Memory in time: electrophysiological comparison between reality filtering and temporal order judgment.

Orbitofrontal reality filtering (ORF) denotes a little known but vital memory control mechanism, expressed at 200-300ms after stimulus presentation, that allows one to sense whether evoked memories (thoughts) refer to present reality and can be acted upon, or not. Its failure induces reality confusion evident in confabulations that patients act upon and disorientation. In what way ORF differs from temporal order judgment (TOJ), that is, the conscious knowledge about when something happened in the past, has never been explored. Here we used evoked potential analysis to compare ORF and TOJ within a combined experimental task and within a comparable time frame, close to the experienced present. Seventeen healthy human subjects performed an experiment using continuous recognition tasks that combined the challenges of ORF and TOJ. We found that the two mechanisms dissociated behaviorally: subjects were markedly slower and less accurate in TOJ than ORF. Both mechanisms evoked similar potentials at 240-280ms, when ORF normally occurs. However, they rapidly dissociated in terms of amplitude differences and electrical source from 310 to 360ms and again from 530 to 560ms. We conclude that the task of consciously ordering memories in the immediate past (TOJ) is effortful and slow in contrast to sensing memories' relation with the present (ORF). Both functions invoke similar early electrocortical processes which then rapidly dissociate and engage different brain areas. The results are consistent with the different consequences of the two mechanisms' dysfunction: while failure of ORF has a known clinical manifestation (reality confusion as evident in confabulation and disorientation), the failure of TOJ, as tested here, has no such known clinical correlate.

Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking.

Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.

Pharmacokinetics of raclopride formulations. Influence of prolactin and tolerability in healthy male volunteers.

The pharmacokinetic and pharmacodynamic properties of raclopride, a new antipsychotic, were investigated in 16 healthy men. Single 4 mg doses were administered as intravenous infusion, oral solution and 2 extended release (ER) formulations. Total plasma clearance was about 100 ml/min (6.0 L/h), of which renal clearance accounted for 0.2 ml/min, indicating extensive metabolism. The volume of distribution was 1.5 L/kg; mean absolute bioavailability was 65 to 67% following the oral solution and the ER formulations. A transient increase in plasma prolactin levels followed both the intravenous infusion and the oral solution. The ER formulations resulted in a lower increase, which appeared later. However, the area under the prolactin level curve was similar after administration of all dosage forms. The frequency and severity of the most commonly reported side effects (tiredness and restlessness) were higher after the intravenous infusion than after the ER capsules. These findings indicate that such capsules may be advantageous for clinical antipsychotic treatment with raclopride.

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were "very much" or "much" improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Remoxipride--a new potential antipsychotic compound. Tolerability and pharmacokinetics after single oral and intravenous administration in healthy male volunteers.

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5-100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 l/kg (SD = 0.10) and the mean half-life 4.1 h (range 2.6-6.6). The recovery of unchanged remoxipride in urine was 10-36%, and the mean renal clearance was 32 ml/min (SD = 13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD = 41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.

Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication?

Plasma concentrations of THC were measured by gas-liquid chromatography and mass spectrometry following three routes of administration and correlated with clinical effects. Plasma concentrations peaked at 3 minutes after intravenous injection and then sharply declined. The peak "high" occurred at 30 minutes while plasma concentrations were declining. This lag between plasma concentration and "high" continued during most of the span of the drug's effects. The situation was quite similar following smoking, except that peak plasma concentrations were lower. After oral administration of THC, absorption was slow, with peak concentration occurring at 1 to 2 hours. Plasma concentrations were much lower. Correlations between plasma concentrations of drug and "high" were significant but not impressive. The degree of "high" was quite variable in relation to the prevailing plasma concentration. Conjunctival injection was found so long as plasma concentration of THC could be measured. Pulse rate increases occurred at lower concentration after oral administration than after the other two routes. It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance. The mode of administration will become important should THC or some homolog become a therapeutic agent.

The new selective D2-dopamine receptor antagonist raclopride--pharmacokinetics, safety and tolerability in healthy males.

Raclopride, a new potential antipsychotic drug, with high selectivity and affinity for central D2-dopamine receptors, was in this first human study administered to 8 healthy male volunteers in single oral doses from 0.1 to 16 mg. Two subjects, known to be slow metabolizers of debrisoquine, were also included. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. The maximum plasma concentrations of raclopride (Cmax) and the area under the raclopride curve vs time (AUC) increased proportionally with dose. No deviant kinetic parameters were seen in the slow debrisoquine metabolizers. Only minor deviations in biochemical and physiological safety parameters were found. Raclopride was well tolerated by all subjects at doses up to 8 mg but not at 16 mg because of akathisia. No other extrapyramidal side-effects were recorded. The drug induced a rapid and transient increase of plasma prolactin concentrations.

Placebo in clinical drug trials--a multidisciplinary review.

The use of placebo in controlled clinical trials is a very difficult matter from an ethical point of view. Scientifically it offers probably the best way of obtaining fast and valid conclusions, thus promoting medical progress for the benefit of future patients. On the other hand, some patients may stand the risk of obtaining a suboptimal therapy in a placebo-controlled trial. In general, this latter aspect must be given precedence. Therefore the use of placebo control should be minimized and other control methods encouraged. However, in certain well-defined instances the use of a placebo control can be justified, provided the ethical implications can be handled.

[The clinical importance of angiography in the diagnosis of periarteritis nodosa]. / Die klinische Bedeutung der Angiographie bei der Diagnose der Periarteriitis nodosa

Report on a 53 years old patient with renal failure. Angiography showed multiple micro-aneurysms in kidneys and liver, in some instances also in the pancreatic, duodenal and mesenterial arteries. Muscle biopsy confirmed the suspicion of arteriitis nodosa. Clinically the diagnosis of necrotizing arteriitis is difficult. Angiography settles the diagnosis, but only positive findings of micro-aneurysms prove it. The differential diagnosis is discussed and illustrated.

Influence of food intake on the bioavailability of zimeldine and its active metabolite, norzimeldine.

The possible influence of concomitant food intake on the bioavailability of the novel antidepressant zimeldine and its active metabolite norzimeldine was assessed in ten healthy female volunteers, who ingested a single dose of 200 mg zimeldine on an empty stomach and together with a standardized breakfast of 1 840 kJ. The plasma concentrations of zimeldine and norzimeldine were measured by a selective modern liquid chromatographic technique. Neither the peak concentration nor time to reach peak concentration nor elimination half-life nor the total area under the curve (AUC) of zimeldine was affected by concomitant food intake. For norzimeldine, the peak concentration showed a 10% reduction, but there was no change in any other parameter. Thus, the bioavailability of zimeldine and of its active metabolite norzimeldine is unaffected by food intake, suggesting that the drug need not be taken in a strictly defined relation to meals.

Antithrombotic effects of lidocaine and related compounds on laser-induced microvascular injury.

The aim was to study whether topically applied local anaesthetics and related compounds exert an antithrombotic effect. The assay was carried out through vital microscopy of the microcirculation in the hamster cheek pouch model as injured by laser microbeam irradiation, essentially in order to record the differences in the incidence of thrombus formation between two main experimental and control series. The application of lidocaine hydrochloride was found to inhibit thrombus formation and also to restore the microcirculation after laser-induced injury. The other investigated compounds, mono-ethyl-glycinexylidide, tocainide and bupivacaine were found to be less active with regard to inhibition of thrombus formation and flow restitution effects. It is concluded that an antithrombotic effect may be attributed to lidocaine in particular.

Splanchnic elimination and systemic toxicity of bupivacaine and etidocaine in man.

Fifteen healthy young volunteers were studied in connection with an intravenous infusion of a local anaesthetic agent. Seven received bupivacaine and eight etidocaine in a dose rate of 2 mg.min-1 over a period of 150 min. The hepatic blood flow and arterial-hepatic venous differences of the two drugs were measured. The estimated hepatic blood flow increased during the infusion of both drugs. While the splanchnic extraction ratio decreased during infusion of bupivacaine to 0.41 +/- 0.13, the same variable did not change (0.76 +/- 0.07) when etidocaine was infused. After 150 min infusion, the splanchnic clearance of bupivacaine and etidocaine was 0.76 +/- 0.27 and 1.32 +/- 0.21 1.min-1, respectively. Slight symptoms of central nervous toxicity were noted towards the end of the bupivacaine infusion, while no such symptoms appeared with etidocaine. A comparison between earlier published data on the blocking properties and the disposition pharmacokinetics of the two drugs shows that etidocaine is likely to confer a clinical advantage over bupivacaine as regards toxicity.

[Regional myocardial perfusion redistribution through coronary drugs. II. Influence of dipyridamole and oxyfedrin on regional perfusion distribution]. / Die regionale myokardiale Perfusionsumverteilung durch koronarwirksame Pharmaka. II. Beeinflussung der regionalen Perfusionsverteilung durch Dipyridamol und Oxyfedrin

The influence of Dipyridamol and Oxyfedrin on regional myocardial precapillary microperfusion patterns was investigated in groups of 15 and 13 patients by means of selective double lable perfusion scintigraphy. Automatic impulse rate integration allows the comparison of different perfusion areas in the same scintigram as well as the comparison of different identical regions in different scintigrams. The scans were taken in two positions (frontal and l.a.o.). Microperfusion patterns were measured before and after the intravenous application of the drug. We found a typical shift of the microperfusion patterns with both medicaments. Under the influence of Oxyfedrin and Dipyridamol there was an increase of the relative microperfusion intensity in the vicinity of the major arteries but there were great differences as to the degree of their reaction maximum. Besides the results of the groups some typical cases are demonstrated. The method allows a satisfactory measurement of differences in the regional precapillary myocardial perfusion under the influence of coronary active drugs. We believe that statements on physiologic and pathologic functions are possible.

[Selective coronary perfusion scintigraphy. II. Abnormal coronary perfusion pattern (author's transl)]. / Das selektive koronare Perfusionsszintigramm II. Pathologische koronare Perfusionsverteilung

Integrated assessment of selective coronary angiorgrams and perfusion scintigrams of 86 patients with coronary-artery insufficiency revealed anatomical and topographical details which could not be achieved with one of these methods alone. Pathological perfusion patterns were quite different from normal ones. The functional effects of single, centrally located stenoses, of more peripheral and multiple narrowings, as well as of anastomoses and collaterals were adequately demonstrated by selective coronary perfusion scintigraphy and prevented diagnostic errors. It is, therefore, an additional aid in the diagnosis of coronary-artery disease.

Influence of alaproclate on antipyrine metabolite formation in man.

Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.

Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users.

Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.

Bioavailability of D-propoxyphene, acetyl salicylic acid, and phenazone in a combination tablet (Doleron): interindividual variation and influence of food intake.

The influence of food intake on the bioavailability of three analgesic compounds--propoxyphene chloride, acetyl salicylic acid and phenazone--in a combination tablet, Doleron, has been examined in eight healthy volunteers. A single oral dose was given both on an empty stomach and together with a standardized breakfast meal. The plasma concentrations of propoxyphene, its major metabolite norpropoxyphene, salicylic acid and phenazone were determined by mass fragmentography, spectrofluorimetry and gas chromatography. Concomitant food intake had no consistent influence on the bioavailability of any of the components. Hence, doleron may be taken together with meals as well as between meals. Large interindividual variations in propoxyphene and phenazone concentrations were found, indicating that an optimal effect will not always be obtained by standard doses.

Maternal and foetal drug levels after epicutaneous application of a local anaesthetic formulation containing ketocaine for possible use as pain relief in labour.

A local anaesthetic formulation (A 2358) containing ketocaine, a local anaesthetic drug, was applied epicutaneously to the low back. Two compresses soaked with A 2358 were applied for 1 hour in 26 normal labours for relieving referred pain from the low back. The maternal blood ketocaine levels remained low, compared to higher systemic levels reported in other studies. Maternal heart rate and blood pressure were stable during the application time. The mean umbilical vein/maternal vein and umbilical artery/maternal vein concentration ratios were 0.20 +/- 0.10 and 0.21 +/- 0.09. In addition, the foetal heart rate findings and the conditions of the neonates were satisfactory, thus suggesting the foetal safety of this analgesic method.