Double Hit of Hydroxichloroquine and Amiodarone Induced Renal Phospholipidosis in a Patient with Monoclonal Gammopathy and Sclerodermiform Syndrome: A Case Report and Review of the Literature.

Phospholipidosis is a rare disorder which consists of an excessive intracellular accumulation of phospholipids and the appearance of zebra bodies or lamellar bodies when looking at them using electron microscopy. This disease is associated with certain genetic diseases or is secondary to drugs or toxins. Drug-induced phospholipidosis encompasses many types of pharmaceuticals, most notably chloroquine, amiodarone or ciprofloxacin. Clinically and histologically, renal involvement can be highly variable, with the diagnosis not being made until the zebra bodies are seen under an electron microscope. These findings may require genetic testing to discount Fabry disease, as its histological findings are indistinguishable. Most of the chemicals responsible are cationic amphiphilic drugs, and several mechanisms have been hypothesized for the formation of zebra bodies and their pathogenic significance. However, the relationship between drug toxicity and phospholipid accumulation, zebra bodies and organ dysfunction remains enigmatic, as do the renal consequences of drug withdrawal. We present, to our knowledge, the first case report of acute renal injury with a monoclonal gammopathy of renal significance, lesions, and sclerodermiform syndrome, with zebra bodies that were associated with the initiation of a hydroxychloroquine and amiodarone treatment, as an example of drug-induced-phospholipidosis.

Clozapine versus other antipsychotics during the first 18 weeks of treatment: A retrospective study on risk factor increase of blood dyscrasias.

Blood dyscrasias excluding agranulocytosis received limited attention in antipsychotic-treated patients during the first 18 weeks of therapy, although severe clinical conditions have been reported in a few cases. We extracted data records of 285 Caucasian patients after 18 weeks of antipsychotic treatments to investigate risk factors of blood dyscrasias. We observed a higher risk to develop both transient and persistent anemia, neutrophilia and eosinophilia in clozapine-treated patients, whereas in those treated with other atypical antipsychotics when compared to a reference group under typical antipsychotics, emerged an increased risk for transient neutrophilia and eosinophilia. Male patients revealed a higher risk of persistent eosinophilia, neutrophilia, and leukocytosis. Concomitant treatments with mood stabilizers or benzodiazepines proved to be risk factors for transient anemia, antidepressants for transient eosinophilia. Severe complications emerged in 3 cases of agranulocytosis. Cross-tabulation analysis showed a higher probability of a poor response in clozapine-treated patients with persistent anemia and a positive with persistent neutrophilia and eosinophilia. Our data evidenced that emerging blood dyscrasias were not associated with critical adverse effects, and only agranulocytosis required a treatment interruption. Other atypical antipsychotics might represent a viable alternative to potentially harmful clozapine and typical antipsychotics at the onset of life-threatening haematological alterations.

Clozapine Rechallenge After Neutropenia or Leucopenia.

To rechallenge with clozapine for a patient who previously has experienced neutropenia or leucopenia or during clozapine treatment is a difficult clinical decision. Herein, we analyzed the results of such a rechallenge in 19 patients. We analyzed all the reports, from the database of the pharmacovigilance department of the Argentine National Administration of Drugs, Foods, and Medical Devices, of patients who were rechallenged with clozapine after a leucopenia or a neutropenia. Nineteen cases of rechallenge after leucopenia or neutropenia were reported between 1996 and 2014. One third of the patients re-exposed to clozapine developed a new hematologic adverse reaction. The second blood dyscrasia was less severe in 83% of the cases and had a shorter median latency as compared with the first (8 weeks vs 182 weeks, P = 0.0045). There were no significant differences for demographic and clinical characteristics of patients who developed a second dyscrasia as compared with those who did not. The present study shows that almost 70% of the patients rechallenged with clozapine after a leucopenia or a neutropenia did not develop a new hematological adverse effect, whereas the remaining 30% had a faster but less serious neutropenia.

Clozapine safety, 40 years later.

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Mechanisms of thrombosis in paraproteinemias: the effects of immunomodulatory drugs.

The introduction of immunomodulatory drugs (IMiDs) has improved clinical outcome in patients with multiple myeloma (MM). However, their use has been associated with a higher risk of cardiovascular complications. The use of IMiDs with dexamethasone, chemotherapy, or in combination with erythropoietic agents enhances the risk of venous thromboembolism (VTE) up to 25%. The pathogenesis of this increased risk of VTE seen with IMiD-based combination therapy is not yet fully understood, but several mechanisms have been proposed to explain the development of this hypercoagulable state. In cancer patients, prothrombotic factors include age, chemotherapy, immobility, enhanced expression of tissue factor of malignant cells, circulating microparticles, and increased vascular endothelial growth factor (VEGF). In patients with paraproteinemias, immunoglobulin-specific mechanisms may also be involved and include hypofibrinolysis, hyperviscosity, procoagulant autoantibody production, effects of inflammatory cytokines, and acquired activated protein C resistance (APCR). In this review we will focus on IMiD-associated effects on specific thrombotic mechanisms.

Paraproteinaemia after allo-SCT, association with alemtuzumab-based conditioning and CMV reactivation.

Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS.

Update on the incidence of metamizole sodium-induced blood dyscrasias in Poland.

Metamizole sodium (metamizole) is a popular non-opioid analgesic and a common non-prescription product in Poland. Controversy exists regarding the level of risk of agranulocytosis or aplastic anaemia associated with its use. Two previous pharmacovigilance studies conducted in Poland found the risk was low. Twenty-four of the 25 haematology centres that provide specialist care for the 30 million adults in Poland participated in this prospective 12-month study. Twenty-one cases of agranulocytosis, 48 of aplastic anaemia, 15 of neutropenia and 11 of pancytopenia were reported. Of these cases, three (two agranulocytosis; one aplastic anaemia) were judged as being possibly related to metamizole. Crude estimates of the rate of agranulocytosis and aplastic anaemia associated with metamizole were 0.16 and 0.08 cases/million person-days of use, respectively. Ongoing national safety surveillance in Poland shows that, despite the possibility of drug-induced blood dyscrasias with metamizole, the risk is very low.

Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study.

Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.

Enfermedades gingivales: una revisión de la literatura / Gingival diseases: a literature review

Las enfermedades gingivales son una amplia familia de patologías diferentes y complejas, que se encuentran confinadas a la encía y son el resultado de diferentes etiologías. El interés por las alteraciones gingivales se basa no tanto en su gravedad, sino en su enorme prevalencia entre la población. Las enfermedades gingivales forman un grupo heterogéneo, en el que se pueden ver problemas de índole exclusivamente inflamatoria, pero también alteraciones de origen genético, traumático o asociadas a alteraciones sistémicas. En el Simposio Internacional de la American Academy of Periodontology, en 1999, se acordó incluir una categoría que hiciera alusión a los problemas únicamente localizados a nivel gingival. En el presente artículo se pretende recopilar toda la información necesaria para entender en qué consisten estos cuadros, en qué mecanismo etiopatogénico se basan y qué estrategias de tratamiento podemos poner en marcha para solucionarlos (AU)

Gingival diseases are a broad family of different and complex pathologies confined to the gingivae and which head from different aetiologies. Interest put on gingival alterations is based not so much on its severity but on its enormous prevalence among the population. Gingival diseases form an amorphous group in which not only problems of exclusively inflammatory nature can be seen, but also alterations of either genetic or traumatic origin or associated with systemic alterations. In 1999, at the International Symposium of the American Academy of Periodontology, it was agreed to include a category which made reference to problems located in the gingivae solely. The present review focuses on a compilation of all the information necessary to understand the meaning of these patterns, which ethiopathogenic mechanisms lay behind them and which strategies can be started up in order to solve them (AU)

Scientific challenges in postmarketing surveillance of ocular adverse drug reactions.

PURPOSE: To highlight the challenges of postmarketing surveillance for drug-related adverse events in the practice of ophthalmology. DESIGN: A retrospective review of the medical literature and postmarketing surveillance databases. METHODS: MEDLINE literature review of sildenafil-associated or amiodarone-associated optic neuropathy and chloramphenicol-associated blood dyscrasias. RESULTS: Sildenafil, amiodarone, and chloramphenicol may all cause adverse ocular events; however, the data are not conclusive. CONCLUSIONS: Reports in peer-reviewed medical journals may be proven incorrect over time. For drug-induced adverse ocular events, there is little true science after the drug reaches the marketplace, so the percentage of incorrect conclusions may be high. Clinicians should be wary of reports of adverse ocular effects until data are confirmed by multiple authors over the long-term. Even so, spontaneous reports from postmarketing surveillance databases may be the first and only signal of an adverse ocular event.