ones. The timely thrombolysis of the acute myocardial infarction is presented under the viewpoint of the economical drug use in cardiovascular disease. Investigations to evaluate the cost-effectiveness of streptokinase and the newer thrombolytics anistreplase and alteplase are carried out in some European countries and in the USA. Parameters of efficacy are the amelioration of cardiac functions, the shortening of the rehospitalization duration, and the extension of the survival time. The use of a thrombolytic within 4 to 6 hours after the onset of the first signs is recommended and economically justified especially in anterior myocardial infarction and also in patients aged 75 years and above. Streptokinase is designated by a low cost-effectiveness ratio. The successful thrombolysis does not result in a continous deterioration of the quality of life in the patients. In this review no attempt was made to extrapolate the findings to the recent situation because of possible national pecularities with regard to the morbidity of and the therapeutic procedures in the acute myocardial infarction and because of the changes in the cost structure and currency parity which occurred in the meantime.

An attempt to characterize alpha-adrenoceptors on human dorsal foot veins in situ.

The effects of specific alpha-adrenergic agonists and antagonists on the congestion-induced change in the vessel diameter were studied in human dorsal foot veins in situ by means of a linear variable differential transformer. The specific agonist at alpha-1-adrenoceptors, phenylephrine, induced venoconstriction, whereas clonidine, the specific agonist at alpha-2-adrenoceptors, in this regard was ineffective, but on the contrary, lowered the phenylephrine-induced increase in venous tone. The phenylephrine-induced reaction could be inhibited in the rank order of their effectiveness by prazosin, the specific antagonist at alpha-1-adrenoceptors, by sodium nitroprusside and by verapamil. These results are in favour of the assumption that in exogenous stimulation of human foot veins by adrenergic agonists in situ, alpha-1-adrenoceptors are especially involved.

Phasic activity of human dorsal foot veins.

Phasic contractions of the dorsal foot veins were detected in 7 male subjects, aged 23 to 49 years, by means of a linear variable differential transformer (LVDT) after congesting the veins by a pressure of 6.7 kPa (50 torr). This phasic activity (PA) had a frequency of 3 to 7 contractions per minute and led to a periodic diminution of the diameter of the distended veins by 12 to 44%. Using a double LVDT, the PA was shown to represent peristaltic waves travelling along the vessel wall concomitantly with the venous return. Determined in 3 out of the 7 subjects, the velocity of the waves amounted to 3.6 to 6.1 mm per second. A rheological significance of the peristaltic waves is assumed.

Adjustment of phenprocoumon dosage utilizing a pharmacokinetic model.

According to a pharmacokinetic model, the adjustment of a phenprocoumon (PPC) standard dosage based on experimentally determined means values of the parameters volume of distribution and biological half-life will yield in more than 50% of the individuals the desired plasma PPC concentration. In 25 patients it was tested, whether the thus derived loading and maintenance doses, 376.8 and 35.2 micrograms PPC per kg b. wt., resp., actually lead to the predicted optimum plasma PPC concentration of 2.0 micrograms/ml. After initiating dosage, the plasma PPC concentrations were determined over a time period of 30 days. As predicted by the model, in 72% of the patients the average steady-state plasma PPC concentrations were within the range of 1.7 and 2.3 micrograms/ml. The data obtained were used to newly calculate mean values of the volume of distribution, the biological half-life, and the total body clearance of PPC. The mean biological half-life of PPC derived was somewhat shorter than that used for the calculation of the standard dose. Quick-values were estimated concomitantly with the plasma PPC concentrations. They revealed an optimum anticoagulation (15-25%) in 96% of the patients.

Interactions of dihydroergotamine with etilefrine in human leg veins in vitro and in situ.

The aim of the present study was to provide evidence for an interaction of dihydroergotamine (DHE) and etilefrine (Et) with regard to their constrictor effect on human leg veins both in vitro and in situ. In isolated strips of the femoral vein, DHE exerted a concentration-dependent sustained contraction which also continued after washing out the preparation. Et induced a reversible contraction of the strip at considerably higher concentrations as compared to DHE and noradrenaline. When DHE (0.01 mumol/l) and Et (6 mumol/l) were simultaneously applied, there was only an additive venoconstrictor effect. The influence of DHE and Et on the compliance of dorsal foot veins was studied in 14 male volunteers by means of a variable differential transformer. In the short-term experiment, an oral dose of 10 mg DHE was ineffective, whereas after the subcutaneous injection of 1 mg DHE a significant venoconstrictor effect was observed. Et, orally given in a dose of 10 mg, was also ineffective, while 20 mg Et caused a short-lasting effect which could not be augmented by the concurrent intake of 10 mg DHE. When 10 mg Et were administered 30 or 60 min after a single oral dose of 10 mg DHE, a distinct venoconstrictor effect occurred. These findings suggest that no pharmacodynamic synergism of the two drugs can be expected when DHE and Et directly act on the veins. The augmentation of the venoconstrictor in situ effect of Et after pretreating the volunteers with DHE could result from an amelioration of the oral bioavailability of Et by DHE, i.e., from a pharmacokinetic interaction of the two drugs.

A simple approach to estimate the variability of individual plasma drug concentrations in patients at a standardized multiple dosing regimen.

Equations were derived to simulate the course of plasma drug concentration versus time curves for a multiple dosing regimen of drugs with a long biological half-life in those cases when Vrel and t1/2 or k in a particular subject do not correspond to the average values underlying the calculation of a standard dose. Extreme course can be expected only when Vrel and t1/2 show deviation from the average values in the opposite direction. Thus, smaller Vrel and longer t1/2 result in an increase, greater Vrel and shorter t1/2 in a decrease in plasma drug concentration after giving the standard dose. An analysis of the course of plasma drug concentration curves at the loading phase permits the estimation of the actual t1/2 in the particular subject. As an application example, the loading phase of digitoxin is presented. The procedure allows an individual dosage adjustment on the condition that plasma drug concentration in the particular subject can be monitored regularly.

[Venous tonus-modifying effect, pharmacokinetics and undesired effects of dihydroergotamine]. / Venentonisierender Effekt, Pharmakokinetik und unerwünschte Wirkungen von Dihydroergotamin.

In the present review the clinical pharmacology of dihyroergotamine (DHE) is described. The decisive pharmacodynamic effect of DHE, i.e. the tonicization of the capacitance vessels leading to the acceleration of the venous backflow is described by the methods suitable for the detection of this activity in man. In the paragraph on pharmacokinetics the kinetic parameters of DHE at present known are discussed with regard to the usual forms of application. Emphasis is placed on the poor oral bioavailability of DHE as a result of a distinct first-pass metabolism in the liver. Taking into consideration several recently published cases of ergotism after prophylactic use of DHE, the ability of DHE is discussed to raise the peripheral resistance. The symptoms and the incidence of ergotism are reported on and reference is given to particular conditions which favour its occurrence. Among the measures of a medicamentous therapy of ergotism the use of drugs such as sodium nitroprusside and nitroglycerin which exert a direct spasmolytic effect on the vascular muscles is of special importance. Since DHE is at present the only medicament that possesses a reliable constrictor effect on the capacitance vessels, its clinical application demands special caution due to the narrow therapeutic margin of safety.

[Use of heparin in combination with dihydroergotamine for the postoperative prevention of thrombosis in hip joint surgery]. / Zur Anwendung von Heparin in Kombination mit Dihydroergotamin zur postoperativen Thromboseprophylaxe bei Hüftgelenkoperationen.

The risk of thromboembolism is particularly high in patients involved in hip replacement arthroplasty. Therefore, besides physico-mechanical measures, early mobilisation, compression bandages and physiotherapy they need an additional pharmacological prophylaxis of thromboembolism. In the present study the prophylactic efficacy of low-dose heparin in combination with dihydroergotamine was investigated in 200 patients undergoing hip replacement. While in comparison to the only administration of low-dose heparin the frequency of thromboses of the deep veins of the leg did not decrease significantly, the decrease of the frequency of pulmonary embolism under the combination obtained statistical significance. The results are compared with those of studies published in international literature. Consequently, the application of low-dose heparin in combination with dihydroergotamine represents a simple, highly effective prophylaxis against thromboembolism, but is not free from side-effects.

A pharmacokinetic model of the adjustment of phenprocoumon (Falithrom) dosage.

The model presented here is based on a phenprocoumon (PPC) standard dose calculated per kg body weight by adapting it to experimentally obtained mean values of biological half-life (t1/2) and relative volume of distribution (Vrel) of PPC taken from the literature. Moreover, this dose is apt to produce a desired plasma PPC concentration leading to an optimum pharmacodynamic effect. This dose which amounts to 35.2 micrograms PPC per kg body weight will nearly be equal to the clinically used 3-mg dose related to a normal subject of 70 kg, if an absorption loss of 15 per cent is taken into consideration. By means of mathematical equations derived for this purpose, the course of plasma PPC concentration versus time curves is simulated over a time period from the administration of a standard loading dose of 376.8 micrograms PPC per kg body weight until steady state is reached. The simulation of curves is based on the presupposition that the values of t1/2 and Vrel of PPC in an individual subject do not correspond to the values of these parameters underlying the calculation of the standard dose. More than 50 per cent of the combinations of t1/2 and Vrel tested leads to the desired plasma PPC concentration at steady state. The model is suited to estimate the extent of extreme deviations of plasma PPC concentration, i.e., further accumulation of PPC or decrease in plasma PPC level, and to obtain information about the respective combinations of t1/2 and Vrel causing these deviations. Application of the basic principles of the present model to clinical practice would allow to further optimize and individualize the adjustment of multiple dosing regimen of the oral anticoagulant PPC.

A comparative plethysmographic study of the venoconstrictor effect of dihydroergotamine and dihydroergotoxine on the deep veins of the calf in healthy subjects and patients suffering from varicosis.

The venoconstrictor effect of dihydroergotamine and dihydroergotoxine was compared in ten volunteers and in tne patients suffering from varicosis of the leg veins. The dihydrogenated ergot alkaloids were administered subcutaneously in a dose of 0.5 mg each. The influence on the capacitance reaction was determined by occlusion plethysmography of the calf. In addition, the arterial resistance was measured in the same region. Dihydroergotamine reduces the capacitance reaction in volunteers only at the high occlusion pressure levels 8.0 and 10.7 kPa after a lag of 40 min, whereas dihydroergotoxine does not show any significant influence. On the other hand, dihydroergotamine and dihydroergotoxine lead to a significant decrease in capacitance reaction in the patients after 20 and 60 min, respectively. However, the effect if dihydroergotamine (2.1 ml/100 ml tissue) is significantly greater than that of dihydroergotoxine (1.2 ml/100 ml tissue) and nearly normalizes the increased capacitance reaction. The two drugs increase the arterial resistance more clearly in the volunteers than in the patients, and dihydroergotoxine more often than dihydroergotamine tends to decrease resistance when the pre-existent resistance value is low.

[Intravenous fibrinolytic treatment in chronic ischemic heart disease (author's transl)]. / Intravenöse Fibrinolysetherapie bei chronischer koronarer Herzkrankheit.

In 13 male patients (mean age 49.1 years) with chronic ischemic coronary heart disease (7 transmural and 2 intramural myocardial infarctions), angina pectoris and signs of ischemia during exercise an intravenous streptokinase therapy was performed. The treatment was installed 18.9 months after infarction or after onset of angina pectoris. Before and after intravenous streptokinase therapy the following parameters were measured: history, heart volume, exercise-ECG, Swan-Ganz pulmonary artery measurements during exercise, aortic and left ventricular pressures, coronary angiography, left ventricular angiography. 1. Angina pectoris disappeared in 1 and became better in 4 patients. In none of the patients angina pectoris became worse. 2. The parameters for ischemia were not changed overall by the therapy. But in single patients signs of exercise-induced ischemia were influenced. 3. Mean values of left ventricular function (EF, LVEDP) were not changed. 4. Angiographic changes were discrete. 5. Complications of therapy and worsening of subjective parameters did not occur. 6. The angina pectoris behaviour in 5 patients (became better) is explained by changes of blood properties. The not-appearance of coronary artery occlusions is explained by the inhibition of platelet aggregation. 7. It is suggested that the effect of intravenous streptokinase therapy should be examined in patients with short-lasting angina pectoris and subgroups, such as initial angina pectoris.

[Comparison of 99mTc-trend scintigraphy and left ventricular angiography in 33 patients (author's transl)]. / Treffsicherheit der 99mTc-Trend-Szintigraphie Vergleich von szintigraphischen mit lävokardiographischen Befunden.

In 33 patients (30 male, 3 female, mean age 48 years) 99mTc-Trend Scintigraphy (Schad) was compared with left ventricular angiography. 25 patients suffered of a chronic myocardial infarction. In 26 patients complete or partial agreement between the two methods was seen. The scintigraphy showed false negative results in the apical region and false positive results in the basal segments. The comparison of both methods shows that 99mTc-Trend Scintigraphy can be used to evaluate non-invasively the function of the left ventricle.

[Social fate (return to work) after coronary heart surgery and/or aneurysmectomy (author's transl)]. / Soziales Schicksal bei operierten und konservativ behandelten Koronar- und Aneurysmapatienten.

The "return to work"-rate of 4 groups of patients with myocardial infarction (MI) is evaluated (all coronary angiography): Group 1: 314 patients after aorto-coronary bypass operation: mean age 50.5 years. Time after infarction 28 months, after surgery 18 months. The social fate of 52% were not yet decided. 20% got pension, 25% returned to work. Group 2: 86 patients after conservative treatment of myocardial infarction: mean age 42 years. Time after MI 18 months. The social fate of 21% was not yet decided, 41% got pension, 36% returned to work. Patients with one-vessel disease returned to work in 52%, with two-vessel disease in 20% and with three-vessel disease in 12.5%. Group 3: 24 patients after aneurysmectomy: mean age 47 years. Time after infarction 28 months, time after operation 11 months. Social fate of 8 out of 24 patients was not yet decided, 7 out of 24 got pension, 5 out of 24 returned to work. Group 4: 27 patients with conservatively treated left ventricular aneurysm: mean age 43 years. Time after infarction 42 months. The social fate of 2 out of 27 patients was not yet decided, 14 out of 27 got pension, and 8 out of 27 returned to work. Exercise-tolerance is no good indicator for the work status 18 months after myocardial infarction, 18 months after aorto-coronary bypass, 18 months after aneurysmectomy and 42 months after conservative treatment of left ventricular aneurysm. Selection of patients (all were examined by coronary angiography because of limitation by angina pectoris in daily life activities) may be partly responsible for the poor long-term work status. But more important seems to be the "tied social network". Decision for "return to work" or "pension" should be made 6 months after MI or after operation.