Differential effects of 4-aminopyridine and 2,4-diaminopyridine on the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis

The central effects of 4-aminopyridine (4-AP), a blocking agent of voltage-dependent potassium channels, and its more polar analogue, 2,4-diaminopyridine (2,4-DAP), were studied after i.p. injection and direct intrastriatal administration in rats. The effects of the drugs on the release of acetylcholine (ACh) and dopamine (DA) were quantified by means of an in vivo microdialysis sampling technique. Both neurotransmitters were determined by on-line HPLC analysis. Both aminopyridines increased the release of ACh dose dependently when administered intrastriatally. After peripheral administration, however, 4-AP but not 2,4-DAP induced an increase in the release of ACh. These results are interpreted as being due to the greater lipid solubility of 4-AP compared to 2,4-DAP and hence its better penetration through the blood-brain barrier. Intrastriatal administration of 4-AP induced a much lower increase in the release of DA compared to ACh, whereas there was no change in the release of DA after peripheral administration. These results indicate that the sensitivity of excitable membranes to the releasing effects of 4-AP is not the same for DA- and ACh-containing neurotransmitter systems.     

Alpha and gamma interferon in the treatment of advanced renal cell carcinoma

Thirty-two patients with proven progressive metastatic renal cell carcinoma were treated with the combination of 0.1 mg/m2 (2 X 10(6) IU/m2) r-interferon (r-IFN)-gamma and 6 micrograms/m2 (2 X 10(6) IU/m2) r-IFN-alpha. In case of progressive disease (PD) or stable disease (SD), after 8 weeks, the dose of r-IFN-alpha was escalated by 6 micrograms/m2 every 2 weeks until the maximum tolerable dose was reached, while r-IFN-gamma was maintained at the low dose. The rationale for this study is provided by the dose-related efficacy of IFN-alpha as a monotherapy, the potent immunostimulatory activity of IFN-gamma, and the alleged synergistic effect of the combination. Fourteen patients are evaluable for 8 weeks of low-dose combination treatment (7 X SD, 5 X PD, 2 X early progression), while so far 6 of 24 patients (25%) who started dose escalation of IFN-alpha have reached a partial response. These data indicate better efficacy with higher doses of IFN-alpha. Because of the infrequent administration and the relative low doses, compared to other trials, the treatment regimen was well tolerated. Although preliminary results are promising, definite efficacy remains to be proven.     

Feasibility of high resolution CT in the demonstration of the vestibular aqueduct (Ménière) and otospongiosis of the labyrinth

Ever since the introduction of temporal bone imaging by means of high-resolution CT, it appears that the combination of high spatial resolution, high density resolution and the freedom of patient positioning for scanning of optimal otological planes may play a unique role in the diagnosis and follow-up of a number of otological disorders. Two examples are described here. The first is the possibility of determining whether the vestibular aqueduct in idiopathic Ménière's disease is obliterated or not, and if so, whether it is a bony or a fibrous obliteration. Although the results are preliminary, there are indications that all three cathegories occur and that the efficacy of drainage of the endolymphatic sac can be evaluated prior to surgery. The second example is the possibility of outlining and quantifying the bone mineral loss in cases of labyrinthine otospongiosis. Preliminary studies have outlined that there is a relationship between the degree of decalcification and the severity of sensorineural hearing loss. These examples show high-resolution, thin-section multiplanar CT to have great potential in the diagnosis and treatment of otological disorders. This will become evident as the techniques that were used here are worked out in more detail and become more widely known.     

Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse

Intravenous self-administration studies in nonhuman primates suggest that the opioid receptor agonist-antagonist buprenorphine may be useful in the pharmacotherapy of cocaine abuse. In the present studies, behavioral and neurochemical interactions between cocaine and buprenorphine were examined using a conditioned place preference (CPP) procedure and in vivo microdialysis. Cocaine-induced CPP was linearly related to the dose administered (0-5.0 mg/kg). Buprenorphine (0-0.9 mg/kg) also elicited CPP in a dose-related manner; an inverted U-shaped function was obtained. Subthreshold doses of cocaine (1.5 mg/kg) and buprenorphine (0.01 mg/kg), themselves incapable of eliciting CPP, produced a significant CPP when given together. Moderate doses of cocaine (5.0 mg/kg) and buprenorphine (0.075 mg/kg), which were individually capable of eliciting CPP, produced a significantly larger CPP when given in combination. In the in vivo microdialysis studies, a low dose of buprenorphine (0.01 mg/kg) produced a progressive increase in extracellular dopamine in the nucleus accumbens, reaching approximately 200% of basal levels after 5 hr. Cocaine (5.0 mg/kg) rapidly increased extracellular dopamine concentrations (180% of basal values within 20 min), which returned to baseline in 2 to 3 hr. This effect of cocaine was significantly potentiated by coadministering buprenorphine (0.01 mg/kg); under this condition the peak increase in extracellular dopamine reached 260% of baseline values. These neurochemical findings are consistent with the CPP results and indicate that buprenorphine can interact with cocaine in a synergistic manner. In contrast to previous speculations, these results suggest that buprenorphine may enhance rather than attenuate the rewarding properties of cocaine.     

Pharmacokinetics and mechanism of renal excretion of short acting sulphonamides and N4-acetylsulphonamide derivatives in man

Summary The pharmacokinetics of short acting sulphonamides and a series of N₄-acetylsulphonamide derivatives has been investigated. Sulphonamides with a sulphur atom two atomic bond distances from the N₁ atom are excreted by active tubular secretion, e.g. sulphamethizole, sulphaethidole and sulphathiazole. When the sulphur atom is replaced by an oxygen or nitrogen atom, active renal excretion no longer occurs. N₄-acetylsulphonamides are excreted by active tubular secretion. The renal clearance values of the N₄-acetylsulphonamides are not influenced by the substituent at the N₁ position. Two groups of N₄-acetylsulphonamides can be distinguished. One has a T_1/2 of 4–6 h and a renal clearance value of 20–60 ml/min and the second has a T_1/2 of 10–20 h and a renal clearance of less than 10 ml/min. N₄-acetylsulphonamides are deacetylated to the extent of about 5%.     

The use of tetrodotoxin for the characterization of drug-enhanced dopamine release in conscious rats studied by brain dialysis

Summary The effect of TTX (infused during brain dialysis of the striatum and nucleus accumbens) on the in vivo release of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, was investigated. In addition it was studied whether the increase in the release of dopamine, induced by various pharmacological treatments, was sensitive to TTX infusion. The following drugs were studied: haloperidol, amphetamine, haloperidol co-administered with GBR 12909, morphine and MPP⁺. Dialysis was carried out in the striatum, except for morphine, which was studied in the nucleus accumbens. The infusion of TTX revealed three different types of pharmacologically enhanced dopamine release in conscious rats. First, action potential dependent dopamine release (exocytosis), which was observed in untreated animals as well as in animals treated with haloperidol, haloperidol + GBR 12909, and morphine. Second, action potential independent release (carrier-mediated) was established in the case of amphetamine. Third, action potential independent DA release, probably caused by neurotoxic reactions was observed during MPP+ infusion. Send offprint requests to B. H. C. Westerink     

A novel specificity of anticytoplasmic autoantibodies directed against eosinophil peroxidase.

Vasculitis associated anticytoplasmic autoantibodies (ANCA) are directed against enzymes in the granules of both neutrophils and monocytes. These autoantibodies can be detected by indirect immunofluorescence technique (IIFT) using ethanol-fixed cytospins. We here report the identification of a novel specificity of autoantibodies, present in the sera of eight patients, that reacted only with eosinophils in the IIFT. By immunoprecipitation and ELISA experiments it was shown that the autoantibodies in these sera were directed against eosinophil peroxidase (EPO). There was no apparent influence on initial substrate conversion rate, but reduced plateau levels suggested increased inactivation of the enzyme in the course of the peroxidase reaction. Flow cytometry studies demonstrated the presence of EPO on the surface of primed eosinophils. Anti-EPO sera and purified anti-EPO immunoglobulins significantly increased the release of reactive oxygen species from primed eosinophils. The patients with anti-EPO antibodies suffered from clinically diverse disorders, with more or less generalized manifestations involving the kidneys, blood vessels, lungs and/or joints.     

Temporal Context Actively Shapes EEG Signatures of Time Perception

Our subjective perception of time is optimized to temporal regularities in the environment. This is illustrated by the central tendency effect: When estimating a range of intervals, short intervals are overestimated, whereas long intervals are underestimated to reduce the overall estimation error. Most models of interval timing ascribe this effect to the weighting of the current interval with previous memory traces after the interval has been perceived. Alternatively, the perception of the duration could already be flexibly tuned to its temporal context. We investigated this hypothesis using an interval reproduction task in which human participants (both sexes) reproduced a shorter and longer interval range. As expected, reproductions were biased toward the subjective mean of each presented range. EEG analyses showed that temporal context indeed affected neural dynamics during the perception phase. Specifically, longer previous durations decreased contingent negative variation and P2 amplitude and increased beta power. In addition, multivariate pattern analysis showed that it is possible to decode context from the transient EEG signal quickly after both onset and offset of the perception phase. Together, these results suggest that temporal context creates dynamic expectations which actively affect the perception of duration.SIGNIFICANCE STATEMENT The subjective sense of duration does not arise in isolation, but is informed by previous experiences. This is demonstrated by abundant evidence showing that the production of duration estimates is biased toward previously experienced time intervals. However, it is yet unknown whether this temporal context actively affects perception or only asserts its influence in later, postperceptual stages as proposed by most current formal models of this task. Using an interval reproduction task, we show that EEG signatures flexibly adapt to the temporal context during perceptual encoding. Furthermore, interval history can be decoded from the transient EEG signal even when the current duration was identical. Thus, our results demonstrate that context actively influences perception.