Barbara Casolla

An improved simple LC–MS/MS method for the measurement of serum aripiprazole and its major metabolite

BACKGROUND AND OBJECTIVES Current liquid chromatographic tandem mass spectrometry (LC-MS/MS) methods to measure serum levels of aripiprazole (Ar) and dehydroaripiprazole (DHAr) are sensitive, but difficult to use in a hospital context. We aimed to develop a rapid LC-MS/MS method allowing reliable level measurement in the presence of co-administered drugs, withdrawing samples from 22 patients with acute agitation receiving 9.75 mg aripiprazole IM injection. METHOD We developed a sensitive and selective HPLC-MS/MS method to measure serum Ar and DHAr levels in a hospital laboratory, requiring minimal sample preparation and inferior sample volume compared to previous LC-MS/MS methods. Analytes were separated on a reversed-phase HPLC (run-time, 10 min). A triple quadrupole tandem mass spectrometer was used for quantitative analysis in positive mode by a multiple reaction monitoring. Samples were drawn 2, 4, 6, and 24h post-injection. RESULTS Calibration curves (2-1000 ng/mL for Ar and 3.5-500 ng/mL for DHAr) were linear, with mean correlation coefficient >0.9998. Within- and between-day precision and accuracy were within 10%. Mean recovery was 95.2 ± 4.5% for Ar and 97.6 ± 7.2% for DHAr. Ar and DHAr peaks were not affected by other co-administered psychotropic drugs. CONCLUSION Our method measured Ar and DHAr concentrations reliably, simply and rapidly without employing many reagents, as currently existing methods.

Sumatriptan succinate: pharmacokinetics of different formulations in clinical practice

Introduction: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and in some patients, neurological aura symptoms. Triptans are frequently prescribed drugs for the treatment of the acute migraine attack, considering their capability to provide wide efficacy and tolerability. Areas covered: This review discusses pharmacodynamics and pharmacokinetics of sumatriptan succinate, considering the clinical impact of new drug formulations in the treatment of acute migraine and cluster headache. The data were obtained by searching the following keywords in MEDLINE: sumatriptan succinate, pharmacokinetics, pharmacodynamics, triptans, migraine, new delivery systems, relative to the period 1989 – 2012. Expert opinion: Subcutaneous sumatriptan has been considered as the most efficacious treatment in the acute phase of migraine both on pain alone as well as on associated autonomic symptoms. Pharmacologically, pharmacokinetic parameters, in particular bioavailability, Tmax and Cmax are responsible for the wide efficacy of the compound and the limited adverse effect (AE) profile. The new drug formulations that are the most similar to the pharmacokinetics parameters of the subcutaneous one are promising because they both improve pharmacokinetic bioavailability bypassing the first-pass metabolism and increase patient compliance.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis

Objective: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). Methods: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models. Results: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. Conclusions: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Pharmacokinetic evaluation of frovatriptan

Introduction: Migraine is the most common painful neurological disorder, affecting 13% of the general population. Triptans represent a powerful pharmacological tool in acute migraine treatment, however, a significant portion of treated patients cannot have access to this class due to possible adverse affects. Today, a total of seven triptan molecules are available, representing a commonly prescribed migraine treatment. Although there is a need of extensive use of triptans, only 25% of migraine patients are using triptans. Areas covered: This review includes triptans and evidence for the use of frovatriptan. A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan, considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches. The data were obtained by searching the following key words in MEDLINE: pharmacokinetic, pharmacodynamic, triptans, frovatriptan, migraine, menstrual migraine, relatively to the period 1988 – 2011. Expert opinion: Frovatriptan has been developed in order to improve safety and efficacy of triptans. It shows a favorable tolerability and efficacy profile, limited to 24/48-h headache recurrence, when compared with other triptans. Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans. In fact, among triptans, frovatriptan showed the highest potency at the 5-HT1B receptor (8.2) and the longer half-life (26 h). These parameters determine the clinical properties of frovatriptan; in particular the lowest rate of headache recurrence in comparison with other triptans.

Pharmacokinetic evaluation of almotriptan for the treatment of migraines.

Introduction: Migraine is a multifactorial neurovascular disorder characterized by recurrent episodes of disabling pain attacks, accompanied with gastrointestinal, neurological systems dysfunction. The pharmacologic treatment of migraine is classically divided in the management of the acute attack and preventive strategies. Acute treatments consist of triptan, ergot, opioid, antiemetic and NSAIDs. Areas covered: This article discusses pharmacodynamics and pharmacokinetics of zolmitriptan. The data were obtained by searching the following keywords in MEDLINE: zolmitriptan, pharmacokinetics, pharmacodynamics, triptans, migraine, menstrual-related migraine, cluster headache, relatively to the period 1989 – 2012. Expert opinion: Zolmitriptan has been considered effective treatment in the acute phase of migraine, menstrual-related migraine and cluster headache attacks. Pharmacokinetic parameters may vary as a consequence of gender differences, inter- and intra-subjects variability and delivery system. Zolmitriptan was developed with the aim of obtaining a lipophilic compound in order to be more rapidly absorbed and centrally active. Pharmacologically, pharmacokinetic parameters are responsible for its wide efficacy and the limited adverse effect profile.

The conditioned eyeblink reflex: A potential tool for the detection of cerebellar dysfunction in multiple sclerosis

The delayed conditioned eyeblink reflex, in which an individual learns to close the eyelid in response to a conditioned stimulus (e.g. a tone) relies entirely on the functional integrity of a cerebellar motor circuitry that involves the contingent activation of Purkinje cells by parallel and climbing fibres. Molecular changes that disrupt the function of this circuitry, in particular a loss of type-1 metabotropic glutamate receptors (mGlu1 receptors), occur in Purkinje cells of patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis as a result of neuroinflammation. mGlu1 receptors are required for cerebellar motor learning associated with the conditioned eyeblink reflex. We propose that the delayed paradigm of the eyeblink conditioning might be particularly valuable for the detection of subtle abnormalities of cerebellar motor learning that are clinically silent and are not associated with demyelinating lesions or axonal damage. In addition, the test might have predictive value following a clinically isolated syndrome, and might be helpful for the evaluation of the efficacy of drug treatment in multiple sclerosis.

Treatment of perimenstrual migraine with triptans: an update.

Pure menstrual migraine (PMM) and menstrually related migraine (MRM) are difficult challenges in migraine management. Triptans are a class of highly selective serotonin receptor agonists, which interfere with the pathogenesis of migraine and are effective in relieving the associated neurovegetative symptoms. In recent years triptans have been extensively proposed for the treatment of severe, disabling, and recurrent perimenstrual migraine attacks. This review summarizes the different levels of recommendations for the use of triptans in the treatment of perimenstrual migraine. This review is also intended to offer an updated reasonable guide to physicians treating perimenstrual migraine in daily practice.

Influence of Chronic Ethanol Consumption on the Neurological Severity in Patients With Acute Cerebral Ischemia

Background and Purpose— We tested the hypothesis that excessive chronic ethanol consumption is associated with more severe ischemic strokes. Methods— We recruited patients with supratentorial cerebral ischemia within 48 hours of symptom onset. We defined heavy drinkers by a weekly consumption of ethanol of ≥300 g and severe strokes by a National Institutes of Health Stroke Scale score≥6. Results— Of 436 patients, 60 were heavy drinkers. Being a heavy drinker was independently associated with baseline National Institutes of Health Stroke Scale scores ≥6 (odds ratio, 2.35; 95% confidence interval, 1.12–5.26; P=0.023) at the logistic regression analysis. This result was not modified with the propensity analysis. Conclusion— An excessive chronic ethanol consumption is associated with higher baseline stroke severity.

Stroke prediction after transient ischemic attacks in patients admitted to a stroke unit.

Background: Transient ischemic attacks (TIAs) bear a presumed high risk of early recurrence of stroke. Data in the literature, however, are inconsistent, as recurrence rates range from 9.5 to 20%, at 90 days. Aims: The study was designed to determine the risk of stroke after TIA. Methods: 94 consecutive patients referred to a Stroke Unit for TIA or minor stroke, within 24 h of symptom onset, were recruited. Eleven of the 94 patients (12%, 95% CI: 7–20%) had a relapse within 90 days. The relapse consisted of a TIA for 9 patients (10%, 95% CI: 5–17%), or of a stroke for 2 subjects (1%, 95% CI: 0–8%). More than a quarter of the relapses occurred within 1 week from the first TIA. ABCD2, ABCD2-I and ABCD-E+ scores were similar among people with or without relapse. Conclusions: The data seem to confirm previous reports on the relatively low relapse rate for stroke, when TIA patients are promptly assisted in dedicated structures. The findings stress the potential benefit of early intervention in subjects with TIA.

Chronic obstructive pulmonary disease is associated with altered neuropsychological performance in young adults.

Background: Subjects with ischemic lesions have an increased risk of dementia. In addition, Alzheimer’s disease (AD) and vascular cognitive impairment share many risk factors. These observations suggest that different diseases that cause altered blood perfusion of the brain or hypoxia promote AD neurodegeneration. In this case-control, cross-sectional study, we sought to test the hypothesis that hypoxia facilitates cognitive decline.Methods: We looked for altered neuropsychological performance in subjects with chronic obstructive pulmonary disease (COPD) without apparent cardio- or cerebrovascular diseases or risk factors for atherosclerosis. A selected, homogeneous group of workers from two ceramic factories in a small town of central Italy was enrolled in this study. Results: The COPD patients had a slightly, but significantly worse performance than controls in a number of neuropsychological tests. Conclusion: The findings are consistent with the working hypothesis that chronic hypoxia facilitates cognitive decline.