Benzamides as melanotropic carriers for radioisotopes, metals, cytotoxic agents and as enzyme inhibitors.

Benzamide derivatives are known as antipsychotic and antiemetic drugs. Owing to its neurotropic characteristic this class of compounds was found useful for imaging melanoma and melanoma metastases. [(123I)]BZA (N-(2-diethylaminoethyl)-4-[(123I)]iodobenzamide) was the first example which was clinically applied as an imaging agent demonstrating high tumor uptake. This finding initiated research efforts to further improve the affinity and pharmacological properties of this agent. In order to optimize the use of these molecules with respect to costs and wide spread distribution, (99m)Tc labeled benzamides have been developed. Indeed, several (99m)Tc complexes were found suitable for melanoma imaging; however, they were less eligible than radioiodinated benzamides. Besides their use as radiotracers benzamides have been evaluated for magnetic resonance imaging. Molecular imaging with paramagnetic metal contrast agents for magnetic resonance tomography (MRT) is hampered by the inferior sensitivity of MRT. Biochemical trapping was thought to overcome this problem using the polyamine transporter of melanoma cells. One of the neutral, DTPA based Gd complexes comprising 2-(diethylamino)ethylamine and bis-(2-aminoethyl)amine in the side chain led to intracellular uptake values well above the MRI detection limit. An overview about benzamides used for molecular imaging and as transporters for cytostatic agents as well as inhibitors for histone deacetylases concludes this review, demonstrating that benzamide derivatives represent a versatile class of compounds leading to novel imaging and therapeutic agents.

Injury reduction by the airbag in accidents.

Today an increasing number of automobiles are being equipped with additional passive safety devices: driver and passenger airbags. To examine the efficiency of the airbag in real road traffic accidents, a collective study was conducted from 181 traumatology centres throughout Germany. The inquiry was answered by 81 per cent of the medical centres contacted. From the evaluation of 122 accident victims in 1993 who were protected with an airbag the following was concluded. The patients treated in surgical and in traumatological departments suffered predominantly superficial injuries of the head, cervical vertebra and thorax. Some of these chiefly superficial wounds, such as abrasions and bruises, were initiated by contact with the airbag. It is remarkable that 72.1 per cent of the airbag-protected patients suffered a maximum of MAIS 2. What is also notable is the continuing high number of patients suffering from severe injuries (AIS 3+) of the lower extremities.

[Protective air bags in traffic accidents. Change in the injury pattern and reduction in the severity of injuries]. / Der Airbagschutz beim Verkehrsunfall. Anderung im Verletzungsmuster und Reduktion der Verletzungsschwere.

The effectiveness of air bags, drivers-side and passenger-side, as an additional passive safety system in motor vehicles was tested in a collective study in which 47 trauma centers in Germany participated. The inquiry was answered by 80% of 181 hospitals. The evaluation of a total of 119 air bag-protected patients involved in accidents, who were treated in German trauma centers in the year 1993 shows predominant minor injuries on the head-, cervical- and thorax-region. Some patients had superficial injuries caused by air bag in their face and chest area, such as abrasions and contusions. It is notable, that a large number of patients continue to suffer severe injuries (AIS 3+) in their lower extremities. The trend of the industry to equip more and more vehicles with air bags must be sustained. According to manufacturer statements, in 1994 already more than 60% of all mass produced vehicles in Germany will be provided with this modern passive safety system.

Arginine vasopressin facilitates reversal learning in albino, but not hooded rats.

Male Holtzman albino and Long-Evans hooded rats were administered one microgram of arginine vasopressin (AVP) or a placebo each day after the acquisition trials of a visual white-black discrimination. Animals were then trained in the reversal of the discrimination. Performance was assessed by the number of trials to criterion during acquisition and reversal. Treatment with AVP resulted in significantly fewer trials to criterion during reversal learning in Holtzman albino rats, but did not influence reversal learning in Long-Evans hooded rats. These results provide evidence that AVP may have differential actions on memory processes in different strains of rats.

[Antipyrine clearance as a measure of drug metabolism in patients with diabetes mellitus]. / Antipyrin-Clearance als Mass des Arzneimittelmetabolismus bei Patienten mit Diabetes mellitus.

Antipyrine-clearance calculated from a single 24 hrs blood sample following i. v. injection of 1 g was determined in insulin dependent diabetics (n = 20), patients with liver cirrhosis (n = 8), with fatty liver + hepatitis (n = 5) and alcoholics with normal liver morphology (n = 3). Antipyrine-clearance values in normal subjects amounted to 58,7 +/- 4,8 ml/min (means +/- s), in cirrhotics to 11,8 +/- 10,1 ml/min (p less than 0.01), in patients with fatty liver to 43,3 +/- 10,1 ml/min (p less than 0.01), and in alcoholics to 62,5 +/- 18,6 ml/min. In diabetics, diseased for many years, also a decrease in the clearance values was seen (41 +/- 17,5 ml/min; p less than 0.05). 15 out of them were below the 2 s range of normal subjects. Thus, the drug-metabolizing capacity in diabetics seems to be markedly reduced, and drug dosage might have to take account of this fact.

Biliary and renal excretion of paracetamol in man.

In 6 postsurgery patients with T tubes inserted in their common bile ducts, biliary excretion of paracetamol amounted to 2.6% of an oral dose (1 g), consisting of unchanged paracetamol (0.57%) and conjugates of sulfate (0.36%), glucuronic acid (0.36%) and cysteine (1.63%). Renal recovery in the same patients was 35.3%, consisting of 2.6% unchanged paracetamol, 12.7% paracetamol sulfate, 9.0% glucuronide, 3.9% cysteine conjugate and 4.0% mercapturate.

On the influence of zimelidine on left ventricular contractility.

The cardiovascular effects of the antidepressant zimelidine were studied in healthy volunteers ( n = 10) during a period of six days. The following parameters were examined: plasma level of the substance, blood pressure and--by means of ECG echocardiogram, carotid pulse curve and phonocardiogram--heart rate, myocardial contractility parameters, afterload and systemic arterial resistance. At therapeutic plasma levels zimelidine did not cause any significant increase in heart rate at unchanged blood pressure in contrast to classical tricyclic antidepressant. Furthermore, the inotropy parameters e.g. circumferential fibre shortening rate, systolic time intervals, and fibre shortening did not show any alterations after zimelidine. Decreases of peripheral resistance and afterload were negligible.

Pharmacokinetics of tocainide in patients with combined hepatic and renal dysfunction.

The disposition of tocainide following an i.v. infusion of tocainide HCl 100 mg was studied in 6 patients with decompensated cirrhosis (ascites) and renal dysfunction. In one patient with active hepatic necrosis the terminal plasma half-life was 57.4, and in the others the half life ranged from 16.0 to 29.0 h. The increase in half-life was correlated with biochemical evidence of renal dysfunction, but not with individual tests of hepatic function. Non-renal clearance of tocainide was similar to values reported previously in healthy subjects and patients with acute myocardial infarction. The apparent volume of distribution of tocainide was increased and the pattern of distribution was abnormal in some patients, as plasma concentrations increased after an initial fall and the elevated concentrations then persisted for several hours. This abnormality appeared to be most marked in patients with the greatest degree of liver dysfunction.

Plasma levels of lidocaine after intramuscular injection and subsequent infusion in patients with acute myocardial infarction.

It has been proposed that prophylactic administration of lidocaine i.m. can prevent ventricular arrhythmias during myocardial infarction. Thus we studied the pharmacokinetics of lidocaine after i.m. injection of 300 mg in the deltoid muscle and subsequent infusion to maintain antiarrhythmically effective plasma levels. The mean duration for exceeding a threshold concentration of 1.5 mg/l after 300 mg lidocaine i.m. was about 2 h; maximum concentrations were reached after 10 min and amounted to 3.2 mg/l (n = 10). By varying the infusion onset after i.m. injection (1 or 2 h later) and the infusion rates from 0.029-0.039 mg/kg X min, steady-state plasma levels of lidocaine were found to be in the therapeutic range (1.5-6 mg/l) for 5 h of observation. Long-lasting infusions (greater than 10 h) may result in increased plasma concentrations of lidocaine due to reduced body clearance.

Metabolic effects of prenalterol in diabetic patients.

In 16 non-diabetic and 16 diabetic patients prenalterol, dobutamine and dopamine infusions (5 micrograms/kg/min for 30 min) were given. The haemodynamic and metabolic changes were similar in diabetics and non-diabetics. Prenalterol has the most pronounced haemodynamic effect on heart rate (increase 25-47%) and the heart rate-blood pressure-product (increase 54-81%). The metabolic effects were moderate. The slight lipolytic effect of prenalterol documented its functional selectivity for beta 1-adrenoceptors.

Echocardiographic comparison between prenalterol and dobutamine.

Prenalterol, a new cardioselective beta 1-adrenoceptor agonist, was compared with the beta-stimulator dobutamine by computer-assisted echocardiography. Prenalterol decreased preload, increased heart rate and induced an increase in contractility for a longer time in comparison with dobutamine. The small influence on blood pressure and afterload indicates selective beta 1-receptor-effect by a result of slight changes in the peripheral vascular resistance.

[Nitroglycerin also as a broncholytic]. / Nitroglycerin wirkt auch broncholytisch.

0,8 mg nitroglycerin administered sublingually to 10 patients with asthma bronchiale and chronic obstructive pulmonary disease effects a reduction of airway resistance up to 21% in the second and fifth minute. Even one hour after application the oscillatory resistance (Ros) is 15% lower than at the beginning. In the same patients 0,4 mg inhaled fenoterol has a stronger effect (-30%). After intravenous administration of nitroglycerin (2,5 mg/h) over 15 minutes there is a significant decrease of the plethysmographic measured resistance (Rt) (-23%), an increase of the vital capacity and a decrease of the residual volume. Side effects are a small reduction of pO2 and blood pressure and an increase of heart rate. Orthostatic disturbances may occur. The venous lactate concentration does not change. The investigation shows that patients with obstructive airway disease may benefit from the application of nitroglycerin.

[Echocardiographic measurements of hemodynamic effects and pharmacokinetics of prenalterol (author's transl)]. / Echokardiographisch ermittelte Dosis-Wirkungs-Beziehung von Prenalterol.

The dose-dependent haemodynamic effects and pharmacokinetics and parenteral prenalterol (0.5-10 microgram/kg/min), a new cardioselective beta-1-adrenoceptor agonist, have been studied in 10 healthy volunteers by computed echocardiography. Prenalterol induced a dose-dependent strong and persistent increase in contractility (FV 46%, VCF70 64%, STI 12%), heart index (46%) and heart rate (27%) and a moderate not significant decrease in VED (14%). Afterload and mean arterial blood pressure was nearly unaltered. The hemodynamically effective threshold concentration of prenalterol in plasma was 20-30 nmol/l, the mean value of maximum concentration 493 nmol/l; 1 hour after stopping the infusion prenalterol plasma level was about 90 nmol/l. A strong linear correlation between the haemodynamic alterations and the logarithm of prenalterol plasma concentrations was not apparent.

[Lidocaine prophylaxis in the pre-hospital phase of acute myocardial infarction (author's transl)]. / Lidocain-Prophylaxe in der Prähospitalphase des akuten Myokardinfarkts.

In a double blind study performed in cooperation with 69 emergency doctors and general practitioners in the catchment areas of the university and of the city hospital in Lübeck the action of intramuscular lidocaine on mortality and on the incidence of arrhythmias was investigated in patients with acute myocardial infarction aged less than 70 years. The mortality in the lidocaine group was significantly lower than in the placebo group. The incidence of ventricular arrhythmias up to 120 minutes after the lidocaine injection was also lower than in the placebo group. However, the only case of primary ventricular fibrillation was in the lidocaine group. As the difference in mortality between the two groups appeared at a time when an antifibrillatory action of lidocaine can no longer be assumed one must question whether the positively beneficial effect was real or whether the lower mortality was in fact due to primarily milder disease in the lidocaine group.

[Comparative studies on the use of equimolar 14C-labeled glucose and fructose infusions in normal subjects and patients with liver cirrhosis]. / Vergleichende Untersuchungen zur Verwertung äquimolarer 14C-markierter Glukose- und Fruktoseinfusionen bei Gesunden und Kranken mit Leberzirrhose.

In 11 normal subjects (NS) and 12 patients with liver cirrhosis (LC) the utilisation of 14C-glucose and 14C-fructose infusions (0.75 g/kg/h for 4 h) was compared. There were nor relevant side effects. Lactate and pyruvate were in both groups during fructose infusion slightly increased compared to glucose infusion. The free fatty acids were significantly decreased. The serum glucose level rose more in LC than in NS when given fructose infusion. During glucose and fructose infusion in LC higher insulin concentrations were calculated than in NS. 15 min after infusion of 14C-fructose 20% of the total serum activity was 14C-glucose, after 2 to 4 h the level was 30%. Differences between NS and LC were not found to be significant. The specific activity of 14CO2 was the same in both the 14C-glucose infusion and the 14C-fructose infusion. The glucose oxidation was impaired in LC, but not the 14CO2-exhalation during infusion of 14C-fructose. Unimpaired 14CO2-exhalation, and normal utilisation and conversion to glucose are arguments for the use of fructose in infusion treatment of cirrhotics.