A prospective, randomized, open-label trial comparing telmisartan 80 mg with valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring.

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of telmisartan 80 mg with valsartan 80 mg throughout a 24 h dosing interval. DESIGN: A prospective, randomized, open-label, blinded end point, parallel group study. Treatment efficacy was compared using ambulatory blood pressure monitoring (ABPM), cuff sphygmomanometry and calculated responder rates. Tolerability was assessed by physical examination, laboratory parameters, 12-lead electrocardiogram, blood pressure and heart rate monitoring, and evaluation of adverse events. SETTING: Thirty-five centres in the United States. PATIENTS: Four hundred and twenty-six patients with mild to moderate essential hypertension entered the study. Ninety-two per cent (n=393) completed the study. INTERVENTIONS: Patients underwent a four-week, single-blind, placebo run-in period before being randomly assigned to once-daily oral telmisartan 80 mg (n=214) or valsartan 80 mg (n=212) for an eight-week, open-label treatment period. RESULTS: Treatment with telmisartan was associated with a significantly greater mean reduction from baseline in the last 6 h ABPM mean for diastolic blood pressure compared with the valsartan-treated group (-7.5+/-0.6 mmHg versus -5.2+/-0.6 mmHg, respectively, P<0.01). Secondary analyses showed significantly greater efficacy with telmisartan 80 mg than with valsartan 80 mg, including greater mean reductions from baseline of ABPM (systolic blood pressure and diastolic blood pressure) during the daytime (06:00 to 21:59) and morning (06:00 to11:59) hours, and larger decreases in trough cuff blood pressure (P<0.01). Both treatments showed placebo-like tolerability profiles. CONCLUSIONS: Telmisartan 80 mg once daily was superior to valsartan 80 mg once daily in reducing diastolic blood pressure during the last 6 h of the 24 h dosing interval. These results may be due to telmisartan's longer plasma half-life or to a higher potency compared with valsartan, such that a higher dose of valsartan may produce effects similar to those of 80 mg telmisartan. These data confirm the long duration of action of telmisartan with consistent and sustained control of blood pressure over 24 h and during the last 6 h of the dosing interval. Both treatments were well tolerated; the adverse event data confirmed the excellent tolerability profiles of telmisartan and valsartan that have been reported previously.

A role for sigma binding in the antipsychotic profile of BMY 14802?

BMY 14802 was identified as a potential antipsychotic drug in traditional model systems, and this identification was confirmed in modern behavioral and electrophysiological systems. The drug appears to be atypical as an antipsychotic in its lack of activity in models predictive of the potential to produce extrapyramidal side effects and tardive dyskinesia. Indeed, this suggestion is corroborated by clinical findings to date. The atypical profile of BMY 14802 extends to its neurochemical actions and appears to find its basis in regionally selective, indirect modulation of the dopamine system. Furthermore, BMY 14802 exhibits interactions with sigma binding sites in vitro and in vivo, a notion supported by data from neurophysiological, behavioral, and biochemical investigations. BMY 14802 also appears to be neuroprotective in some model systems and may have utility in the treatment of stroke (Boissard et al. 1991). BMY 14802 appears to interact with 5-HT1A receptors, but this interaction does not seem to contribute significantly to the potential antipsychotic actions of the drug. Moreover, the formation of active metabolites of BMY 14802 does not appear to occur in animals or humans to an extent of physiological or behavioral relevance. If clinically efficacious, BMY 14802 may treat the symptoms of schizophrenia by a mechanism novel for antipsychotic drugs: regionally selective, indirect modulation of dopaminergic systems by specific interaction at sigma sites.

Short forms of the "reference-" and "working-memory" Morris water maze for assessing age-related deficits.

Short forms of the reference- and working-memory versions of the Morris water maze, each limited to 10 trials, were examined for their reliability and sensitivity to age-related deficits in 16- and 24-month F-344 rats, relative to 2- to 2.5-month young controls. The reference-memory task used long intertrial intervals of 23 h, but required learning only one target location, while the working-memory task used shorter intertrial intervals of 60 min but required learning many different target locations. The reference-memory task was very reliable, revealed large age-related deficits, and correctly identified almost all aged rats as impaired relative to young controls. The working-memory task was less reliable, revealed smaller deficits than the reference memory task at 24 months, and did not discriminate as well between 2.5- and 24-month rats. Furthermore, in the working-memory task 16- and 24-month rats had longer swim paths than 2- to 2.5-month rats on the first trial of each trial pair, which is suggestive of a deficit in processing spatial information and raises questions about the validity of this test as a specific test of working memory. Although the working-memory procedures may be preferable under certain conditions, perhaps as a measure specific to hippocampal dysfunction, the reference-memory task seems more sensitive to age-related deficits and more accurately identifies older rats as impaired. These results are consistent with previous reports that age-related deficits in acquiring spatial learning tasks are common and that the magnitude of the deficit increases as the length of the retention interval increases.

A 1-heteroaryl-4-piperidinyl-methyl pyrrolidinone, BMY 21502, delays the decay of hippocampal synaptic potentiation in vitro.

The effects of the substituted pyrrolidinone, BMY 21502, on the properties of cell membranes, synaptic transmission and synaptic plasticity, were assessed in area CA1 of hippocampal slices from the rat. Application of the compound to the bath had no consistent direct effects on parameters of the cell membrane or evoked synaptic potentials, at concentrations of less than 30 microM. In a blind experimental design, BMY 21502 at 1.0 and 10 microM, but not 25 microM, significantly delayed the decay of long-term potentiation in slices obtained from young animals; in slices obtained from very old rats (2.5-3.2 yr), 10 microM BMY 21502 significantly delayed decay of long-term potentiation. Therefore BMY 21502 was active in a physiological model that may predict of cognitive enhancement.

Acute administration of the antidepressant trazodone increases noradrenergic locus coeruleus neuronal firing in rats.

Extracellular single-unit recordings were made from noradrenergic locus coeruleus neurons in chloral hydrate-anesthetized male Sprague-Dawley rats. Acute intravenous administration of the antidepressant trazodone produced a mild excitation of firing of these cells (ED25 = 0.128 mg/kg; ED50 = 0.659 mg/kg). These findings, in combination with previous work showing that trazodone inhibits the firing of serotonergic dorsal raphe neurons indicate that trazodone modulates monoaminergic neuronal activity in the brain and suggest a unique electrophysiological profile for this drug among antidepressants.

The adenosine antagonist 8-cyclopentyltheophylline reduces the depression of hippocampal neuronal responses during hypoxia.

Exposure of rat hippocampal slices to hypoxic conditions for 15 min produced a rapid, profound, but completely reversible depression of evoked synaptic potentials. The specific A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) significantly reduced hypoxia-induced synaptic depression in a concentration-dependent manner. It is concluded that adenosine, which is neuroprotective when exogenously applied during severe hypoxia because of its ability to depress synaptic transmission, may have an important and exploitable endogenous role in the protection of sensitive neurons.

Effects of a potential antipsychotic, BMY 14802, on firing of central serotonergic and noradrenergic neurons in rats.

BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazinebutanol HCl) is a novel potential antipsychotic drug which does not bind to dopamine receptors, does bind to 5-HT1A receptors, and also binds stereoselectively to sigma sites. The effects of acute systemic administration of this compound on spontaneously firing serotonergic dorsal raphe neurons and noradrenergic locus coeruleus neurons were assessed by means of extracellular single unit recordings in chloral hydrate anesthetized male Sprague-Dawley rats. (+/-)-BMY 14802 produced inhibition of firing of serotonergic dorsal raphe neurons when given intravenously (ED50 = 0.19 mg/kg) and intragastrically (effective dose = 20 mg/kg). Racemic and enantiomeric BMY 14802 mainly produced mild increases in firing (approximately 60% or less) of noradrenergic locus coeruleus neurons, with (-)-BMY 14802 slightly more potent (ED25 = 0.31 mg/kg i.v.) than (+)-BMY 14802 (ED25 = 0.55 mg/kg i.v.), and the racemate being intermediate (ED25 = 0.36 mg/kg i.v.). These electrophysiological studies demonstrate that in this rat preparation acute systemic administration of BMY 14802 produces changes in serotonergic and noradrenergic brain function.

The thieno[3,2-c]pyridine and furo[3,2-c]pyridine rings: new pharmacophores with potential antipsychotic activity.

Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.

Inhibition of serotonergic dorsal raphe neurons by systemic and iontophoretic administration of buspirone, a non-benzodiazepine anxiolytic drug.

Extracellular single-unit recordings were made from serotonergic dorsal raphe neurons in chloral hydrate anesthetized male Sprague-Dawley rats. Buspirone, a clinically effective non-benzodiazepine anxiolytic drug, caused inhibition of firing of these neurons when given by intravenous (ED50 = 0.011 mg/kg, i.v.), intraperitoneal (ED50 = 0.088 mg/kg, i.p.), and intragastric (effective dose = 1.0-20.0 mg/kg, i.g.) injection. Buspirone also inhibited these cells when it was administered to the outside of recorded neurons by microiontophoresis (effective currents = 2-15 nA). Iontophoretically applied buspirone did not potentiate nor block the effects of iontophoretically applied GABA. Systemic administration of two putative buspirone metabolites (1,2-pyrimidinyl piperazine and 5-hydroxy buspirone) in relatively high doses had a weak effect and no effect, respectively, on dorsal raphe neuronal firing. It is concluded that buspirone potently and directly inhibits the firing of serotonergic dorsal raphe neurons in the rat. Since buspirone inhibits the firing of serotonergic dorsal raphe neurons and binds to 5-HT1A receptors, the present study supports the notion that central serotonergic systems may be involved in the therapeutic effects of anxiolytic drugs.

Buspirone analogues. 2. Structure-activity relationships of aromatic imide derivatives.

Several analogues of the novel anxiolytic buspirone were synthesized and evaluated in vivo for tranquilizing activity and their ability to reverse neuroleptic-induced catalepsy. The in vitro binding affinities of these compounds were also examined for both the alpha 1 and dopamine D2 receptor systems. The general structure-activity relationships of this series highlight compounds 17, 21, and 32 as having anticonflict activity. Each of these structures contains the 1-(2-pyrimidinyl)piperazine moiety linked by a tetramethylene chain to a variable cyclic imide moiety. Compound 32 (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) was found to be equipotent with buspirone in its anxiolytic activity and was therefore selected for extensive preclinical characterization. The pharmacology of buspirone and 32 is contrasted, and the potent serotonin agonist properties of 32 are discussed with reference to its potential contribution to the anxioselective mechanism of this compound.

Pharmacological and clinical effects of buspirone.

Clinical trials have demonstrated that buspirone (BuSpar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or chlorazepate. Buspirone has a unique structure and a pharmacologic profile which distinguishes it from the benzodiazepines. Because it lacks the anticonvulsant, sedative, and muscle-relaxant properties associated with other anxiolytics, buspirone has been termed "anxioselective." Animal studies suggest that it lacks potential for abuse, and this finding is supported by clinical investigations. Further preclinical work supports the contention that buspirone lacks liability to produce physical dependence or to significantly interact with central nervous system depressants such as ethanol. Moreover, biochemical investigations have not identified any direct interaction of buspirone with the benzodiazepine-gamma-aminobutyric acid-chloride ionophore complex. Pharmacologic studies on the molecular level indicate that buspirone interacts with dopamine and serotonin receptors. Recent behavioral, electrophysiological, and biochemical studies have clearly demonstrated that early hypotheses that buspirone might be considered a neuroleptic are no longer tenable. Recent evidence indicates that other neurotransmitter systems (serotonin, norepinephrine, acetylcholine) mediate buspirone's effects. It is hoped that future studies can define the mechanism by which buspirone alleviates the clinical manifestations of anxiety.

Neuropharmacology of buspirone.

Buspirone is a clinically effective anxiolytic with a unique structure and pharmacology which distinguishes it from the benzodiazepines. It has been termed anxioselective because it lacks anticonvulsant, sedative, or muscle-relaxant properties. Preclinical evidence suggests it lacks potential for abuse or physical dependence and interacts minimally with CNS depressants such as alcohol. Rather than working through traditional benzodiazepine mechanisms, buspirone affects diverse aspects of the brain's neurochemical circuitry. For example, it exerts potent influences on the nigrostriatal and mesolimbic dopamine systems, the dorsal raphe serotonergic system, and the locus coeruleus noradrenergic system. Although without direct receptor interaction, potentiation of cholinergically mediated behavior and involvement with GABAergic neurotransmission have also been demonstrated.

Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices.

Extracellular and intracellular recordings were made from dorsal raphe (DR) neurons in frontal rat brain slices maintained in vitro. A population of neurons was found which displayed electrophysiological and pharmacological characteristics of serotonin-containing DR neurons recorded in vivo. Recorded extracellularly, these neurons displayed biphasic or triphasic action potentials of 1.5-3.0 ms duration, and discharged with a slow and steady rhythm. Recorded intracellularly these neurons displayed action potentials of about 1.8 ms duration, which were followed by large (10-20 mV) after hyperpolarizations which normally lasted 200-800 ms. These presumed serotonergic DR neurons were inhibited by LSD and serotonin. They were excited by norepinephrine, or the alpha-agonist phenylephrine, and these activations could be reduced or blocked by alpha-adrenoreceptor antagonists including the selective alpha 1-antagonist, prazosin. The major difference between the in vitro recordings and previous in vivo recordings from anesthetized animals was a reduction in the number of spontaneously firing DR neurons. This was probably due, at least in part, to a disfacilitation of serotonergic DR neurons in the slice caused by the functional removal of a tonic noradrenergic input.

Intracellular studies on the role of calcium in regulating the activity and reactivity of locus coeruleus neurons in vivo.

EGTA, a specific calcium chelator, was injected intracellularly into presumed noradrenergic neurons of the rat locus coeruleus to evaluate the importance of calcium-dependent processes in regulating the activity and reactivity of these cells in vivo. The amplitude and duration of postactivation after hyperpolarizations induced by intracellular depolarizing pulses were markedly reduced in EGTA-treated cells; this change was associated with: (1) an increase in spontaneous firing rate; (2) a reduction in postactivation inhibition of firing; and (3) an increased reactivity to sensory stimulation. In control cells the reversal potential of the after hyperpolarization was at least 25 mV below 'resting' levels, indicating that an increase in potassium conductance was probably involved. Since EGTA virtually abolished the after hyperpolarization, the data are consistent with the concept that the after hyperpolarization is mediated by a calcium-activated potassium current. A calcium-dependent release of norepinephrine acting via alpha 2-adrenoceptors might also contribute to the after hyperpolarization. In conclusion, the influx of calcium into locus coeruleus neurons appears to serve a negative feedback function in the regulation of both spontaneous activity and reactivity to orthodromic stimulation.

Morphine tolerance and dependence in the locus coeruleus: single cell studies in brain slices.

Extracellular single unit recordings in vitro from the locus coeruleus in rat brainstem slices revealed the presence of spontaneously active neurons. These cells fired between 0.1 and 3.0 spikes/s and were inhibited by nM concentrations of morphine and clonidine. Locus coeruleus neurons in slices from animals treated chronically, but not subacutely, with morphine exhibited a significant decrease in sensitivity to morphine. This tolerance appeared to be specific for opiates since no decrease in sensitivity was seen for the alpha 2-adrenoceptor agonist clonidine. However, in contrast to what has been reported in vivo, no signs of dependence (withdrawal activation) were evident in slices from morphine tolerant animals.

Intracellular identification of central noradrenergic and serotonergic neurons by a new double labeling procedure.

The purpose of this study was to ascertain the identity of presumed noradrenergic or serotonergic neurons recorded by single cell techniques in the mammalian brain. A double labeling method was developed in which intracellular injections of a red fluorescing dye (ethidium bromide) could be co-localized with the formaldehyde-induced green fluorescence of norepinephrine or yellow fluorescence of serotonin. By this method, neurons of the rat locus coeruleus that display a characteristic activation-inhibition response to noxious stimuli were confirmed to be noradrenergic; the slow, rhythmically firing neurons of the dorsal raphe nucleus were confirmed to be serotonergic.

Serotonin-induced depolarization of rat facial motoneurons in vivo: comparison with amino acid transmitters.

Intracellular recordings were obtained from facial motoneurons in anesthetized rats. The effects of iontophoretically applied serotonin were compared to those of the excitatory amino acids glutamate and DL-homocysteic acid (DLH), and the inhibitory amino acids, glycine, GABA and muscimol, under various conditions of membrane polarization and intracellular chloride concentration. Iontophortically applied serotonin caused a depolarization of facial motoneurons which was accompanied by increased input resistance and increased neuronal excitability. Experiments comparing the response to serotonin with those of glycine, GABA, and muscimol demonstrated that the serotonin effect does not involve changes in membrane conductance to chloride. Comparisons of serotonin with glutamate and DLH at varying levels of membrane hyperpolarization indicated that the serotonin-induced depolarization is not caused by increased conductance to sodium or calcium, and differs in its underlying ionic mechanism from depolarizations induced by glutamate and DLH. Results were consistent with the hypothesis that serotonin causes depolarization, increased input resistance, and increased excitability in rat facial motoneurons by decreasing resting membrane conductance to potassium ions. Such changes in motoneurons in the brain stem and spinal cord probably account for some of the physiological and behavioral effects observed during pharmacological activation of serotonin receptors.