Lack of reinforcing effect of the benzodiazepine and tricyclic antidepressant combination of diazepam and dothiepin.

Fixed combinations of a tricyclic antidepressant (TCA) with a benzodiazepine (BZD) for the treatment of depressive syndromes enjoy remarkable acceptance among patients and prescribing physicians. In order to investigate if the widespread use of one such fixed TCA-BZD combination might be due to its high positive reinforcing effect, we tested each drug alone and in combination in an operant conditioning paradigm (fixed ratio 1 time-out 150 s) of intravenous self-administration in rats and compared their reinforcing effects to that of cocaine. Diazepam proved to be of only moderate reinforcing strength. Dothiepin alone was ineffective as a reinforcer but essentially abolished the reinforcing effect of diazepam when given in combination with it. These data indicate that the widespread acceptance of the fixed diazepam-dothiepin combination by the therapeutic community is not due to an increase in the positive reinforcing effect of diazepam by dothiepin but that, in contrast, addition of dothiepin might even decrease diazepam's moderately positive reinforcing effect.

Systematic screening for pharmacokinetic interactions during drug development.

The possible involvement of a new chemical entity in pharmacokinetic drug interactions is an important safety issue. Not all relevant drug combinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications. In this respect the typical approaches currently used, including interaction studies with high risk drugs and compounds frequently given as comedication, or studies involving standard inhibitors and standard substrates are unsatisfactory. A better approach is to characterize drugs according to their effects on the underlying pharmacokinetic processes. Indeed, recent progress in understanding drug interaction mechanisms and in the development and refinement of in vitro test systems enables in many cases experiments to be designed which predict the occurrence of drug interactions. This paper illustrates systematic investigational procedures based on mechanism of interaction. Interaction mechanisms involving drug absorption, distribution, metabolism, and/or excretion are briefly summarized. Detailed proposals are derived which allow identification of the possible role of a new drug in interaction mechanisms for which valid test systems are available. Emphasis is placed on the rational selection of experiments with optimal cost-effectiveness. In vitro methods are integrated in the schemes wherever possible. In addition, it is proposed that pharmacoepidemiological screening, starting in phase II of drug development, be used to identify those relevant drug interactions missed by the mechanism-based approach. As exemplified by several recently discovered interactions it should be possible, by implementation of the proposed procedure, to avoid most serious unexpected adverse effects due to pharmacokinetic drug interactions.

[Internal medicine aspects and characteristics of nutrition in patients with cerebral cognitive deficits]. / Internistische Aspekte und Besonderheiten der Ernährung bei Patienten mit Hirnleistungsstörung.

The reason of cerebral disorders is estimated to be internal diseases in a quarter of the patients. Metabolic causes could be hypoxemia, electrolyte disorders, disorders of the acid-base balance, liver diseases, renal diseases, metabolic disorders and chronic deficiency conditions of several vitamins and iron, cardiovascular causes include heart diseases, which go along with reduced cardiac output. Further cerebral disorders could also occur in cases of neoplasia, severe infections and chronic pain conditions. Also a lot of pharmacological agents given in high doses, especially psychotropic drugs, can cause confusion conditions and severe cerebral disorders. Physiological and pharmacological peculiarities in older people, which concern the absorption in the gastrointestinal tract, the distribution in the organism, the biotransformation and the excretion, are shown, further the problems of the aging process at the cell-level. Changes of the body composition respectively of the organs and organ systems, and the decrease of the low-fat body mass and the combined decrease of the whole body water represent the most important figure. As with increasing age the daily energy absorption and energy turnover decrease, the peculiarities of the nutrition are discussed in detail. While malnutrition in the outpatients with dementia is rare, there might be a lack especially in patients under hospital or rent house care in the presence of considerable mental and/or physical handicaps: this happens when home nursing is not possible any longer. Further guidelines for the handling of patients with eating-related behavioral problems are discussed. Through proper arrangements eating difficulties should be prevented and an adequate training of the relatives and the nursing stuff is advisable. Suitable medication and dietetic intervention may be prophylactic and curative against malnutrition especially in the field of vitamins, trace elements and other essential nutritive substances.

Double-blind, placebo-controlled, pharmacokinetic and -dynamic studies with 2 new formulations of piracetam (infusion and sirup) under hypoxia in man.

In a double-blind, placebo-controlled study, pharmacokinetics and pharmacodynamics of 12 g piracetam in 2 different formulations were investigated utilizing blood gas analysis, EEG mapping and psychometry under a transient, reversible, hypoxic hypoxidosis. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2, found in 6,000 m altitude), which was inhaled for 23 minutes under normobraic conditions by 18 healthy volunteers. They received after an adaptation session randomized at weekly intervals 12 g piracetam i.v. (250 ml infusion over 30 minutes), 12 g piracetam p.o. (60 ml sirup) and placebo. Blood levels were determined by means of an HPLC at the hours 0, 1, 2, 4, 6, 8 and 24. The 2 formulations showed a very similar time-course, with slightly higher blood levels in the 1st hour after the intravenous than oral administration, and vice versa thereafter. The elimination half-life was 4.3 hours for both formulations, the area under the curve and the clearance value were also almost identical. Evaluation of blood gases, EEG mapping and psychometry were carried out at 0, 2, 4, 6 and 8 hours post-drug. Blood gas analysis demonstrated a drop in SaO2 from 99 to 73 and 70%, in PO2 from 100 to 35 and 33 mmHg, in PCO2 from 36 to 31 and 31 mmHg in the 14th and 23rd minute of inhalation, respectively. pH increased from 7.43 to 7.48 in the respective minutes, while base excess and standard bicarbonate remained stable. EEG mapping exhibited under hypoxia a marked increase of total power, mostly due to an augmentation of delta/theta, and a decrease of alpha activity, which reflects deterioration of vigilance. Both piracetam preparations significantly attenuated this vigilance decrement, with 12 g piracetam i.v. showing its encephalotropic peak effects in the earlier hours, 12 g piracetam sirup in the later hours. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymopsyche, which was mitigated by both piracetam preparations, mostly in the 6th hour. Both formulations were well tolerated.

Pharmacokinetics of piracetam: a study on the bioavailability with special regard to renal and non-renal elimination.

The basis of this investigation was a trial on the relative bioavailability of a recently developed galenic formulation of piracetam. The open, randomized, single-blind crossover study was performed in 16 healthy male volunteers aged between 20 and 31 years. Under fasting conditions, they were given a single oral dose of 1600 mg piracetam either of the test drug or the reference drug. Blood samples and urine specimens were collected over 24 hours. The quantitative analysis was performed with a high sensitive HPLC-method. The pharmacokinetic analysis was carried out with the PC-based program TopFit. An identical bioavailability of the test drug was found (AUC0-24, AUC0-infinity, Cmax, by comparison to the reference drug. No relevant difference in piracetam excretion between test and reference drug was found, however, in contrast to previous references only about two thirds of the given oral dose could be detected in the urine after administration. A statistically significant difference (p = 0.001) between total clearance and renal clearance was observed. Because an incomplete absorption of the drug in the upper gastrointestinal tract is excluded, an additional extrarenal pathway of piracetam must be discussed; the hypothesis of an exclusive renal elimination of this drug should be overruled.

[Principles of the pharmacokinetics and pharmacodynamics of calcium antagonists]. / Grundlagen der Pharmakokinetik und Pharmakodynamik von Kalziumantagonisten.

Today calcium antagonists (Ca-antagonists) are widely used agents in the management of various diseases of the circulatory system. More than 20 years ago the Ca-antagonists of the so-called 1st generation (Verapamil, Diltiazem, Nifedipine) were introduced for treatment of angina pectoris and later of essential hypertension. In the last decade an increasing number of agents structurally related to dihydropyridines were developed for the treatment of hypertension and/or coronary heart disease or cerebral disorders; the main target was to reduce side effects and to guarantee once or at least twice daily administration. Therefore the Ca-antagonists of the so-called 2nd generation (e.g. Amlodipine, Felodipine, Isradipine, Nitrendipine, Nicardipine, Nimodipine, Nisoldipine) tend to longer elimination-half-lives; Amlodipin is an exception with an elimination-half-life of 30 hours on the average. Apart from elimination rates, however, the biopharmaceutical and pharmacokinetic characteristics of all Ca-antagonists are similar: they are highly cleared drugs and are relatively highly protein bound. As they are subject to significant hepatic first-pass-metabolism old age and hepatic disease will increase their plasma-concentrations. Renal impairment affects little their pharmacokinetics since the fraction eliminated unchanged by the kidneys is small. For most agents, plasma-concentration-response relationships have been described. With exception of nicardipine a linear pharmacokinetic in all Ca-antagonists was demonstrated. Drugs and food affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. With regard to the acute pharmacodynamic effects the Ca-antagonists show similar qualitative effects, though there are quantitative differences. Orally administered dihydropyridine-derivatives induce acute hypotensive effects, whereas the other compounds show clinically relevant hypotensive effects only when administered chronically per os or less pronounced when given as intravenous infusion.

The importance of prospective planning of pharmacokinetic trials. Considerations of studies on the phenytoin-digoxin-(P-D) and phenytoin-digitoxin-(P-DT) interaction.

To study possible pharmacokinetic interactions between two compounds a single-dose or a multiple dose experimental design may be used. Two prospective trials on the possible pharmacokinetic interaction between phenytoin (P) and digoxin (D) or digitoxin (DT) were performed in healthy volunteers. It is demonstrated that an statistically significant pharmacokinetic interaction was found only after multiple dosing under conditions of steady-state, whereas after single dosing no interaction was observed. In case of investigating possible pharmacokinetic interactions a multiple dosing trial design appears to be advantageous.

[The status of H2-blocker therapy today]. / Der Stellenwert der H2-Blockertherapie heute.

In the light of recent findings the therapeutic importance of various H2-blockers (e.g. cimetidine, ranitidine, famotidine) in short-term and long-term treatment of peptic ulcers is discussed. Special interest is paid to the clinical pharmacology (pharmacokinetics, pharmacodynamics) and undesired effects of the compounds. New aspects in the pathogenesis of peptic ulcer disease were considered, with regard to the pharmacologic profile of H2-blocker.

[Gastrointestinal absorption of theophylline, especially with reference to retard preparations]. / Zur gastrointestinalen Absorption von Theophyllin insbesondere im Hinblick auf Retardpräparate.

Little is known about the absorption of theophylline from definite parts of the intestine, though there are many depot or slow-release formulations of theophylline on the market and this topic should be of relevant importance. Most of these formulations are releasing the drug for up to 24 hours while passing the bowels. In this prospective, open, randomised, study with an interchange trial design the absorption of theophylline from the colon was studied in eight healthy male volunteers: 400 mg theophylline was given intravenously and in two different forms into the colon transversum by application with an endoscope. Under these conditions, theophylline was absorbed in an amount of 54% on the average with some variation due to the applied formulation. Therefore, it could be concluded that theophylline is absorbed to a clinically relevant extent from the large intestine. These results are remarkable with regard to the development and pharmaceutical profiles of retard or slow-release formulations of theophylline and the undesired effects of this therapy.

[Studies of biological availability. A critical assessment based on a study of spironolactone preparations]. / Zur Problematik der Bioverfügbarkeits-untersuchungen. Eine kritische Betrachtung anhand einer Studie über Spironolactonpräparate.

Investigations have been performed to determine the relative bioavailability of canrenone from an improved spironolactone preparation, Deverol drgs., in comparison with canrenone from a spironolactone standard preparation on the Austrian market (Osiren drgs.). This was carried out by comparing the areas under the serumconcentration-time-curves under conditions of steady-state after oral application of both preparations. Additionally the contents of spironolactone in the two preparations tested were determined. By intraindividual comparison of the areas under the serum-concentration-time-curves of canrenone a relative bioavailability of 99.37% of canrenone from Deverol drgs. could be calculated versus canrenone from the standard. However a remarkable different content of spironolactone in the preparations was found: in 50 mg of Deverol drgs. 50.5 mg spironolactone and in 100 mg of Osiren drgs. 109.6 mg spironolactone were found. Determination of drug contents in products appears to be necessary to determine their relative bioavailability correctly, because the usual range of +/- 5% may be overshot as demonstrated in our investigation.

Pirenzepin does not alter the pharmacokinetics of theophylline.

The possible pharmacokinetic interactions between pirenzepin and theophylline were investigated in an open single blind trial. Aminophylline (6.5 mg/kg body weight) was administered intravenously in five healthy male volunteers before and after chronic oral pirenzepin therapy (50 mg twice daily 5 days before to 2 days after giving aminophylline). To study the theophylline pharmacokinetics, serum and urine samples were collected up to 48 hours after aminophylline administration. It was demonstrated, that pirenzepin does not affect theophylline pharmacokinetics. Therefore, pirenzepin may be combined with aminophylline or theophylline without the risk of an interaction, which usually affect the coadministration of other antiulcer drugs, e.g. cimetidine, with theophylline.

Acute effects of pirenzepin on bronchospasm.

The response to pirenzepin, a new acetylcholine receptor blocking agent, was assessed and compared to placebo in patients with reversible bronchoconstriction. A single intravenous injection of 20 mg of pirenzepin induced a significant reduction of airway resistance compared to placebo (p less than 0.05). The anticholinergic substance pirenzepin appears to be useful in the treatment of bronchospasm.

Survival of gentamicin-loaded carrier erythrocytes in healthy human volunteers.

Resealed erythrocytes are potential slow release carriers for drugs and enzymes. We have investigated carrier erythrocyte survival in human volunteers using gentamicin (G) as encapsulated cell marker; G was readily incorporated into red cells by hypo-osmotic dialysis (87% efficiency of incorporation) and did not exit from carrier cells in vitro. Six healthy young volunteers were injected with 59 +/- 7 ml carrier erythrocytes containing 56 +/- 13 mg G. G levels were measured in plasma and haemolysed whole blood by RIA. After an initial phase of cell loss (up to 4.5 h post-injection) the carrier erythrocytes survived in circulation with a half-life of 22 days, as was indicated by intracellular G concentration. G levels were detectable in plasma during the first 90 min after injection. This indicates haemolysis of some carrier cells. In conclusion, carrier erythrocytes appear to circulate longer than any other drug carrier under investigation and may well serve as innocuous slow release system.

Pharmacokinetics and bioavailability of isosorbide-5-mononitrate in humans.

The relative bioavailability of isosorbide-5-mononitrate from two different formulations (MONOCLAIR, ISMO) was investigated in a double-blind randomized cross-over study in 8 healthy human subjects. After single orale doses of 40 mg the plasma concentration and the urinary excretion of isosorbide-5-mononitrate were measured over 24 hours. The comparison of the results obtained over the whole experimental period showed a significantly higher plasma concentration with a higher renal excretion after MONOCLAIR, the latter changes being insignificant as compared with those after ISMO, the reference drug. Thus the two formulations are judged to be at least equivalent with regard to their drug bioavailability.

Quinidine-digoxin interaction: are the pharmacokinetics of both drugs altered?

An open randomized crossover trial to investigate quinidine-digoxin interactions under steady-state conditions with special attention to quinidine pharmacokinetics was performed in 6 healthy male volunteers. Coadministration of quinidine sulphate induces a prolongation of digoxin elimination half-life (means +/- SD) from 33.0 +/- 8.0 to 43.9 +/- 6.2 hours, causing an augmentation of 0/48 AUC (means +/- SD) from 37.8 +/- 14.1 to 100.2 +/- 30.4 ng/ml.h. This increase in serum digoxin concentration-time course was caused by a decrease of both renal clearance (means +/- SD) from 150.7 +/- 46.5 to 79.0 +/- 23.3 ml/min and of minor importance, total clearance (means +/- SD) from 198.8 +/- 66.4 to 91.7 +/- 21.9 ml/min. A decrease in apparent volume of distribution of digoxin (means +/- SD) from 520.1 +/- 115.2 to 344.5 +/- 78.2 l could also be observed: When digoxin was given additionally, two quinidine-pharmacokinetic parameters were altered: renal quinidine clearance decreased from (means +/- s) 61.2 +/- 11.5 to 45.7 +/- 13.7 ml/min, causing a prolongation of elimination half-life of quinidine (means +/- s) from 10.34 +/- 1.76 to 12.28 +/- 1.23 hours. These altered parameters induced an augmentation in 0/48 AUC of quinidine of 11% on the average but this change was not statistically significant because of the relatively large standard-deviation in serum quinidine concentrations. Considering the reduction of renal digoxin clearance, the mechanism mainly responsible for the quinidine-digoxin interaction, the decrease in renal quinidine clearance, appears to be most remarkable as well.

On the interaction between phenytoin and digoxin.

An open, randomized, single-blind cross over trial to investigate phenytoin-digoxin interactions at steady state was performed in 6 healthy male volunteers. Coadministration of phenytoin caused a significant reduction in the elimination half-life of digoxin from 33.9 to 23.7 h and a diminution in AUC0-48 from 31.6 to 24.4 ng X ml-1 X h. Renal digoxin clearance was not significantly altered from 135.7 to 120.3 ml X min-1. Assuming no change in beta-acetyldigoxin absorption, the in decrease time-course the serum digoxin concentration was due to a significantly increased total digoxin clearance from 258.6 to 328.3 ml X min-1. An insignificant reduction in the digoxin distribution volume from 749.4 to 668.0 l was also observed. No relevant change in the pharmacokinetic parameters (elimination half-life, area under the serum concentration time-curve, protein binding) of phenytoin was observed when phenytoin and digoxin were co-administered. The data suggest that with this drug combination the serum digoxin concentration should be carefully monitored and, if necessary, the daily digoxin dose should be increased.

The diltiazem-digoxin interaction.

To study the interaction between the calcium antagonist diltiazem and digoxin, a randomized crossover trial under steady-state conditions was carried out in 24 healthy male subjects. Diltiazem with digoxin induced an average increase of steady-state plasma digoxin concentration and AUC over 48 hr of 22.4%. This is caused by the prolongation of elimination t1/2 from 36.2 +/- 11.2 to 44.5 +/- 11.5 hr (means +/- SD) and the impairment of total digoxin clearance, dropping from 146.6 +/- 37.9 to 107.9 +/- 18.4 ml/min. Average reduction in renal clearance (from 102.1 +/- 35.5 to 85.5 +/- 42.7 ml/min) was not statistically reproducible. Apparent volume of distribution was not relevantly altered. Diltiazem kinetics did not change significantly when digoxin was concurrently given.

Absorption of doxorubicin-hydrochloride and mitomycin-C after instillation into noninfected and infected bladders of dogs.

The described investigations were carried out in order to determine the degree of absorption of doxorubicin, and mitomycin-C after intravesical instillation into noninfected or Staphylococcus aureus-infected bladders in beagle dogs. The drug concentrations in the bladder wall were determined using diffusion chambers with permeable membranes. Two hours after end of instillation of 10 mg. doxorubicin, a concentration of 1.4 ng. per ml. was measured in the bladder wall of noninfected animals, and 3.75 ng. per ml. in that of infected animals (p less than 0.05). The simultaneously measured serum concentration reached mean peak levels after 30 minutes. The concentrations in infected animals were 3 times higher (1.9 ng. per ml.) than in noninfected animals (0.6 ng. per ml.) (p less than 0.05). After instillation of 1 mg. per kg. bw. mitomycin-C the concentration in both groups of animals was below 0.06 micrograms per ml. Doxorubicin concentrations were determined with a radioimmunoassay and mitomycin-C with a micro-agar diffusion method.