Cumulative effects of penfluridol, a long-acting neuroleptic drug, as assayed by its behavioral actions. (1/11)

Penfluridol, a long-acting neuroleptic drug, was repeatedly given to rats well trained on the discriminated avoidance schedule (intertrial interval, 25 sec; warning duration, 5 sec), and accumulation of the effects were investigated by observing the behavioral changes. When penfluridol was orally given in a dose of 2-8 mg/kg once daily for 10 consecutive days, the suppression of avoidance response was progressively enhanced until the 3rd-4th day. But from the 4th day, the maximum level of suppression was maintained during the later medication. On its withdrawal, the avoidance response was gradually restored, returning to the initial level in 3-4 days. When 8 mg/kg was given at 1-2 weeks after the withdrawal, the same suppression was observed as after the single administration of the same dose. The progressive enhancement of suppression in the early half of the medication period evidently indicated the cumulative effect. The degree of suppression during the plateau showed a linear correlation with the dosage, and was estimated to be about 3,5 times as high as in the corresponding single administration.  (+info)

Dual pharmacological properties of a cyclic AMP-sensitive potassium channel. (2/11)

Bovine adrenal zona fasciculata cells express a novel K+ current (IAC) that sets the resting potential while it couples adrenocorticotropin and angiotensin II receptors to membrane depolarization and cortisol secretion. IAC is distinctive among K+ channels both in its activation by ATP and its inhibition by cyclic AMP. Whole-cell and single-channel patch-clamp recording was used to establish a pharmacological profile of IAC K+ channels. IAC was blocked by antagonists of cyclic nucleotide-gated channels, including the diphenylbutylpiperidine (DPBP) antipsychotic pimozide and l-cis-diltiazem. Other DPBPs, including penfluridol and fluspirilene, also potently inhibited this channel. The inhibition of IAC by DPBPs was selective because 200-fold higher concentrations of penfluridol were required to inhibit voltage-gated IA K+ channels in adrenal zona fasciculata cells. Standard K+ channel antagonists blocked IAC at concentrations 100- to 100,000-fold higher than the DPBPs. IAC channels were also inhibited by the sulfonylureas glyburide and tolbutamide but at concentrations higher than those that typically block ATP-sensitive inward rectifier K+ channels. Overall, the relative order of potency and associated IC50 values for IAC antagonists were as follows: penfluridol (0.187 microM) > fluspirilene (0.232 microM) > pimozide (0.354 microM) >> l-cis-diltiazem (24.9 microM) approximately quinidine (24.1 microM) > bupivacaine (113.2 microM) > tolbutamide (784.4 microM) > BaCl2 (1027 microM) > 4-aminopyridine (2750 microM) > tetraethylammonium (24,270 microM). IAC channels are unique in combining the pharmacological properties of K+-selective channels with those of cyclic nucleotide-gated cation channels. The potent block of IAC channels identifies DPBPs as a new class of K+ channel antagonists and suggests additional targets for these neuroleptics in the central nervous system.  (+info)

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand. (3/11)

The drug sensitivity characteristics and Plasmodium falciparum pfmdr1 status of five isolates of P. falciparum recently isolated from patients presenting for treatment from the Thailand/Myanmar border have been investigated. The aim of the study was to avoid the criticisms of some earlier studies by focusing on newly collected isolates from a specific geographic location. Three of the isolates studied exhibited clear resistance to chloroquine similar to that observed in the K1 Thai standard isolate obtained in the 1970s, and the other two isolates were of intermediate sensitivity to chloroquine with concentrations of drug that inhibit parasite growth by 50% of 50 and 43 nmol. The sensitivity of all isolates was enhanced by verapamil but we found no clear association between chloroquine sensitivity and gene copy number or intra-allelic variation of pfmdr1. In contrast, clear cross-resistance was seen between mefloquine and halofantrine, with the most sensitive isolates carrying the K1 mutation in pfmdr1.  (+info)

Differential inhibition of T-type calcium channels by neuroleptics. (4/11)

T-type calcium channels play critical roles in cellular excitability and have been implicated in the pathogenesis of a variety of neurological disorders including epilepsy. Although there have been reports that certain neuroleptics that primarily target D2 dopamine receptors and are used to treat psychoses may also interact with T-type Ca channels, there has been no systematic examination of this phenomenon. In the present paper we provide a detailed analysis of the effects of several widely used neuroleptic agents on a family of exogenously expressed neuronal T-type Ca channels (alpha1G, alpha1H, and alpha1I subtypes). Among the neuroleptics tested, the diphenylbutylpiperidines pimozide and penfluridol were the most potent T-type channel blockers with Kd values (approximately 30-50 nm and approximately 70-100 nm, respectively), in the range of their antagonism of the D2 dopamine receptor. In contrast, the butyrophenone haloperidol was approximately 12- to 20-fold less potent at blocking the various T-type Ca channels. The diphenyldiperazine flunarizine was also less potent compared with the diphenylbutylpiperadines and preferentially blocked alpha1G and alpha1I T-type channels compared with alpha1H. The various neuroleptics did not significantly affect T-type channel activation or kinetic properties, although they shifted steady-state inactivation profiles to more negative values, indicating that these agents preferentially bind to channel inactivated states. Overall, our findings indicate that T-type Ca channels are potently blocked by a subset of neuroleptic agents and suggest that the action of these drugs on T-type Ca channels may significantly contribute to their therapeutic efficacy.  (+info)

An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1. (5/11)

Bovine adrenal zona fasciculata (AZF) cells express a background K(+) channel (I(AC)) that sets the resting potential and acts pivotally in ACTH-stimulated cortisol secretion. We have cloned a bTREK-1 (KCNK2) tandem-pore K(+) channel cDNA from AZF cells with properties that identify it as the native I(AC). The bTREK-1 cDNA is expressed robustly in AZF cells and includes transcripts of 4.9, 3.6, and 2.8 kb. In patch clamp recordings made from transiently transfected cells, bTREK-1 displayed distinctive properties of I(AC) in AZF cells. Specifically, bTREK-1 currents were outwardly rectifying with a large instantaneous and smaller time-dependent component. Similar to I(AC), bTREK-1 increased spontaneously in amplitude over many minutes of whole cell recording and was blocked potently by Ca(2+) antagonists including penfluridol and mibefradil and by 8-(4-chlorophenylthio)-cAMP. Unitary TREK-1 and I(AC) currents were nearly identical in amplitude. The native I(AC) current, in turn, displayed properties that together are specific to TREK-1 K(+) channels. These include activation by intracellular acidification, enhancement by the neuroprotective agent riluzole, and outward rectification. bTREK-1 current differed from native K(+) current only in its lack of ATP dependence. In contrast to I(AC), the current density of bTREK-1 in human embryonic kidney-293 cells was not increased by raising pipette ATP from 0.1 to 5 mm. Further, the enhancement of I(AC) current in AZF cells by low pH and riluzole was facilitated by, and dependent on, ATP at millimolar concentrations in the pipette solution. Overall, these results establish the identity of I(AC) K(+) channels, demonstrate the expression of bTREK-1 in a specific endocrine cell, identify potent new TREK-1 antagonists, and assign a pivotal role for these tandem-pore channels in the physiology of cortisol secretion. The activation of I(AC) by ATP indicates that native bTREK-1 channels may function as sensors that couple the metabolic state of the cell to membrane potential, perhaps through an associated ATP-binding protein.  (+info)

Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression. (6/11)

The effects of diphenylbutylpiperidine (DPBP) antipsychotics on Ca2+ currents and prolactin (PRL) synthesis were studied in rat pituitary growth hormone (GH) cell lines (GH3 and GH4C1). In whole-cell patch-clamp experiments, DPBPs including fluspirilene, penfluridol, and pimozide at concentrations ranging from 0.25 to 5 microM each blocked current through low threshold T-type as well as high threshold L-type channels. Each of the drugs preferentially blocked T-type current, and complete inhibition was observed at concentrations as low as 1 microM. Inhibition of L-type channels by DPBPS was enhanced at depolarized holding potentials and promoted by prolonged channel activation. At concentrations similar to those which blocked Ca2+ currents, each of the three DPBPs markedly reduced basal PRL production by GH cells. PRL synthesis stimulated by the dihydropyridine Ca2+ agonist R5417 or thyrotropin releasing hormone (TRH) was also inhibited. The inhibitory effects of the DPBPs were observed at the level of gene transcription. Penfluridol and fluspirilene inhibited basal, Ca2(+)- and TRH-stimulated expression of a fusion gene construct containing the 5'-flanking sequence of the rat PRL gene linked to the luciferase gene. The effect was concentration-dependent with the IC50 values for both drugs of less than 1 microM. Nimodipine also reduced basal, R5417, and TRH-stimulated expression of the reporter gene construct. Similar results were obtained with a reporter gene construct containing the 5'-flanking sequence of the rat GH gene. The GH luciferase construct was only slightly responsive to R5417 and TRH; however, these responses were reduced by fluspirilene and nimodipine at concentrations of less than 1 microM. These studies demonstrate that the DPBP antipsychotics block T- as well as L-type Ca2+ channels in GH cells and inhibit PRL production at the level of transcription. They also indicate that functioning Ca2+ channels are necessary for TRH-stimulated PRL gene transcription.  (+info)

Evaluation of penfluridol in hospitalised chronic schizophrenic. (7/11)

Thirty chronic schizophrenic patients completed 12 week treatment with a single weekly dose of 20 mg penfluridol, a new long acting oral neuroleptic. The patients were evaluated by using modified rating scale. Significant reduction in scores was demonstrated in 15 out of 26 symptom variables. Few side effects were reported which were easily controlled by conventional antiparkinson agents. Laboratory investigations remained within normal limits.  (+info)

Calcium-dependent inhibition of adrenal TREK-1 channels by angiotensin II and ionomycin. (8/11)

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