Pregnancy outcomes after exposure to tocilizumab: A retrospective analysis of 61 patients in Japan.

Mod Rheumatol. 2016 Sep;26(5):667-71

Authors: Nakajima K, Watanabe O, Mochizuki M, Nakasone A, Ishizuka N, Murashima A

Abstract
OBJECTIVES: To assess the effects of tocilizumab on pregnancy outcomes in Japanese patients with rheumatic disease.
METHODS: Data from Chugai's tocilizumab safety database (April 2005 to October 2014) were retrospectively analyzed to identify pregnancy outcomes in patients exposed to tocilizumab.
RESULTS: Data were available for 61 pregnancies exposed to tocilizumab, and outcomes were reported for 50 of those pregnancies. In 36 births, no congenital anomalies were identified; however, six neonatal abnormalities were reported: five cases of low birth weight (<2500 g) and one case of neonatal asphyxia. Of 36 births, tocilizumab was resumed during lactation in two patients, with no subsequent adverse events reported in newborns. The spontaneous abortion rate was 18.0% (9 of 50 pregnancies), which is comparable to the rate in the general population. The five terminated pregnancies included one case of caudal regression syndrome.
CONCLUSIONS: The present retrospective study of 61 pregnancies exposed to tocilizumab at conception indicated no increased rates of spontaneous abortion or congenital abnormalities in patients with rheumatic disease. However, further study is necessary to confirm the benefit-risk profile of tocilizumab treatment during pregnancy.

PMID: 26873562 [PubMed - indexed for MEDLINE]

Towards better understanding of patient centric drug product development in an increasingly older patient population.

Int J Pharm. 2016 Oct 30;512(2):334-342

Authors: Stegemann S

Abstract
The substantial reduction in premature death and longevity is an achievement of modern societies and advances in technology, medical and pharmaceutical sciences. Derived from the effective management of acute and chronic diseases throughout the lifetime the typical age related, later life stage diseases will become more dominant characteristics in future patients as well as other age related impairments or life conditions. Naturally, this leads to patients with complex clinical and functional patterns that are accompanied by the necessity of therapeutic interventions and polypharmacy. With the increasing number of older people and especially those with very high age in the society, new distinct older patient populations are evolving that require patient centered therapies and drug products to maintain safety and efficacy as well as effectiveness. Understanding how the patient populations and their characteristics change from a clinical, daily functioning and a patient perspective is crucial to move towards patient centric drug products.

PMID: 26807529 [PubMed - indexed for MEDLINE]

Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice.

Psychopharmacology (Berl). 2017 Apr 18;:

Authors: Montalvo-Ortiz JL, Fisher DW, Rodríguez G, Fang D, Csernansky JG, Dong H

Abstract
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility.
METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL.
RESULTS: Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter.
CONCLUSIONS: These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

PMID: 28421257 [PubMed - as supplied by publisher]

Primary Cutaneous Aspergillosis in a Preterm Infant.

Pediatr Infect Dis J. 2016 Jun;35(6):704-6

Authors: Frick MA, Boix H, Camba Longueira F, Martin-Gomez MT, Rodrigo-Pendás JÁ, Soler-Palacin P

Abstract
Primary cutaneous aspergillosis is rare in premature infants. It requires combined medical and surgical strategies. Liposomal amphotericin B is recommended as first-line therapy, but salvage regimens with others antifungal agents, such as voriconazole, have been reported. Voriconazole's pharmacodynamics is unknown in this population. We report a case of severe toxicity to voriconazole in a preterm patient with primary cutaneous aspergillosis.

PMID: 26974892 [PubMed - indexed for MEDLINE]

Sofosbuvir and Simeprevir Treatment of a Stem Cell Transplanted Teenager With Chronic Hepatitis C Infection.

Pediatr Infect Dis J. 2016 Jun;35(6):708-10

Authors: Fischler B, Priftakis P, Sundin M

Abstract
There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response.

PMID: 26928522 [PubMed - indexed for MEDLINE]

Five-year Antibody Persistence and Booster Response After 1 or 2 Doses of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children.

Pediatr Infect Dis J. 2016 06;35(6):662-72

Authors: Klein NP, Baine Y, Kolhe D, Baccarini CI, Miller JM, Van der Wielen M

Abstract
BACKGROUND: We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children.
METHODS: In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up.
RESULTS: At year 5, ≥64.0% of 1-dose and ≥74.6% of 2-dose recipients had hSBA titers ≥8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ≥8. One month postvaccination, all booster dose recipients and ≥78.5% of primary dose recipients exhibited hSBA titers ≥8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile.
CONCLUSIONS: With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.

PMID: 26928521 [PubMed - indexed for MEDLINE]

Daptomycin for Children in Clinical Practice Experience.

Pediatr Infect Dis J. 2016 06;35(6):639-41

Authors: Garazzino S, Castagnola E, Di Gangi M, Ortolano R, Krzysztofiak A, Nocerino A, Esposito S, D'Argenio P, Galli L, Losurdo G, Calitri C, Tovo PA, SITIP Daptomycin Study Group

Abstract
Data on daptomycin use in the pediatric setting are scanty. We conducted a multicenter, retrospective study on 46 children treated with intravenous daptomycin at a mean dosage of 7.0 mg/kg/d, for a median of 14 days. Three children had adverse events possibly related to daptomycin. The drug was overall well tolerated, even with prolonged treatment.

PMID: 26910590 [PubMed - indexed for MEDLINE]

Pharmacokinetics, Safety and Tolerability of Single Oral or Intravenous Administration of 200 mg Tedizolid Phosphate in Adolescents.

Pediatr Infect Dis J. 2016 06;35(6):628-33

Authors: Bradley JS, Flanagan SD, Arrieta AC, Jacobs R, Capparelli E, Prokocimer P

Abstract
BACKGROUND: Tedizolid is a novel oxazolidinone antibacterial US FDA approved for treatment of acute bacterial skin and skin structure infections in adults. This study assessed the pharmacokinetics, safety and tolerability of tedizolid phosphate in adolescents (12-17 years old) after administration of a single intravenous (IV) or oral dose.
METHODS: In this multicenter, open-label study, a single IV infusion (N = 10) or oral dose (N = 10) of 200 mg tedizolid phosphate was administered to adolescents already receiving antibacterial treatment for presumed or documented infection. Blood and urine samples were collected predose and over 24 hours.
RESULTS: Tedizolid pharmacokinetics was generally similar after IV or oral administration of 200 mg tedizolid phosphate. Mean (standard deviation) half-life values were similar for oral and IV routes, 8.3 (2.0) and 6.6 (0.7) hours, respectively. Absolute oral bioavailability of tedizolid (90% confidence interval) was 88.8% (70.4%-112.1%). Geometric mean ratio (90% confidence interval) of area under the concentration-time curve values for adolescents relative to values previously reported for adults after 200 mg of single-dose IV or oral administration were 0.847 (0.736-0.975). Tedizolid was well tolerated.
CONCLUSIONS: Overall pharmacokinetics of tedizolid was similar after administration of a single oral or IV 200 mg dose, and bioavailability was high. Exposure profiles were similar to those in adults. With clinical outcomes based on area under the concentration-time curve/minimum inhibitory concentration and current susceptibility of Gram-positive pathogens, results suggest that the 200 mg daily regimen of tedizolid phosphate can be extended to adolescents for clinical trials, and that dose adjustment may not be required when switching routes.

PMID: 26910588 [PubMed - indexed for MEDLINE]

Treatment of Congenital Toxoplasmosis: Safety of the Sulfadoxine-Pyrimethamine Combination in Children Based on a Method of Causality Assessment.

Pediatr Infect Dis J. 2016 06;35(6):634-8

Authors: Teil J, Dupont D, Charpiat B, Corvaisier S, Vial T, Leboucher G, Wallon M, Peyron F

Abstract
BACKGROUND: The treatment of newborns and infants with congenital toxoplasmosis is standard practice. Some observational studies have examined safety in newborns, but most of these failed to provide sufficient details for a provisional assessment of causality. The aim of this study was to evaluate the clinical and biological adverse effects of the combination of sulfadoxine-pyrimethamine.
METHODS: Sixty-five children treated for 1 year with a combination of sulfadoxine-pyrimethamine (1 dose every 10 days) for congenital toxoplasmosis were followed up to evaluate abnormal hematological values and potential adverse events using a standardized method of causality assessment.
RESULTS: Nine patients (13.8%) presented at least 1 adverse clinical event that was nonspecific, such as diarrhea on the day of drug administration, vomiting and agitation. In 1 patient, erythema appeared at the end of the treatment and resolved within 10 days. None of these events was attributed to the treatment. Six patients (9.2%) developed an adverse hematological event (neutropenia, n = 3; eosinophilia, n = 2 and both anemia and eosinophilia, n = 1) that was considered to be possibly related to the sulfadoxine-pyrimethamine combination. Four treatments were temporarily interrupted, and toxicity was observed after readministration of treatment in 1 case only. However, none of these adverse events was life threatening.
CONCLUSIONS: According to our results and previously published data, the combination of sulfadoxine-pyrimethamine seems to be well tolerated. However, the sample size of our study was too small to rule out the risk of less frequent, but nevertheless severe, reactions and, in particular, of hypersensitivity reactions.

PMID: 26906163 [PubMed - indexed for MEDLINE]

Linezolid is Associated with Improved Early Outcomes of Childhood Tuberculous Meningitis.

Pediatr Infect Dis J. 2016 06;35(6):607-10

Authors: Li H, Lu J, Liu J, Zhao Y, Ni X, Zhao S

Abstract
BACKGROUND: Linezolid serves as an important component for the treatment of drug-resistant tuberculosis although there is little published data about linezolid use in children, especially in childhood tuberculous meningitis (TBM).
METHODS: In this study, we retrospectively reviewed records of childhood TBM patients who started treatment between January 2012 and August 2014. A total of 86 childhood TBM patients younger than 15 years old were enrolled. Out of 86 children, 36 (41.9%) received the regimen containing linezolid.
RESULTS: Thirty-two (88.9%) of 36 linezolid-treated cases had favorable outcomes, and 35 (70.0%) cases were successfully treated in the control group. The frequency of favorable outcome of linezolid group was significantly higher than that of control group (P = 0.037). In addition, compared with cases with fever clearance time of <1 week, the control group had more cases with fever clearance time of 1-4 weeks (P = 0.010) and >4 weeks (P = 0.000) than linezolid group. Furthermore, there was no significant difference in the frequency of adverse events between the two regimens (P = 0.896). In addition, the patients with adverse events were more likely to have treatment failure, the P value of which was 0.008.
CONCLUSIONS: Our data demonstrate that linezolid improves early outcome of childhood TBM. The low frequency of linezolid-associated adverse effects highlights the promising prospects of its use for treatment of childhood TBM.

PMID: 26901441 [PubMed - indexed for MEDLINE]

Adverse drug reactions during drug-resistant TB treatment in high HIV prevalence settings: a systematic review and meta-analysis.

J Antimicrob Chemother. 2017 Apr 16;:

Authors: Schnippel K, Firnhaber C, Berhanu R, Page-Shipp L, Sinanovic E

Abstract
Objectives: To estimate the prevalence of adverse drug reactions or events (ADR) during drug-resistant TB (DR-TB) treatment in the context of settings with high HIV prevalence (at least 20% of patients).
Methods: We conducted a systematic review and meta-analysis of articles in PubMed and Scopus. Pooled proportions of patients experiencing adverse events and relative risk with 95% CI were calculated.
Results: The search yielded 24 studies, all observational cohorts. Ten reported on the number of patients experiencing ADR and were included in the meta-analysis representing 2776 study participants of whom 1943 were known to be HIV infected (70.0%). An average of 83% (95% CI: 82%-84%) of patients experienced one or more ADR. Among the seven articles ( n  =   664 study participants) with information on occurrence of severe ADR, 24% (95% CI: 21%-27%) of patients experienced at least one severe ADR during drug-resistant TB treatment. Sixteen of the 24 studies analysed the relative risk of ADR by HIV infection, nine of which found no statistically significant association between HIV infection and occurrence of drug-related ADR. There was insufficient information to disaggregate risk by concomitant treatment with HIV antiretrovirals or by immunosuppression (CD4 count).
Conclusions: No randomized clinical trials were found for WHO-recommended treatment of drug-resistant TB treatment where at least 20% of the cohort was coinfected with HIV. Nearly all patients (83%) experience ADR during DR-TB treatment. While no significant association between ADR and HIV coinfection was found, further research is needed to determine whether concomitant antiretrovirals or immunosuppression increases the risks for HIV-infected patients.

PMID: 28419314 [PubMed - as supplied by publisher]

Clindamycin-associated acute generalized exanthematous pustulosis.

J Clin Pharm Ther. 2017 Apr 17;:

Authors: Croy C, Buehrle K, Austin Szwak J

Abstract
WHAT IS KNOWN AND THE OBJECTIVE: Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous reaction that usually occurs following medication exposure. Clindamycin has rarely been linked to dermatologic side effects, including AGEP.
CASE SUMMARY: This report details the case of a patient who developed AGEP with vancomycin and clindamycin use. After discontinuing clindamycin, the rash improved significantly.
WHAT IS NEW AND CONCLUSION: Timely management of adverse skin reactions to antibiotics is paramount, and early identification of the culprit agent can allow for an alternative agent to be utilized. Clindamycin should be considered a potential causative agent for patients with skin reactions.

PMID: 28417476 [PubMed - as supplied by publisher]

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.

Oncotarget. 2017 Mar 22;:

Authors: Goncalves PH, Heilbrun LK, Barrett MT, Kummar S, Hansen AR, Siu LL, Piekarz RL, Sukari AW, Chao J, Pilat MJ, Smith DW, Casetta L, Boerner SA, Chen A, Lenkiewicz E, Malasi S, LoRusso PM

Abstract
PURPOSE: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial.
METHODS: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.
RESULTS: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC.
CONCLUSION: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

PMID: 28415633 [PubMed - as supplied by publisher]

Epidemiology of Itch.

Curr Probl Dermatol. 2016;50:5-10

Authors: Weisshaar E

Abstract
Epidemiology is the study of disease frequency and the associations between risk factors and outcome in a population. Clinical populations are highly selective and depend for instance on perceived severity of symptoms and access to health services. Assessment of a disease in the community and in specific populations is an important measure for the purpose of health planning as well as for the understanding of associations between disease and factors in the environment. Itch is definitely the most frequent symptom of the skin and can occur in acute and chronic skin diseases and other diseases like end-stage renal disease, cholestasis, and hematological, neurological, and psychiatric diseases. This diversity may explain why research on the epidemiology of itch was disregarded for a long time. A recent European study demonstrated that the prevalence of itch among dermatological patients is 54.4%. The prevalence of acute itch in the general population is 8.4% and for chronic itch it is 13.5%; however, with a recurrent symptom it is important to consider different prevalence estimates (point, 12-month, and lifetime prevalence). The lifetime prevalence of chronic itch in the general populations is 22%, demonstrating that more than 1 in 5 people experience chronic itch once in their life. This shows that research in this field should not only focus on patients. This chapter briefly summarizes major facts on the epidemiology of itch in the general population and in some patient populations.

PMID: 27578064 [PubMed - indexed for MEDLINE]

Classification of Itch.

Curr Probl Dermatol. 2016;50:1-4

Authors: Ständer S

Abstract
Chronic pruritus has diverse forms of presentation and can appear not only on normal skin [International Forum for the Study of Itch (IFSI) classification group II], but also in the company of dermatoses (IFSI classification group I). Scratching, a natural reflex, begins in response to itch. Enough damage can be done to the skin by scratching to cause changes in the primary clinical picture, often leading to a clinical picture predominated by the development of chronic scratch lesions (IFSI classification group III). An internationally recognized, standardized classification system was created by the IFSI to not only aid in clarifying terms and definitions, but also to harmonize the global nomenclature for itch.

PMID: 27578063 [PubMed - indexed for MEDLINE]

Novel melanoma therapies and their side effects.

Cutis. 2016 Jun;97(6):426-8

Authors: González N, Ratner D

Abstract
In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

PMID: 27416087 [PubMed - indexed for MEDLINE]

Study of warfarin utilization in hospitalized patients: analysis of possible drug interactions.

Int J Clin Pharm. 2016 Oct;38(5):1048-51

Authors: Guidoni CM, Camargo HP, Obreli-Neto PR, Girotto E, Pereira LR

Abstract
Background Drug-drug interactions in patients taking warfarin may contribute to a higher risk of adverse events. Objective To identify and evaluate the prevalence and characteristics of potential DDIs with warfarin. Methods A cross-sectional study was performed in a Brazilian tertiary hospital. The electronic prescriptions of the patients receiving warfarin between January 2004 and December 2010 were analyzed. Socio-demographic, clinical, and therapeutic variables were collected. Warfarin drug-drug interactions were classified as either risk A, B, C, D, or X according to the Lexi-Interact™ Online database. Results A total of 3048 patients were identified who were prescribed warfarin. Of the 154,161 total drug prescriptions issued, 42,120 (27.3 %) were for warfarin. Evaluation of the prescriptions showed that 63.1 and 0.1 % of patients received concomitant drugs classified as having class D or X risk. It was found that 20,539 (48.7 %) prescriptions had at least one drug with a D or X risk. Patients were prescribed an average of 1.4 (±0.4) concomitant medications with a class D or X warfarin-DDI risk, the most frequent being acetylsalicylic acid and amiodarone. Conclusion The results demonstrate a high prevalence of concomitant drug prescriptions with the potential for clinically relevant DDIs with warfarin, the most frequent being acetylsalicylic acid and amiodarone.

PMID: 27365092 [PubMed - indexed for MEDLINE]

[The new drugs of 2014: what is worthwile saving].

Assist Inferm Ric. 2015 Jul-Sep;34(3):154-8

Authors:

PMID: 26488932 [PubMed - indexed for MEDLINE]

[Incidence, management and costs of adverse effects in chronic hepatitis C patients on triple therapy with telaprevir or boceprevir: first 12 weeks of treatment].

Enferm Infecc Microbiol Clin. 2015 May;33(5):331-6

Authors: Guglieri-López B, Ventura-Cerdá JM, Gómez-Álvarez S, Climente-Martí M

Abstract
INTRODUCTION: The aim of the study was to analyze the incidence, management and cost associated to hematological and dermatological adverse effects (AE) in chronic hepatitis C patients on triple therapy (TT) with telaprevir (TVR) or boceprevir (BOC).
METHODS: An analysis was made on the data recorded on patients who started treatment with TVR or BOC associated with peginterferon alfa and ribavirin in a 12-week follow-up period.
RESULTS: Fifty-three patients were included (TVR n=36; BOC n=17). Thrombocytopenia (83% TVR vs. 88% BOC) followed by neutropenia (89% TVR vs. 82% BOC) were the most common AE. Dermatological AE were observed in 32% of patients. Eleven patients required treatment discontinuation (all of them received TVR), and toxicity was the main reason for discontinuation (64%). The percentage of patients who required supportive treatment for management of AE was 66%. The most used supportive treatment was erythropoietin. Eight patients required emergency health care, and 2 were hospitalized due to AE. Total cost of additional supportive resources was 32,522€ (625 [SD=876]€/patient) (TVR 759 [SD=1,022]€/patient vs. BOC 349 [SD=327]€/patient; P>.05). Patients with gradeiii-iv toxicity required greater supportive care with higher costs, compared to patients with gradei-ii toxicity (849 [SD=1,143]€/patient vs. 387 [SD=397]€/patient; P=.053).
CONCLUSION: The addition of new protease inhibitors to conventional treatment leads to a higher incidence of hematological AE in our study, compared to data described in clinical trials. The elevated incidence of AE involves the use of supportive care, increasing total costs of therapy.

PMID: 25128462 [PubMed - indexed for MEDLINE]

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