Enea Traini

Nimodipine and Its Use in Cerebrovascular Disease: Evidence from Recent Preclinical and Controlled Clinical Studies

Nimodipine is a 1,4-dihydropyridine-derivative Ca2+-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca2+-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospam in SAH patients.

Dopamine, vesicular transporters and dopamine receptor expression and localization in rat thymus and spleen

The localization of dopamine stores and the expression and localization of vesicular monoamine transporter (VMAT) type-1 and 2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat thymus and spleen by immunohistochemical, immunochemical techniques and by RT-PCR. In the thymus dopamine immunoreactivity was developed in the cortico-medullary junction and in the medulla, but not in the thymic cortex. In the spleen, dopamine stores were found in reticular structures in the white pulp border and in the white pulp, but not in the red one. Both thymus and spleen expressed VMAT-1 and VMAT-2 immunoreactivity as well as dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity. Immunohistochemistry revealed VMAT-1, VMAT-2 and dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity primarily in the thymic cortical-medulla transitional zone and to a lesser extent in the medulla but not in the cortex. In the spleen, VMAT-1, VMAT-2 and dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity was located primarily in the white pulp border and to a lesser extent in the white pulp. These findings indicate that both thymus and spleen express a dopaminergic system characterized by the presence of dopamine, vesicular monoamine transporters and the five subtypes of dopamine receptors. The presence of these dopaminergic markers suggests that dopamine likely originating from immune cells and/or from sympathetic neuroeffector plexus is released in the lymphoid microenvironment. Based on the microanatomical localization of dopaminergic markers investigated, a role of dopamine in maturation and selection of lymphocytes and activation of immune responses is suggested.

Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimers disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

Leucocyte Subset Redistribution in a Human Model of Physical Stress

This study has investigated, under controlled conditions, peripheral mononuclear cells (PMNC) subset redistribution in a human experimental stress model consisting of cycloergometer activity in healthy male volunteers exposed to a stressful stimulus. After stressful stimuli, leucocyte subpopulations undergo a stereotyped redistribution peculiar for each PMNC cytotype. PMNC subpopulations involved to a greater extent were natural killer (NK) cells and lymphocytes T “memory” cells. The post-stress period was characterized by a decrease of the NK subpopulation. Our findings confirm the view of a sensible functional reduction of immunocompetence in stress conditions. This brings to the opening, even if for a short time, an “immunological window.”. This window remains open throughout the time of the stimulus, probably representing the basis of the progressive reduction of the competency of immune system. Catecholamines support the acute effects of stress influencing the anatomical redistribution of lymphocyte subpopulation and intermediating acute effects on PMNC. Cortisol, acting for longer time, contributes to create and maintain both the neutrocytosis and lymphopenia in the post-stress period following lymphocytosis.

Effect of growth factors and steroid hormones on heme oxygenase and cyclin D1 expression in primary astroglial cell cultures

Astrocyte activity may be modulated by steroid hormones and GFs. This study investigates the interaction between glucocorticoids or estrogens and GFs on the expression of heme oxygenase‐1 (HO‐1) and cyclin D1 in astrocyte cultures at 14 days treated for 48 or 60 hr with dexamethasone (DEX) or 48 hr with 17β‐estradiol (E2) alone or with GFs added only in the last 12 or 24 hr. Twelve‐ or twenty‐four‐hour epidermal growth factor (EGF) treatment significantly enhanced HO‐1 expression in astrocyte cultures pretreated for 48 hr with DEX. A highly significant increase in HO‐1 expression was obtained after the last‐12‐hr EGF treatment in 48‐hr E2‐pretreated astrocyte cultures; this enhancement was particularly significant in 48‐hr E2‐pretreated cultures as well as in the last‐12‐hr insulin‐treated ones pretreated for 48 hr with E2. Sixty‐hour DEX‐alone pretreatment as well as the last‐12‐hr EGF treatment in 60‐hr DEX‐pretreated astrocyte cultures showed a significant increase of cyclin D1 expression. A significant decrease of cyclin D1 expression in the last‐12‐hr insulin‐like growth factor‐I (IGF‐1)‐treated cultures pretreated for 60 hr with DEX was observed. A highly significant enhancement in cyclin D1 expression in 14 days in vitro astrocyte cultures pretreated with E2 alone for 48 hr and treated in the last 12 hr with IGF‐1 in 48‐hr E2‐pretreated cultures was found. Finally, the data highlight an interactive dialogue between the growth factors and glucocorticoids or estrogens during the maturation of astroglial cells in culture that may control the HO‐1 and cyclin D1 expression as well as proliferating astroglial cells during the cell cycle.

Apathy in Alzheimer’s Disease: Any Effective Treatment?

Objective. This review has evaluated the effectiveness of pharmacological treatment of apathy in patients with Alzheimers disease (AD). Methods. A systematic literature search was conducted on published clinical trials assessing the effects of pharmacological treatment on apathy in AD over the last 10 years. Results. Fourteen studies considered of good quality were included in the analysis (4 randomized controlled trials, 9 open-label studies, and 1 retrospective analysis). Cholinesterase inhibitors were investigated in 9 studies, monoaminergic compounds such as methylphenidate and modafinil in two trials and one trial, respectively, and Ginkgo biloba (EGb 761 extract) and citalopram in one study each. Cholinesterase inhibitors did not show statistical significant effect in 1 RCT study but were associated to improvement in 3 open-label studies. Methylphenidate elicited a small but significant activity accompanied by relevant side effects such as high blood pressure, cough, and osteoarticular pain. EGb 761 was well tolerated and countered apathy. Other treatments induced modest improvements or were ineffective. Conclusions. Apathy treatment remains a challenge and there is no evident advantage of any specific pharmacotherapy tested so far. The development of controlled studies according to updated guidelines for the diagnosis of apathy in patients with AD is desirable.

Nicardipine use in cerebrovascular disease: A review of controlled clinical studies

Nicardipine is a dihydropyridine-type Ca(2+) channel blocker (CCB) with strong antihypertensive activity and with a peculiar cerebrovascular profile. This paper has reviewed the main controlled clinical studies on nicardipine in pathologies associated with cerebrovascular impairment. Subarachnoid haemorrhage (SAH) is managed with CCBs to prevent vasospasm and improve clinical outcomes. Nimodipine is the CCB licensed for this indication. Former studies did not demonstrate an advantage of nicardipine versus nimodipine in SAH. A more recent approach administering the drug intra-arterially or using implants of nicardipine prolonged-release showed a decreased incidence of vasospasm, delayed ischemic deficits and improved clinical outcome after severe SAH. Nicardipine is recommended for elevated blood pressure after acute ischemic stroke or intracerebral haemorrhage and is effective in prevention of stroke. More recent investigations were focused on the treatment of cognitive deterioration of vascular origin. In this setting nicardipine has been investigated in more than 6000 patients, with improvement of cognitive deterioration in more than 60% of patients treated. The anti-hypertensive activity of nicardipine, its safety and effectiveness in cognitive domain, suggests re-considering this drug in the treatment of cognitive impairment of vascular origin and for reducing the risk of recurrent stroke in patients at high risk of it.

Morphological and conduction changes in the sciatic nerve of spontaneously hypertensive rats

The morphology and function of sciatic nerve were investigated in spontaneously hypertensive rats (SHR), either control or hydralazine-treated, and in normotensive Wistar Kyoto rats of 6 months of age. In control SHR decreased percentages of class I fibers (20-15 microm in diameter), of axonal NFP-H 200 kDa neurofilament protein immunoreactivity and of nerve conduction velocity were found. The percentages of class III (10-5 microm in diameter) and IV (<5 microm in diameter) and of S100beta-immunoreactive Schwann cell profiles were increased. Treatment with the hypotensive drug hydralazine countered sciatic nerve changes. The shift of nerve composition vs. smaller fibers is probably the cause of reduced nerve conduction velocity found in SHR and is consistent with the occurrence of a sympathetic hyper innervation in this animal model of hypertension. Our findings support the hypothesis that arterial hypertension may represent a risk factor of neuropathy.

Pharmacokinetics and bioequivalence study of two tablet formulations of lovastatin in healthy volunteers.

Lovastatin is a lipid-lowering agent indicated for primary hypercholesterolemia. This study has assessed single-dosing pharmacokinetics of lovastatin and of its main metabolite, lovastatin beta-hydroxyacid, and has compared the pharmacokinetics of two formulations of lovastatin, a test lovastatin generic (LVSG), and a reference (mevinacor 40 MSD) preparation. The pharmacokinetics and bioequivalence of the two formulations of lovastatin were evaluated by a two-way cross-over randomized double blinded study, in 36 healthy volunteers after a single oral dose of 2 × 40 mg per subject. On plasma samples, collected at given intervals of time (0–24h), lovastatin and its main active metabolite were assayed by high pressure liquid chromatography with positive turbo ion spray ionization tandem mass spectrometry detection. The pharmacokinetic parameters, area under the curve total (AUCt) and to infinity (AUCinf), peak plasma concentration (Cmax), time to attain peak (tmax), and elimination half-life (t1/2) were determined and analyzed statistically. Only minor differences in the pharmacokinetics of lovastatin and lovastatin hydroxyacid between LVSG and mevinacor were found. Analysis of variance (ANOVA) did not show any significant difference between the two formulations, and 90% confidence intervals fell within the acceptable range for bioequivalence. The tolerability profile was good and comparable for the two formulations of lovastatin. Our study, which was performed with the largest number of subjects compared with those published in literature, indicates the bioequivalence of LVSG and mevinacor tablets. The high inter-subject variability of parameters investigated indicate the need of appropriate sample size in pharmacokinetics studies with lovastatin.

Comparative crossover, randomized, open-label bioequivalence study on the bioequivalence of two formulations of thioctic acid in healthy volunteers.

An open-label, randomized, crossover single-dose study, using two periods and two sequences with a washout period of seven days was conducted to assess the comparative bioavailability of thioctic (alpha-lipoic) acid (ALA) 600 mg formulation and that of a reference formulation. Blood samples were collected up to +6 h post dosing, the plasma was separated, and thioctic acid concentrations were determined by high-performance liquid chromatographic method with single mass spectrometry detection (HPLC-MS) and a lower limit of quantification of 190.1 ng/ml. Mean values of the individual Cmax were 1338.6 ± 751.8 ng/ml and 1215.8 ± 560.5 ng/ml for the test and reference preparations, respectively. Mean ± standard deviation (SD) total area under the curve up to the last measurable concentration (AUCt) was 3510.9 ± 1088.6 ng ×  h/ml for the test formulation and 3563.5 ± 1374.1 ng ×   h/ml for the reference formulation. Mean ± SD total area under the curve (AUCinf) was 6925.6 ± 4045.8 ng ×  h/ml for the test formulation and 7797.1 ± 5963.1 ng ×  h/ml for the reference preparation. Terminal elimination half-life was 5.68 ± 5.05 h for the test and 6.11 ± 6.15 h for the reference formulations. Time of maximum concentration (tmax) was 1.24 ± 1.23 h for the test and 2.05 ± 1.21 h for the reference formulations. Ninety percent confidence intervals were comprised within the bioequivalence acceptance criteria (80–125%) for all of the parameters analyzed except tmax. The comparison between males and females showed no significant difference for the two drug treatment.