Cost-benefit effectiveness of angiotensin-II receptor blockers in patients with uncomplicated hypertension: A comparative analysis.

OBJECTIVE: The treatment of hypertensive patients (HTs) requires a long-term commitment of compliance for the patient and resources by the healthcare system. This poses an economic dilemma in countries where universal healthcare is standard. The aim of this study was to evaluate the costs/health benefit and effectiveness of treatment with angiotensin-II receptor blockers (ARBs) in uncomplicated essential hypertension. DESIGN AND METHODS: The daily and annual economic commitment for treating patients with ARBs was estimated using pharmacy dispensing records and the BP-lowering effects of candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan was evaluated retrospectively. In 114 HTs (mean age 59.4±13.5year, 57.5% men), the BP-lowering effect of ARBs as in monotherapy and in fixed-dose combination (FDC) with hydrochlorothiazide at the doses commonly used in the market to reach BP control (i.e. BP <140/90mmHg) was analyzed. The BP lowering-effect was evaluated after an average of 6-month follow-up consulting medical professionals. Analysis of variance for repeated measures was provided. RESULTS: Treatment with candesartan (14.1%) and olmesartan (32,4%) versus other ARBs resulted in a significant decrease in BP as for mono- than for FDC therapy. Our studies suggest that daily (data not shown) and annual costs of olmesartan were higher than candesartan as in mono- (4577.71±1120.55 vs. 894.25±127.75 €) than for FDC therapy (5715.90±459.90 vs. 1580.45±113.15 €). CONCLUSIONS: Treatment: of BP with candesartan appears to be the most favorable option in terms of cost-effectiveness coupled with favorable health outcomes. These data have some limitations, but open the question if candesartan should be preferred to olmesartan in BP management. Further prospective studies comparing ARBs based on their effect on BP control in uncomplicated HTs are needed for validation.

Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis.

Dendritic targeting of mRNA and local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. Here, we demonstrate that epileptogenic stimuli induce a dramatic accumulation of BDNF mRNA and protein in the dendrites of hippocampal neurons in vivo. BDNF mRNA and protein accumulate in dendrites in all hippocampal subfields after pilocarpine seizures and in selected subfields after other epileptogenic stimuli (kainate and kindling). BDNF accumulates selectively in discrete dendritic laminas, suggesting targeting to synapses that are active during seizures. Dendritic targeting of BDNF mRNA occurs during the time when the cellular changes that underlie epilepsy are occurring and is not seen after intense stimuli that are non-epileptogenic, including electroconvulsive seizures and high-frequency stimulation. MK801, an NMDA receptor antagonist that can prevent epileptogenesis but not acute seizures, prevents the dendritic accumulation of BDNF mRNA, indicating that dendritic targeting is mediated via NMDA receptor activation. Together, these results suggest that dendritic accumulation of BDNF mRNA and protein plays a critical role in the cellular changes leading to epilepsy.

Involvement of the neuropeptide nociceptin/orphanin FQ in kainate seizures.

The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been shown to modulate neuronal excitability and neurotransmitter release. Previous studies indicate that the mRNA levels for the N/OFQ precursor (proN/OFQ) are increased after seizures. However, it is unclear whether N/OFQ plays a role in seizure expression. Therefore, (1) we analyzed proN/OFQ mRNA levels and NOP (the N/OFQ receptor) mRNA levels and receptor density in the kainate model of epilepsy, using Northern blot analysis, in situ hybridization, and receptor binding assay, and (2) we examined susceptibility to kainate seizure in mice treated with 1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-benzimidazol-2-one (J-113397), a selective NOP receptor antagonist, and in proN/OFQ knock-out mice. After kainate administration, increased proN/OFQ gene expression was observed in the reticular nucleus of the thalamus and in the medial nucleus of the amygdala. In contrast, NOP mRNA levels and receptor density decreased in the amygdala, hippocampus, thalamus, and cortex. Mice treated with the NOP receptor antagonist J-113397 displayed reduced susceptibility to kainate-induced seizures (i.e., significant reduction of behavioral seizure scores). N/OFQ knock-out mice were less susceptible to kainate seizures compared with their wild-type littermates, in that lethality was reduced, latency to generalized seizure onset was prolonged, and behavioral seizure scores decreased. Intracerebroventricular administration of N/OFQ prevented reduced susceptibility to kainate seizures in N/OFQ knock-out mice. These data indicate that acute limbic seizures are associated with increased N/OFQ release in selected areas, causing downregulation of NOP receptors and activation of N/OFQ biosynthesis, and support the notion that the N/OFQ-NOP system plays a facilitatory role in kainate seizure expression.

Autoradiographic analysis of rat brain kinin B1 and B2 receptors: normal distribution and alterations induced by epilepsy.

Kindling-induced seizures constitute an experimental model of human temporal lobe epilepsy that is associated with changes in the expression of several inflammatory proteins and/or their receptors in distinct brain regions. In the present study, alterations of kinin receptors in the brain of amygdaloid-kindled rats were assessed by means of in vitro autoradiography, using (125)I-labeled 3-4 hydroxyphenyl-propionyl-desArg(9)-D-Arg degrees -[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin (B(1) receptors) and (125)I-labeled 3-4 hydroxyphenyl-propionyl-D-Arg degrees -[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin (B(2) receptors) as ligands. Results demonstrate that B(2) receptors are widely distributed throughout the brain of control rats. The highest densities were observed in lateral septal nucleus, median preoptic nucleus, dentate gyrus, amygdala, spinal trigeminal nucleus, mediovestibular nucleus, inferior cerebellar peduncles, and in most of cortical regions (0.81-1.4 fmol/mg tissue). In contrast, very low densities of B(1) receptors were detected in all analyzed areas from control rats (0.18-0.26 fmol/mg tissue). When assessed in kindled rats, specific binding sites for B(2) receptors were significantly decreased (41 to 76%) in various brain areas. Conversely, B(1) receptor binding sites were markedly increased in kindled rats, especially in hippocampus (CA2 congruent with CA1 congruent with CA3), Amy and entorhinal, peririnal/piriform, and occipital cortices (152-258%). Data show for the first time that kindling-induced epilepsy results in a significant decline of B(2) receptor binding sites, accompanied by a striking increase of B(1) receptor labeling in the rat brain. An altered balance between B(1) and B(2) receptor populations may play a pivotal role in the onset and/or maintenance of epilepsy.

On the role of somatostatin in seizure control: clues from the hippocampus.

The role of the hippocampal somatostatin (somatotropin release-inhibiting factor, SRIF) system in the control of partial complex seizures is discussed in this review. The SRIF system plays a role in the inhibitory modulation of hippocampal circuitries under normal conditions: 1) SRIF neurons in the dentate gyrus are part of a negative feedback circuit modulating the firing rate of granule cells; 2) SRIF released in CA3 interacts both with presynaptic receptors located on associational/commissural terminals and with postsynaptic receptors located on pyramidal cell dendrites, reducing excitability of pyramidal neurons; 3) in CA1, SRIF exerts a feedback inhibition and reduces the excitatory drive on pyramidal neurons. Significant changes in the hippocampal SRIF system have been documented in experimental models of temporal lobe epilepsy (TLE), in particular in the kindling and in the kainate models. SRIF biosynthesis and release are increased in the kindled hippocampus, especially in the dentate gyrus. This hyper-function may be instrumental to control the latent hyperexcitability of the kindled brain, preventing excessive discharge of the principal neurons and the occurrence of spontaneous seizures. In contrast, the hippocampal SRIF system undergoes damage in the dentate gyrus following kainate-induced status epilepticus. Although surviving SRIF neurons appear to hyperfunction, the loss of hilar SRIF interneurons may compromise inhibitory mechanisms in the dentate gyrus, facilitating the occurrence of spontaneous seizures. In keeping with these data, pharmacological activation of SRIF1 (sst2) receptors, i.e. of the prominent receptor subtype on granule cells, exerts antiseizure effects. Taken together, the data presented suggest that the hippocampal SRIF system plays a role in the control of partial complex seizures and, therefore, that it may be proposed as a therapeutic target for TLE.

Mechanisms of action of CHF3381 in the forebrain.

(1) Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. (2) CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly -80% of the NMDA-evoked current, with EC(50) of approximately 5 micro M. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. (3) CHF3381 also inhibited voltage-gated Na(+) currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 micro M). (4) Consistent with the mild effects on voltage-gated Na(+) channels, CHF3381 (100 micro M) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anti-convulsant agent and Na(+) channel blocker lamotrigine (100 micro M) inhibited stimulation-evoked glutamate overflow by approximately 50%. (5) CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. (6) The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.

Delayed epileptogenesis in nociceptin/orphanin FQ-deficient mice.

The neuropeptide nociceptin/orphanin FQ (N/OFQ) is implicated in many biological functions, including nociception, locomotor activity, stress and anxiety, drinking and food-intake. N/OFQ has also been reported to play a facilitatory role in acute kainate-induced seizures. The aim of the present study was to investigate its involvement in a chronic model of temporal lobe epilepsy, kindling epileptogenesis, using N/OFQ knock-out mice and their wild-type littermates as controls. Kindling development was retarded in N/OFQ-deficient mice, in that (compared with controls) they required a significantly greater number of stimulations and a significantly longer time in electrical seizures to reach kindling criteria. These data indicate that N/OFQ is involved in the development of kindling and that it may play a pro-epileptogenic role.

Pro-nociceptin/orphanin FQ and NOP receptor mRNA levels in the forebrain of food deprived rats.

Forebrain injections of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor, previously referred to as ORL1 or OP4 receptor, stimulate feeding in freely feeding rats, while the NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH(2) inhibits food deprivation-induced feeding. To further evaluate whether the N/OFQ-NOP receptor system plays a physiological role in feeding control, the present study evaluated forebrain mRNA levels for the N/OFQ precursor (pro-N/OFQ), as well as for the NOP receptor in food deprived rats. The results obtained show that food deprived rats have lower mRNA levels for the NOP receptor in several forebrain regions; a significant reduction was found in the paraventricular and lateral hypothalamic nuclei and in the central nucleus of the amygdala. Food deprived rats also exhibited lower pro-N/OFQ mRNA levels in the central amygdala. These results suggest that the N/OFQ-NOP receptor system may have a physiological role in feeding control. The observation that food deprivation reduces gene expression of the N/OFQ-NOP receptor system is apparently not consistent with a direct hyperphagic action for N/OFQ. Taking into account that N/OFQ exerts inhibitory actions at cellular level, the present results may be in keeping with the hypothesis that N/OFQ stimulates feeding by inhibiting neurons inhibitory for food intake; under conditions of food deprivation, these neurons may be silent and the N/OFQ-NOP receptor system, which controls them, may also be regulated at a lower level. Consistently, in the present study N/OFQ stimulated food intake in freely feeding rats, but did not further increase feeding in food deprived rats.

Changes in NPY-mediated modulation of hippocampal [3H]D-aspartate outflow in the kindling model of epilepsy.

The anticonvulsant effect of NPY may depend on Y(2) and/or Y(5) receptor-mediated inhibition of glutamate release in critical areas, such as the hippocampus. However, Y(2) and Y(5) receptor levels have been reported to increase and decrease, respectively, in the epileptic hippocampus, implicating that the profile of NPY effects may change accordingly. The aim of this study was to evaluate the differential effects of NPY on glutamate release in the normal and in the epileptic hippocampus. Thus, we pharmacologically characterized the effects of NPY on the release of [(3)H]D-aspartate, a valid marker of endogenous glutamate, from synaptosomes prepared from the whole hippocampus and from the three hippocampal subregions (dentate gyrus and CA1 and CA3 subfields) of control and kindled rats, killed 1 week after the last stimulus-evoked seizure. In the whole hippocampus, NPY does not significantly affect stimulus-evoked [(3)H]D-aspartate overflow. In synaptosomes prepared from control rats, NPY significantly inhibited 15 mM K(+)-evoked [(3)H]D-aspartate overflow only in the CA1 subfield (approx. -30%). Both Y(2) and Y(5) receptor antagonists (respectively, 1 microM BIIE0246 and 1 microM CGP71683A) prevented this effect, suggesting the involvement of both receptor types. In contrast, in synaptosomes prepared from kindled rats NPY significantly inhibited 15 mM K(+)-evoked [(3)H]D-aspartate overflow in the CA1 subfield and in the dentate gyrus (approx. -30%). Only the Y(2) (not the Y(5)) antagonist prevented these effects. These data indicate a critical role for the Y(2) receptor in the inhibitory control of glutamate release in the kindled hippocampus and, thus, suggest that the anticonvulsant effect of NPY in the epileptic brain is most likely Y(2), but not Y(5), receptor-mediated.