An unusual neurological presentation in a patient with primary hypereosinophilic syndrome.

Hypereosinophilic syndromes are characterized by an increased number of blood eosinophils (usually more than 1.5 × 109) infiltrating tissues and causing organ damage through over-production of pro-inflammatory cytokines with heterogeneous clinical presentation. Here we present a case of a 47 years old male, with an unremarkable previous medical history, with a sudden onset of subungual hemorrhage and low back pain. Admitted for right arm weakness and vomiting, was raised the suspicion of acute cerebrovascular syndrome, but a brain CT scan with angiogram and perfusion sequences did not show any signs of early ischaemic lesions; conversely, lab tests revealed an increased peripheral eosinophil blood count. Clinical conditions rapidly worsened and a brain MRI showed multiple sub-acute ischaemic lesions compatible with vasculitis while EEG was in favor of widespread cortical distress. Diagnosis of the hypereosinophilic syndrome was made through peripheral blood smear and osteo-medullar biopsy, which showed a rich prevalence of eosinophils. The molecular biology testing showed FIP1L1-PDGRA gene mutation. Despite the prompt therapy beginning with intravenous corticosteroids and tyrosine-kinase inhibitors with normalization of cell blood count in a few days, the patient remained in minimal consciousness. When facing unusual symptoms onset (low back pain with weakness in one limb) and a highly impaired WBC not consistent with other courses (such as infections, vasculitis, allergies, and other diseases involving the immune system) clinicians should take into account the possibility of a hematological disorder and treat it as soon as possible to avoid a poor prognosis.

Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Progressive thrombosis of cervical and intracranial arteries related to Ponatinib treatment for Chronic Myeloid Leukemia.

Ponatinib is a third-generation Tyrosine Kinase Inhibitor (TKI), approved as first-line treatment for Chronic Myeloid Leukaemia (CML) chronic phase. Here we describe a CML patient with a history of subsequent TIAs and an ischemic stroke during Ponatinib treatment. Patient was admitted for a 3-day history of sudden onset left hemiparesis due to an acute ischemic stroke. MRI showed bilaterally the almost total absence of signal in the intracranial tract of anterior circulation and low signal of cerebral posterior circulation. Digital Subtraction Angiography showed multiple steno-occlusions of both anterior and posterior circulation large vessels. The association between cerebrovascular events and TKIs of second and third-generation has been widely described. So Ponatinib was stopped. To our knowledge, this is the first case of multiple ischemic strokes and recurrent TIAs during treatment with Ponatinib, pointing out the importance of accurate quantification of cardiovascular risk before starting Ponatinib.

Motor performance deterioration accelerates after 50 years of age in Charcot-Marie-Tooth type 1A patients.

BACKGROUND AND PURPOSE: The aim of our study was to describe, by a case-control and cross-sectional design, the correlation between clinical impairment and age in Charcot-Marie-Tooth type 1A (CMT1A) patients. METHODS: Seventy CMT1A patients and 70 sex- and age-matched healthy controls were enrolled. Motor performance was assessed through the 10-m walk test, the 6-min walk test and the 9-hole peg test of the dominant and non-dominant side, and muscle strength was measured by using the Medical Research Council score. In the CMT1A group, disability and quality of life were evaluated using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Short Form 36 (SF-36) questionnaire. Cross-sectional relationships between age and all clinical measures were analyzed and differences in the slopes between cases and controls were calculated. The occurrence of a structural change in the age-related progression of clinical measures was explored. RESULTS: The deterioration of motor performance correlated with age in both groups with a greater slope in CMT1A patients than controls. The deterioration of CMTNS and SF-36 correlated with age in the CMT1A group. The deterioration of all clinical measures with the exception of the SF-36 questionnaire showed a structural change at the 50th year of age. The rate of deterioration was no different between patients and controls until 50 years of age, whereupon it became significantly greater in CMT1A patients. CONCLUSION: Our study supports that the disease progression in CMT1A patients is an age-related process and the 50th year of age represents a critical moment after which the clinical decline becomes faster.

Can valproic acid be an inducer of clozapine metabolism?

INTRODUCTION: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. METHODS: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. RESULTS: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). DISCUSSION: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines.

The detection of recurrent mutations affecting the hormone binding domain (HBD) of estrogen receptor alpha (ERα/ESR1) in endocrine therapy-resistant and metastatic breast cancers has prompted interest in functional characterization of these genetic alterations. Here, we explored the role of HBD-ESR1 mutations in influencing the behavior of breast cancer stem cells (BCSCs), using various BC cell lines stably expressing wild-type or mutant (Y537 N, Y537S, D538G) ERα. Compared to WT-ERα clones, mutant cells showed increased CD44+/CD24- ratio, mRNA levels of stemness genes, Mammosphere Forming Efficiency (MFE), Self-Renewal and migratory capabilities. Mutant clones exhibited high expression of NOTCH receptors/ligands/target genes and blockade of NOTCH signaling reduced MFE and migratory potential. Mutant BCSC activity was dependent on ERα phosphorylation at serine 118, since its inhibition decreased MFE and NOTCH4 activation only in mutant cells. Collectively, we demonstrate that the expression of HBD-ESR1 mutations may drive BC cells to acquire stem cell traits through ER/NOTCH4 interplay. We propose the early detection of HBD-ESR1 mutations as a challenge in precision medicine strategy, suggesting the development of tailored-approaches (i.e. NOTCH inhibitors) to prevent disease development and metastatic spread in BC mutant-positive patients.

The economic burden of preventable adverse drug reactions: a systematic review of observational studies.

INTRODUCTION: Adverse drug reactions (ADRs) are an important cause of morbidity and mortality worldwide. They are associated with healthcare costs due to hospital admissions or prolonged length of stay, as well as additional interventions. The aim of this study was to conduct a systematic review of observational studies to evaluate the economic impact of preventable ADRs. AREAS COVERED: Published observational research investigating the cost of preventable ADRs in Western countries (limited to the USA and European countries). EXPERT OPINION: Several reviews have been carried out in the field of the ADR epidemiology but fewer reviews have investigated the economic impact of ADRs, and at the time of writing, none has focused on preventable ADRs. The reason why future research should focus on the costs of preventable ADRs is that both the costs and the negative clinical outcomes are preventable, and as such, are a key point of public health policy action. Nevertheless, the present review highlights an important and sobering limitation of published research on the cost of preventable ADRs, of which the major limitation is the heterogeneity in methods and in reporting which limit what can be known through the summarizing work of a systematic review.

The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study.

Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results, the present 24-week double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 200 mg/day of lamotrigine or a placebo. A final sample of fifty-one patients completed the study. The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative, positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.

Prescribing patterns of antiepileptic drugs in Italy: a nationwide population-based study in the years 2000-2005.

To evaluate prevalence of use and prescribing patterns of antiepileptic drugs (AEDs) in Italian general practice. Primary care data were obtained from the Health Search Database, a longitudinal observational database implemented by the Italian College of General Practitioners (GPs). We selected 465 061 subjects registered by the end of 2005 in the lists of 320 GPs, homogeneously distributed throughout Italy. Prevalence of AED use was assessed in the entire sample and by drug type, age group, year and main geographic area (north, centre and south/islands). Overall, 24 383 subjects (5.2%) received at least one AED prescription in the study period. Prevalence of AED use (with 95% confidence interval) increased progressively from 7.1 (6.9-7.3) in 2000 to 11.8 (11.5-12.1) in 2005 for old AEDs and from 1.1 (1.0-1.2) to 12.2 (11.9-12.5) for new AEDs. Carbamazepine, phenobarbital and valproic acid were the most common AEDs until 2003, when gabapentin became first. There were no differences in prescribing patterns in the three main geographic areas. Newer AEDs were mostly used in patients aged 65 years and older. The more widespread use of newer AEDs was for mood disorders or pain. Older AED currently remain first line drugs for epileptic disorders. An increasing use of AEDs has been recently observed over a 6-year period in Italian general practice, mostly explained by newer compounds used for conditions other than epilepsy.

Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators.

The disposition of a 25 mg single oral dose of desipramine was investigated in five rapid and four slow hydroxylators of debrisoquin before and during oral administration of 1200 mg cimetidine daily. AUC and elimination half-life of desipramine increased during cimetidine administration in rapid but not in slow hydroxylators. This was the result of a decrease in overall clearance. The urinary recovery of 2-hydroxydesipramine was significantly decreased in rapid hydroxylators during cimetidine administration. We conclude that cimetidine inhibits the metabolism of desipramine in rapid but not in slow hydroxylators.

Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype.

The 2-hydroxylation of desmethylimipramine (DMI) was studied in 14 healthy subjects previously phenotyped with respect to debrisoquin hydroxylation. After a single oral dose (25 mg), slow hydroxylators of debrisoquin had significantly lower total and metabolic clearances and longer plasma half-lives of DMI and excreted less 2-hydroxydesmethylimipramine than did rapid hydroxylators. These findings strengthen the hypothesis that the hydroxylations of debrisoquin and DMI may be under common enzymatic control.

Inhibition of desipramine 2-hydroxylation by quinidine and quinine.

Urinary excretion of desipramine (DMI) and 2-hydroxydesipramine (2-OH-DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2-OH-DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2-OH-DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2-OH-DMI. At similar does the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2-hydroxylation.

Severe phenytoin intoxication in a subject homozygous for CYP2C9*3.

A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.

Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers.

The effect of fluvoxamine on the pharmacokinetics of diazepam and metabolically derived N-desmethyl-diazepam was investigated in eight healthy volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the control session, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p < 0.01). Although peak plasma N-desmethyldiazepam levels were similar in the two sessions, the time required for the metabolite to reach a peak was longer during fluvoxamine intake than in the control session (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under the plasma concentration-time curve values were also significantly increased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethylated metabolite. The magnitude of this interaction is likely to have considerable clinical significance.

Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes.

The 2-hydroxylation of desmethylimipramine (DMI) and the 4-hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2-hydroxydesmethylimipramine (2-OH-DMI) levels were determined by HPLC. The urinary ratio DMI/2-OH-DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4-hydroxydebrisoquine (D/4-OH-D). The two hydroxylations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2-hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P-450 isozyme.