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Background We studied the comparative effectiveness of biosimilar filgrastim vs original filgrastim in patients with chemotherapy-induced neutropenia. Patients and methods This multicenter, observational study was conducted at 14 centers. The study included 337 patients experiencing neutropenia under chemotherapy. Patients were given either filgrastim 30 MIU or 48 MIU (Neupogen®) or biosimilar filgrastim 30 MIU (Leucostim®). Data regarding age, chemotherapeutic agents used, number of chemotherapy courses, previous diagnosis of neutropenia, neutrophil count of patients after treatment, medications used for the treatment of neutropenia, and duration of neutropenia were collected. Time to absolute neutrophil count (ANC) recovery was the primary efficacy measure. Results Ambulatory and hospitalized patients comprised 11.3% and 45.1% of the enrolled patients, respectively, and a previous diagnosis of neutropenia was reported in 49.3% of the patients, as well. Neutropenia occurred in 13.7% (n=41), 45.5% (n=136), 27.4% (n=82), 11.4% (n=34), and 2.0% (n=6) of the patients during the first, second, third, fourth, and fifth cycles of chemotherapy, respectively. While the mean neutrophil count was 0.53±0.48 before treatment, a significant increase to 2.44±0.66 was observed after treatment (p=0.0001). While 90.3% of patients had a neutrophil count, Video abstract

Rosuvastatin, is a widely-used statin for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases. Although rosuvastatin is well tolerated, about 3/10.000 patients can suffer severe myopathy. Rhabdomyolysis is a severe medical condition that causes injury to the skeletal muscle, electrolyte imbalances, acute renal failure and extreme creatine kinase (CK) elevation. Little is known regarding the molecular involvement of rosuvastatin-induced rhabdomyolysis (RIR). It has been demonstrated that genomic variants associated with decreased enzymatic activity of proteins are important determinants in plasmatic and skeletal muscle distribution of rosuvastatin and its toxicity. Until now, no interactions of ticagrelor, ezetimibe and rosuvastatin have been described with the consideration of pharmacogenomics predisposition. The present report involves a whole-exome sequencing (WES), in a patient affected by rosuvastatin-induced rhabdomyolysis. A pharmacogenomic dissection was performed by analyzing a comprehensive subset of candidate genes (n=160) potentially related to RIR. The genes were selected according to their implication in drug metabolism or inherited myopathies. Using an innovative approach of bioinformatics analysis, considering rare and common variants, we identified 19 genomic variations potentially related to the pharmacokinetic/pharmacodynamic modifications of rosuvastatin, ezetimibe and ticagrelor. The affected genes are involved in Phase I metabolism (CYP2C19, CYP2E1, CYP1A1, CYP2D6 and CYP2C9), Phase II metabolism (UGT2B15 and UGT2B7), influx transportation (SLCO1B3 and SLCO2B1), efflux transportation (ABCG8, ABCB11, ABCC4 and ABCB1), drug targeting (NPC1L1) and inherited myopathy etiology (OBSCN). We report three rare, potentially pathogenic molecular variants in CYP2C19, NPC1L1 and OBSCN genes. Pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles in several pharmacogenes involved in drug toxicity. The whole-exome sequencing and bioinformatics analysis presented here represents an innovative way to identify genomic variants contributing with RIR´s origin and evokes the polygenic nature of adverse drug reactions. © 2020 Calderon-Ospina et al.

By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia.

By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia.

cited By 2; International audience; What is known and objective: The complex dose regimens of the direct-acting oral anticoagulants (DOAC) make their appropriate prescribing highly challenging. Inappropriate prescribing of the DOAC remains poorly addressed. We studied the patterns of DOAC prescription and estimated the prevalence of drug-related problems (DRPs) associated with their use. Methods: A cross-sectional study was conducted using data from medical records system of the Lyon teaching hospitals. DRPs, identified among patients who received a DOAC, between 1 January 2010 and 31 July 2013, were categorized according to the Pharmaceutical Care Network Europe Classification System. The prevalence of hospital stays with a DRP was estimated, and a subgroup analysis according to DOAC and their indication for use was provided. Clinical outcomes were not assessed. Results: Of the 4154 hospital stays with at least one DOAC administration [3412 patients; median age (range): 71 years (14–98), 57% female], 70·8% were excluded from the analysis mainly due to missing information for renal function and/or patient weight. Of the 1188 hospital stays that were screened, 100 DRPs were identified (prevalence 8·4%; 95% CI, 6·8–10·0). The highest prevalence was found among patients who received rivaroxaban for atrial fibrillation (14·6%; 95% CI, 10·7–18·5). A too low drug dose was the most frequent DRP (n = 56; 4·7%), followed by a too high drug dose (n = 37; 3·1%), contraindication (n = 5; 0·4%), and pharmacokinetic problem requiring dose adjustment (n = 2; 0·2%). What is new and conclusion: Drug-related problems associated with the DOACs occur quite commonly among hospitalized patients. Although these DRPs were considered to be of minor severity, prescribing protocols to support better prescribing should be disseminated to reduce the risk to patients. Renal function and body weight data should be mandatory on prescriptions to allow cross-checking. © 2016 John Wiley & Sons Ltd

By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia.

Valproic acid (VPA) is a teratogenic drug used in pregnant women for the treatment of epilepsy and mood disorders. Fetal valproate syndrome (FVS) is characterized by a number of abnormalities associated with VPA exposure in utero including neural tube defects, congenital heart defects, limb defects, genitourinary defects, brain, eye and respiratory anomalies, and abdominal wall defects. Complex cardiac defect and trigonocephaly have rarely been reported and multicystic dysplastic kidney has never been detected in FVS. We here report a female infant who was born to a mother with a history of low-dose VPA monotherapy (250 mg/day) during pregnancy and who had presented with a combination of unilateral multicystic dysplastic kidney, multicomplex cardiac defect including severe coarctation of aorta, Ebstein anomaly, secundum atrial septal defect, mesocardia along with trigonocephaly due to metopic craniosynostosis, typical facial appearance and limb defects. To our knowledge, this is the first case presented with multicystic dysplastic kidney, complex cardiac defect, trigonocephaly and other limb and facial defects because of exposure to very low-dose VPA monotherapy (250 mg/day) in utero. We conclude that VPA must be used very cautiously in pregnant women even as monotherapy and in low doses to prevent major congenital defects.

The Netherlands Pharmacovigilance Centre Lareb evaluates the reports as generated by the spontaneous adverse event reporting system in the Netherlands. This article describes the association between the adverse drug reactions (ADRs), headache and migraine and reported suspected drugs. In a case/non-case design, reporting odds ratios were calculated in order to analyse this association. Additionally the results of this analysis were compared with data from literature. Taken together, the ADRs headache and migraine are the second most reported ADR. The results of the analysis of the association between drugs and both ADRs in the Lareb data set are generally in accordance with literature data. Especially drugs causing vasodilative effects have often been associated with headache or migraine.

The Netherlands Pharmacovigilance Centre Lareb evaluates the reports as generated by the spontaneous adverse event reporting system in the Netherlands. This article describes the association between the adverse drug reactions (ADRs), headache and migraine and reported suspected drugs. In a case/non-case design, reporting odds ratios were calculated in order to analyse this association. Additionally the results of this analysis were compared with data from literature. Taken together, the ADRs headache and migraine are the second most reported ADR. The results of the analysis of the association between drugs and both ADRs in the Lareb data set are generally in accordance with literature data. Especially drugs causing vasodilative effects have often been associated with headache or migraine.

Shortly before the all- trans retinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m2 IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m2 IDA daily for 4 days combined with 200 mg/m2 Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR ( P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively ( P = .0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone ( P = .0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/μL ( P = .0001) and increasing age ( P = .0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.

Purpose: The combination of paclitaxel and carboplatin has become a widely used regimen in NSCLC due to phase II reports of moderate toxicity, reasonable activity and easy outpatient administration. Purpose of our present prospective study was to evaluate the dose-response relationship of paclitaxel. Patients and methods: Since July 1996, 198 patients with non-operable NSCLC and measurable disease without previous chemotherapy entered the trial. Ninety nine patients (group A) were randomized to receive paclitaxel 175 mg/m2 in three-hour infusion plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks and 99 (group B) to receive the same regimen with paclitaxel increased to 225 mg/m2. Eligibility criteria included WHO performance status 0-2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis, no prior chemotherapy and adequate renal and hepatic function. Patients in both groups were well-matched with baseline disease characteristics. Results: In group A with 90 evaluable patients, the response rate was 25.6%(6 CR, 17 PR) whereas in group B with 88 evaluable patients, the response rate was 31.8% (3 CR, 25 PR), P = 0.733. Median time to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months, P = 0.044). The median survival was 9.5 months for group A versus 11.4 months for group B (P = 0.16). The one-year survival was 37% for group A and 44% for group B (P = 0.35). The best prognostic factor for one-year survival was the response rate (P < 0.0001). With a relative dose intensity of paclitaxel 0.94 in both groups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038) were more pronounced in group B patients. No toxic death was observed. Conclusions: Higher dose paclitaxel prolongs the median time to progression but causes more neurotoxicity and leucopenia. The better response rate, the longer overall and better one-year survival seen with the higher dose of paclitaxel are not statistically significant. 11 7 799 805

This article reviews the results of an exploratory study on the relationship between the ratings of bradykinesia, obtained by the Schedule for the Assessment of Drug-Induced Movement Disorders (SADIMoD), and the performances on writing and drawing tasks. The pen movements made during these tasks were recorded by means of an electronic digitizing tablet, a special electronic pen and a personal computer. This study was aimed at finding objective parameters for the severity of (antipsychotic-induced) bradykinesia. The results show that the writing tablet device is appropriate at finding movement variables that are related to the clinical ratings for bradykinesia: high scores for bradykinesia involved slowing on a number of duration measures during the execution of the writing and drawing tasks. We were also able to measure (postural) tremor by means of the writing tablet. However, an accelerometer seems to be more appropriate in this respect.

This article reviews the results of an exploratory study on the relationship between the ratings of bradykinesia, obtained by the Schedule for the Assessment of Drug-Induced Movement Disorders (SADIMoD), and the performances on writing and drawing tasks. The pen movements made during these tasks were recorded by means of an electronic digitizing tablet, a special electronic pen and a personal computer. This study was aimed at finding objective parameters for the severity of (antipsychotic-induced) bradykinesia. The results show that the writing tablet device is appropriate at finding movement variables that are related to the clinical ratings for bradykinesia: high scores for bradykinesia involved slowing on a number of duration measures during the execution of the writing and drawing tasks. We were also able to measure (postural) tremor by means of the writing tablet. However, an accelerometer seems to be more appropriate in this respect.

Acute heart failure following itraconazole use: a case report A 44year old woman was admitted to the cardiology department of the Medical Centre Leeuwarden, the Netherlands, with acute heart failure. She had developed dyspnoea that began one week after start of itraconazole oral therapy once daily 200 mg for treatment of onychomycosis. Salbutamol and prednisolone were prescribed, but this gave no improvement in the symptoms. She stopped after four weeks with the itraconazole treatment, but seven weeks later she was admitted to the cardiology department with heart failure NYHA class 4. The electrocardiogram showed a moderate left ventricular function, while heart valves and coronary arteries showed no abnormalities in morphology and function. Troponin levels were not elevated. Treatment with candesartan and furosemide started, supported by a reduced intake of fluids and a low sodium diet. Two weeks later the patient was again admitted with dyspnoea. Seven months after the start of the symptoms the patient was still using candesartan. Besides kidney cysts (since 1985) the patient had no other comorbidities and used no medication. Her kidney function was stable for many years [creatinine 62 μmol/L, eGFR 85 mL/(min·1.73 m2)]. The Naranjo score was 4, which indicates itraconazole being a 'possible' cause of the acute heart failure. In several articles itraconazole is mentioned as possible cause of heart failure, but the mechanism is unknown. The side effect does not seem to be related to azole antimycotics in general. In patients with acute heart failure and/or dyspnoea and itraconazole usage, the side effect has to be taken into account in the differential diagnosis as a possible cause.

Background: Ciclosporin has proven to be effective in patients with corticosteroid-refractory ulcerative colitis (UC). When therapy with this drug fails, infliximab can be considered to avoid colectomy. The efficacy and safety of this sequential approach remain unknown. Aim To assess the efficacy and safety profile of treatment with infliximab after failure of ciclosporin in patients with a corticosteroid-refractory flare of UC. Methods Retrospective review of medical records of patients with a corticosteroid-refractory flare of UC who did not respond to ciclosporin and received salvage therapy with infliximab within a month of discontinuing ciclosporin. The severity of the flare and response to the treatment were graded using the Lichtiger index. Cumulative rates of colectomy were calculated using Kaplan-Meier analysis. Cox regression analysis was performed to identify predictors of colectomy. To evaluate the safety profile of this treatment strategy, any adverse event occurring after the first infusion of infliximab was considered. Results The study population comprised 47 patients with corticosteroid-refractory UC treated with infliximab after failure of ciclosporin. The median baseline Lichtiger index was 13. The mean time from the last ciclosporin dose to the first infliximab infusion was 6 days. After the first infliximab infusion, 13% of patients achieved remission, and 74% partial response. Of the 35 patients who received the third infliximab infusion, 60% achieved remission, and 37% partial response. Fourteen patients (30%) underwent colectomy. The rate of adverse events was 23%. One death occurred in a 40-year-old man who failed ciclosporin and infliximab and underwent surgery 10 days after the first infliximab infusion; he died of nosocomial pneumonia. Conclusions Treatment with infliximab makes it possible to avoid colectomy in two-thirds of corticosteroid-refractory UC patients in whom ciclosporin fails. However, the rates of adverse events and mortality mean that the decision to administer sequential therapy (ciclosporin-infliximab) should be taken on an individual basis. © 2011 Blackwell Publishing Ltd.

De diagnose depressie wordt vaak gesteld in de huisartspraktijk. Het merendeel van deze patienten wordt door de huisarts zelf behandeld, in een kwart van de gevallen medicamenteus. Hoewel de NHG-Standaard Depressie anders adviseert, worden hiervoor sinds 1995 vooral selectieve serotonineheropnameremmers (SSRI’s) gebruikt. Patienten die SSRI’s gebruiken kunnen als bijwerking van het geneesmiddel een verminderde eetlust vertonen. Dit verschijnsel treedt vooral op in de eerste week van het gebruik van het geneesmiddel en verdwijnt bij staken van het middel en als regel na 2 tot 4 weken bij voortgezette behandeling.

[EN] Background: Platinum doublets are standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether neutropenia is: (1) an indicator for treatment efficacy, or (2) associated with specific polymorphisms. Patients and Methods: Four hundred ninety-four patients, treated with cisplatin-docetaxel were retrospectively analyzed. Relative dose intensity (RDI) was assessed for both drugs. Neutrophil counts were assessed only on Day 21 of each cycle. Genotyping was performed for 4 different polymorphisms in ERCC1, XRCC3, XPD-23, and XPD-10. Results: The median overall survival was 9 months. The mean RDI was 0.94 for cisplatin and 0.93 for docetaxel. Four hundred three patients received ¿ 3 cycles of chemotherapy, and 239 received ¿ 6 cycles. Thirty-one percent developed neutropenia, and 19% had Grade (G)3-4 neutropenia. RDI was lower in patients with neutropenia (G1-4; 0.87-0.93) when compared with those without (G0; 0.94-0.95; P

The antiapoptotic effect of melatonin has been described in several systems. In this study, the antagonistic effect of the methoxyindole on dexamethasone-induced apoptosis in mouse thymocytes was examined. Melatonin decreased both DNA fragmentation, and the number of annexin V-positive cells incubated in the presence of dexamethasone. Analysis of the expression of the members of the Bcl-2 family indicated that the synthetic glucocorticoid increased Bax protein levels without affecting the levels of Bcl-2, Bcl-X L, Bcl-X S, or Bak. This effect correlated with an increase in thymocytes bax mRNA levels. Dexamethasone also increased the release of cytochrome C from mitochondria. All of these effects were reduced in the presence of melatonin, which was ineffective per se on these parameters. In addition, the involvement of cAMP on glucocorticoid/melatonin antagonism was examined. Both melatonin and dexamethasone decreased the levels of this nucleotide in mouse thymocytes, indicating that the antagonistic action between both hormones involves a cAMP-independent pathway. In summary, the present results suggest that the antiapoptotic effect of melatonin on glucocorticoid-treated thymocytes would be a consequence of an inhibition of the mitochondrial pathway, presumably through the regulation of Bax protein levels. Fil:Hoijman, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rocha Viegas, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rosenstein, R.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Cisplatin (CDDP) is one of the most commonly used antineoplastic agents in current clinical practice. The major toxicities of CDDP are nonhaematological as nephrotoxicity and ototoxicity. Free oxygen radicals are known to play major role in CDDP-induced acute renal failure in rats. α-Tocopherol is one of the well-known antioxidant agents. This study was designed to investigate the role of α-tocopherol pretreatment against CDDP-induced lipid peroxidation in rat kidney. Male Wistar rats were divided into three groups and treated as follows: control (saline intraperitoneally), CDDP (10 mg/kg, intraperitoneally), α-tocopherol (200 mg/kg, plus CDDP, intraperitoneally). Rats were sacrificed on third day of the treatment, and kidney tissues were obtained and analyzed. CDDP-treated rats showed high malondialdehyde (MDA) levels (p< 0.05). In the CDDP plus α-tocopherol group, renal MDA levels were not significantly different from the controls. These data suggest that α-tocopherol may be used to prevent CDDP-induced lipid peroxidation.

Cisplatin (CDDP) is one of the most commonly used antineoplastic agents in current clinical practice. The major toxicities of CDDP are nonhaematological as nephrotoxicity and ototoxicity. Free oxygen radicals are known to play major role in CDDP-induced acute renal failure in rats. ?-Tocopherol is one of the well-known antioxidant agents. This study was designed to investigate the role of ?-tocopherol pretreatment against CDDP-induced lipid peroxidation in rat kidney. Male Wistar rats were divided into three groups and treated as follows: control (saline intraperitoneally), CDDP (10 mg/kg, intraperitoneally), ?-tocopherol (200 mg/kg, plus CDDP, intraperitoneally). Rats were sacrificed on third day of the treatment, and kidney tissues were obtained and analyzed. CDDP-treated rats showed high malondialdehyde (MDA) levels (p< 0.05). In the CDDP plus ?-tocopherol group, renal MDA levels were not significantly different from the controls. These data suggest that ?-tocopherol may be used to prevent CDDP-induced lipid peroxidation.

Acute heart failure following itraconazole use: a case report A 44year old woman was admitted to the cardiology department of the Medical Centre Leeuwarden, the Netherlands, with acute heart failure. She had developed dyspnoea that began one week after start of itraconazole oral therapy once daily 200 mg for treatment of onychomycosis. Salbutamol and prednisolone were prescribed, but this gave no improvement in the symptoms. She stopped after four weeks with the itraconazole treatment, but seven weeks later she was admitted to the cardiology department with heart failure NYHA class 4. The electrocardiogram showed a moderate left ventricular function, while heart valves and coronary arteries showed no abnormalities in morphology and function. Troponin levels were not elevated. Treatment with candesartan and furosemide started, supported by a reduced intake of fluids and a low sodium diet. Two weeks later the patient was again admitted with dyspnoea. Seven months after the start of the symptoms the patient was still using candesartan. Besides kidney cysts (since 1985) the patient had no other comorbidities and used no medication. Her kidney function was stable for many years [creatinine 62 μmol/L, eGFR 85 mL/(min·1.73 m2)]. The Naranjo score was 4, which indicates itraconazole being a 'possible' cause of the acute heart failure. In several articles itraconazole is mentioned as possible cause of heart failure, but the mechanism is unknown. The side effect does not seem to be related to azole antimycotics in general. In patients with acute heart failure and/or dyspnoea and itraconazole usage, the side effect has to be taken into account in the differential diagnosis as a possible cause.

Acute heart failure following itraconazole use: a case report A 44year old woman was admitted to the cardiology department of the Medical Centre Leeuwarden, the Netherlands, with acute heart failure. She had developed dyspnoea that began one week after start of itraconazole oral therapy once daily 200 mg for treatment of onychomycosis. Salbutamol and prednisolone were prescribed, but this gave no improvement in the symptoms. She stopped after four weeks with the itraconazole treatment, but seven weeks later she was admitted to the cardiology department with heart failure NYHA class 4. The electrocardiogram showed a moderate left ventricular function, while heart valves and coronary arteries showed no abnormalities in morphology and function. Troponin levels were not elevated. Treatment with candesartan and furosemide started, supported by a reduced intake of fluids and a low sodium diet. Two weeks later the patient was again admitted with dyspnoea. Seven months after the start of the symptoms the patient was still using candesartan. Besides kidney cysts (since 1985) the patient had no other comorbidities and used no medication. Her kidney function was stable for many years [creatinine 62 μmol/L, eGFR 85 mL/(min·1.73 m2)]. The Naranjo score was 4, which indicates itraconazole being a 'possible' cause of the acute heart failure. In several articles itraconazole is mentioned as possible cause of heart failure, but the mechanism is unknown. The side effect does not seem to be related to azole antimycotics in general. In patients with acute heart failure and/or dyspnoea and itraconazole usage, the side effect has to be taken into account in the differential diagnosis as a possible cause.

Atypical antipsychotics is known to cause a number of adverse metabolic effects, including weight gain, insulin resistance, hyperglycemia, dyslipidemia and type 2 diabetes mellitus. Aripiprazole is an new atypical antipsychotic that has a safer profile compared to other antipsychotic medications with regard to its effect on weight gain, glucose tolerance and prolactin level. However, recently there have been few case reports on hiperglisemia and diabetic ketoacidosis related by aripiprazole. In this report, we discuss a clinical case with tip 1 diabetes mellitus that developed hiperglisemia during aripiprazole treatment. © 2015, Istanbul Universitesi. All rights reserved.

We aimed to investigate the possible convulsant action of arginine vasopressin (AVP) in both a febrile convulsion model in rat pups and a temporal lobe epilepsy model in adult rats and to define the receptor type which mediates this effect. In rat pups, 125 ng V-2 receptor antagonist significantly prevented hyperthermic seizures, but did not affect seizure latency. In adult rats, the only effective dose and agent was 125 ng V-2 receptor antagonist, which prevented pilocarpine-induced status epilepticus, extended the status epilepticus latency and improved the 24 h survival rate. These data suggest that AVP has a convulsant activity in febrile convulsions and also in seizures independent of fever, and this effect is mediated by V-2 receptors.

We report a 61-year-old woman with a 1-year-history of widespread erythematous scaly patches and plaques as well as red/purplish to brownish confluent plaques. Ulcerated lesions with a purulent, hemorrhagic exudate and sharp elevated borders were located on the lower extremities. Diagnosis of granulomatous mycosis fungoides was supported by histopathologic findings showing an inflammatory reaction with epithelioid and large giant cells associated with features characteristic of mycosis fungoides. Immunohistochemical studies showed a T-helper phenotype of neoplastic cells (CD3+, CD4+, CD45RO+) with expression of the cytotoxic protein TIA-1. Molecular analysis of TCRgamma gene demonstrated a monoclonal rearrangement in the lesional skin. After failure of conventional therapies, 6 cycles of gemcitabine treatment produced partial remission of cutaneous lesions and stable disease throughout a 12-month follow-up period, suggesting that gemcitabine is a promising chemotherapeutic agent for refractory mycosis fungoides.

The Netherlands Pharmacovigilance Centre Lareb evaluates the reports as generated by the spontaneous adverse event reporting system in the Netherlands. This article describes the association between the adverse drug reactions (ADRs), headache and migraine and reported suspected drugs. In a case/non-case design, reporting odds ratios were calculated in order to analyse this association. Additionally the results of this analysis were compared with data from literature. Taken together, the ADRs headache and migraine are the second most reported ADR. The results of the analysis of the association between drugs and both ADRs in the Lareb data set are generally in accordance with literature data. Especially drugs causing vasodilative effects have often been associated with headache or migraine.

AIM: In this study we aimed to clarify the role of mast cells in the development and progression of inflammation in cerulein-induced acute pancreatitis (AP) in rats. We have also examined the effects of ketotifen; a mast-cell stabilizing agent in the treatment of acute pancreatitis and its relation with nitric oxide (NO) synthesis. METHODS: In the first part of the study we planned to examine the effects mast cell stabilization in acute pancreatitis, while the second part was focused on examining the relation between NO synthesis and the potential effects of ketotifen in AP. Wistar albino rats were randomly divided into 6 groups (n: 10). In the first part of the study, AP was induced by four subcutaneous (sc) injections of 20 microg/kg body weight of cerulein at hourly intervals in Groups A and B while Group C was treated with saline as the control group. Group B was pretreated with ketotifen 1 mg/kg (ip). In the second part, the study design was similar except for the inhibition of nitric oxide synthesis by N-nitro L-arginine methyl ester (L-NAME) 30 mg/kg (ip) in Groups D, E and F. Group D was treated with L-NAME and cerulein and Group E was treated with ketotifen, L-NAME and cerulein. Group F was treated with L-NAME and saline as the control group. Serum amylase activity and pancreatic myeloperoxidase activity (MPO) were measured. Pancreatic histology and mast-cell count in pancreatic tissue were evaluated. RESULTS: Mast cell count was found to be increased in the pancreatic tissue in cerulein-induced AP. (2.93+/-0.26 vs 1.98+/-0.26; p

Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m-2, vincristine 2 mg, E 70 mg m-2 on day 1 and prednisone 60 mg on days 1-7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m-2. Randomization was stratified according to stages I-IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P=0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P=0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate- and high-grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients. 68 3 135 143

Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharmacokinetic profile in a larger population, to estimate individual pharmacokinetic parameters and to investigate relationships with clinical outcome. A sparse sampling method was applied during course one, which involved two sampling time-points. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) and volume of distribution. In total, samples were collected of 109 (63%) of 173 patients. Pharmacokinetic-dynamic evaluation could be carried out successfully in 85 (78%) of the sampled patients. CL of lurtotecan showed substantial variability (mean 87 +/- 28 L/h) and was of the same magnitude as in the phase I studies where full pharmacokinetic curves were used. Residual variability in the population estimate of CL was 9.9%. No significant relationships were observed between exposure parameters and toxicity nor likelihood of tumor response, however the latter relationship may well have been obscured by the heterogeneity of the studied population. Prospective implementation of large scale population pharmacokinetic-dynamic analysis is feasible and important to establish whether interpatient variability in drug exposure is a major determinant of toxicity or activity. Invest New Drugs

Citalopram is one of the newer and most potent selective serotonin re-uptake inhibitor (SSRI) drugs. It has a well-established antidepressive action with a favorable adverse event profile. We present a fifty-year-old woman with diffuse photopigmentation who had been diagnosed as suffering from depression. The patient was given citalopram (40 mg/day) for her psychiatric condition and diffuse photopigmentation was noted thereafter. To our knowledge, such an adverse event has not been reported previously.

Summary Background Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity. Patients and methods Twenty-six patients (11 female/15 male, median age 56, range 23–73) were treated over the range of 25–50 mg/m2/week. Dose-limiting toxicity for this schedule was defined as any grade > 2 antiproliferative toxic effect resulting in a > 2-week delay for re-administration of the drug, or any grade > 2 organ-specific toxicity. Patients were monitored clinically and electrophysiologically for neurotoxicity. No prolonged corticosteroid co-medication or prophylactic haematopoietic growth factors were given. Results A median/mean number of 8.5/8.7 consecutive weekly courses were given per patient. The maximum tolerated dose that prevented on-schedule administration of the drug was 50 mg/m2. The main cumulative toxicities were a mild fluid retention and dacryorrhea which became evident as the number of treatment courses increased. Grade 2 alopecia and fatigue were observed only at 45 mg/m2 and higher. Activity was seen at all of the dose levels studied. Conclusions Long-term weekly administration of docetaxel is feasible at doses up to 45 mg/m2/week with acceptable toxicity. Further clinical evaluation is justified at this schedule and 40 mg/m2/week of docetaxel is proposed for phase II studies as an active dose with minimal toxicity.

Biochemical, histopathological and cell culture evaluations compared the nephrotoxicity of cefazolin with that of gentamicin. New Zealand rabbits were dosed with 250 mg cefazolin/animal im twice daily, 3 mg gentamicin/kg im twice daily, or 0.9% NaCl solution for 10 d. The rabbits in drug-treated groups had necrosis of proximal kidney tubules and elevated urinary-gamma glutamyl transferase (uGGT) levels. The results of the histopathological examinations, uGGT analyses and effects in cell culture indicated the nephrotoxicities of both antibiotics were similar.

This article reviews the results of an exploratory study on the relationship between the ratings of bradykinesia, obtained by the Schedule for the Assessment of Drug-Induced Movement Disorders (SADIMoD), and the performances on writing and drawing tasks. The pen movements made during these tasks were recorded by means of an electronic digitizing tablet, a special electronic pen and a personal computer. This study was aimed at finding objective parameters for the severity of (antipsychotic-induced) bradykinesia. The results show that the writing tablet device is appropriate at finding movement variables that are related to the clinical ratings for bradykinesia: high scores for bradykinesia involved slowing on a number of duration measures during the execution of the writing and drawing tasks. We were also able to measure (postural) tremor by means of the writing tablet. However, an accelerometer seems to be more appropriate in this respect.

Background and objective: To compare the application of the cuffed oropharyngeal airway and the laryngeal mask airway on anaesthetized adult patients undergoing minor outpatient surgery. Methods: One hundred patients received intravenous fentanyl, propofol and N2O for the induction and maintenance of anaesthesia. The patients were randomly divided into two groups: a cuffed oropharyngeal airway group (n = 50) and a laryngeal mask airway group (n = 50). After insertion of the device, fibreoptic laryngoscopy was attempted and the degree of success scored. We then compared the first application success rate of both procedures while judging airway intervention requirement, fibreoptic scores, adverse airway events and haemodynamic tolerance. Results: Both devices had an almost similar first-time placement rate (cuffed oropharyngeal airway 84% versus laryngeal mask airway 96%). The cuffed oropharyngeal airway required a higher number of airway interventions (P < 0.001). The laryngeal mask airway had a significantly better fibreoptic view compared with the cuffed oropharyngeal airway (P < 0.001). However, the number of adverse airway events was lower in the cuffed oropharyngeal airway group; there were no significant differences in adverse events and haemodynamic variables between the said two groups. Conclusions: The results suggest that the cuffed oropharyngeal airway was an effective alternative airway in spontaneously breathing patients during short procedures.