Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

Antituberculosis Drug-Associated DRESS: A Case Series.

BACKGROUND: Although antituberculosis drug-associated drug reaction with eosinophilia and systemic symptoms (DRESS) is rarely reported, its diagnosis should not be dismissed. Its management implies an early withdrawal of suspected drugs. OBJECTIVE: The objective of this study was to describe the characteristics of antituberculosis drug-associated DRESS and to identify the most likely involved drugs. METHODS: We searched for potential cases of DRESS with rifampicin, isoniazid, pyrazinamide, and ethambutol reported from January 1, 2005, to July 30, 2015, in the French pharmacovigilance database. A literature review was also performed. RESULTS: Sixty-seven cases of antituberculosis drug-associated DRESS were analyzed (40 women and 27 men, median age of 61 years). Liver and kidneys were the most frequently involved organs. Two patients died from DRESS. Skin tests were performed in 11 patients and were positive in 8 cases. Discrepancies between epicutaneous tests and reintroduction of the culprit drugs were observed for 2 patients with a premature reintroduction of antituberculosis drugs in 1 case. Antituberculosis drugs were the only suspects in 20 cases. As for the literature data, rifampicin was the most suspected drug because of its larger indications, but in case of tuberculosis infections, isoniazid was the most suspected drug. CONCLUSIONS: We described the largest case series of first-line antituberculosis drug-associated DRESS in the literature. All antituberculosis drugs pose a risk of DRESS. An early withdrawal of the culprit drugs is essential. A drug allergy evaluation must be performed to optimize the second-line treatment of tuberculosis infection.

[Pharmacokinetic drug interaction between miconazole mucoadhesive tablet and tacrolimus: About 3 case-reports in transplant patients]. / Interaction pharmacocinétique entre la forme mucoadhésive de miconazole et le tacrolimus : à propos de 3 observations cliniques chez des patients greffés.

Loramyc® is a mucoadhesive tablet of miconazole, indicated for the treatment of oropharyngeal candidiasis in immunocompromised patients. Miconazole, as others azole antifungals, is known for its potent inhibitory properties of cytochromes P450 enzymes and P-glycoprotein (P-gp). Inhibition of cytochromes P450 enzymes and P-gp can produce pharmacokinetic drug interaction. Immunosuppressive agents, such as calcineurin inhibitors (tacrolimus, cyclosporine) are substrates of cytochromes P450 3A4 and P-gp. Nevertheless, the impact of systemic absorption of miconazole mucoadhesive tablet has not been investigated by the laboratory before regulatory approval. No recommendation currently exists in case of co-prescription of Loramyc® and immunosuppressive agents which are counter-indicated as a matter of principle. Herein, we present 3 cases of transplanted patients, requiring miconazole mucoadhesive tablet, who presented a tacrolimus overdose. These cases illustrate that of therapeutic drug monitoring is feasible in order to prevent the occurrence of overdoses and adverse reactions related.

Impact of concomitant medications on obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A - randomized controlled trials (RCTs) with high statistical power; B - RCTs with lower power, non-randomized comparative studies and observational studies; C - retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as 'Z drugs' and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA-associated cardiovascular morbidity.

[Cyamemazine (Tercian®): Exploration of extrapyramidal syndrome cases contained in the French pharmacovigilance database]. / Cyamémazine (Tercian®) et syndromes extrapyramidaux : exploration des cas contenus dans la base nationale de pharmacovigilance.

PURPOSE: Cyamemazine (Tercian®) is currently the most widely prescribed neuroleptic in France. This widespread use is due to its anxiolytics properties and to a claimed good safety profile. Although, prescription of cyamemazine is not devoid of the risks associated with the use of neuroleptics: extrapyramidal syndromes. This study aims at describing extrapyramidal syndromes induced by cyamemazine registered in the French pharmacovigilance database. METHODS: All spontaneous reports of extrapyramidal syndromes in the French pharmacovigilance database between 1st January 1985 and 31th December 2015 were described and analyzed. RESULTS: During this period 132 cases following cyamemazine intake were reported in the French pharmacovigilance database. The extrapyramidal syndromes were considered as "serious" in 77% of cases. More than 80% of the cases were described with a dosage of cyamemazine under 100mg/day and no correlation between drug dose and seriousness of the cases were found. Thirty-six cases were described with a monotherapy of cyamemazine. CONCLUSION: We should keep in mind that despite its widespread use in various indications (e.g. anxiolytic) cyamemazine remains a neuroleptic and could induce extrapyramidal syndromes even with low dosage. Careful monitoring should be performed when introducing and with long-term use of cyamemazine, mostly in elderly patients or patient already being treated with neuroleptics.

The nocebo effect of drugs.

While the placebo effect has been studied for a long time, much less is known about its negative counterpart, named the nocebo effect. However, it may be of particular importance because of its impact on the treatment outcomes and public health. We conducted a review on the nocebo effect using PubMed and other databases up to July 2014. The nocebo effect refers by definition to the induction or the worsening of symptoms induced by sham or active therapies. Examples are numerous and concerns both clinical trials and daily practice. The underlying mechanisms are, on one hand, psychological (conditioning and negative expectations) and, on the other hand, neurobiological (role of cholecystokinin, endogenous opioids and dopamine). Nocebo effects can modulate the outcome of a given therapy in a negative way, as do placebo effects in a positive way. The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response. This raises the important issue of how physicians can at the same time obtain informed consent and minimize nocebo-related risks. Every physician has to deal with this apparent contradiction between primum non nocere and to deliver truthful information about risks. Meticulous identification of patients at risk, information techniques such as positive framing, contextualized informed consent, and even noninformation, is valuable.

Lactic Acidosis in Diabetic Population: Is Metformin Implicated? Results of a Matched Case-Control Study Performed on the Type 2 Diabetes Population of Grenoble Hospital University.

INTRODUCTION: To evaluate the strength of association between lactic acidosis (LA) and well-recognized risk factors for LA, particularly the weight of metformin. METHODS: This study is a matched case-control analysis concerning the type 2 diabetes population from Grenoble Hospital University. Cases of LA were defined biologically with pH < 7.35 and lactates > 5 mmol/L. They were matched to 2 controls defined as type 2 diabetic inpatients who did not present a LA during the study period. We performed a conditional logistic regression. RESULTS: We included 302 cases and 604 controls; mean age was 69.5 years (SD 11.93). Intercurrent diseases were significantly associated with LA. Chronic medical conditions had a minor impact on LA incidence, except hepatocellular dysfunction. Metformin was significantly associated with a higher LA probability in case of acute kidney injury (AKI) (OR = 1.79; p value = 0.020) but not in patients without AKI. DISCUSSION AND CONCLUSIONS: According to this study, metformin, compared to acute medical conditions, seemed not to be associated with LA in patients with type 2 diabetes; however in case of AKI, metformin may be associated with LA.

Drug-induced Raynaud's phenomenon: beyond ß-adrenoceptor blockers.

AIM: Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or ß-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS: A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS: We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by ß-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION: Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Angioedema Triggered by Medication Blocking the Renin/Angiotensin System: Retrospective Study Using the French National Pharmacovigilance Database.

INTRODUCTION: Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. METHODS: The national MedDRA database was searched using the term "angioedema". Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. RESULTS: 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21% of cases (24 patients), or an ACEi in 77% of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90% of cases (tongue: 48.2%, larynx: 23.2%). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. CONCLUSION: Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug.

[Pharmacology of Raynaud's phenomenon]. / Pharmacologie du phénomène de Raynaud.

Raynaud's phenomenon (RP) is characterised by transient ischaemia in the extremities in response to cold or emotions. It can be primary (idiopathic) or secondary to an underlying disease. The pathophysiology of RP is multifactorial and complex. Microvascular impairment is a hallmark of the disease. The objective of this work is to review the different pharmacological treatments currently used in the management of RP, from their mechanism of action to the available evidence regarding their efficacy. We also propose to discuss potential pharmacological targets such as the potentiation of the nitric oxide pathway, or the inhibition of the RhoA-Rho kinase pathway. The last part of this review deals with drug-induced RP. Among various medications, beta-blockers, interferons, tyrosine-kinase inhibitors or cytotoxic agents such as bleomycin are involved.

A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French nationwide study.

BACKGROUND: Voriconazole long-term therapy is suspected to induce cutaneous squamous cell carcinoma (SCC), as suggested by 18 case reports worldwide and 3 retrospective studies. METHODS: To better characterize the natural history of these potentially voriconazole-associated tumors, a nationwide call for notification of skin cancers and other skin lesions observed between 2002 and 2012 in patients treated by voriconazole was launched in France. A multidisciplinary committee evaluated voriconazole involvement in each case. RESULTS: Nineteen SCCs were reported. The committee determined the likelihood of voriconazole involvement to be high in 15 cases, intermediate in 2, and low in 2. In the 17 patients with high/intermediate likelihood of voriconazole involvement, the mean time between voriconazole initiation and SCC diagnosis was 39 ± 18 months (range, 28-84 months), and was shorter in transplant recipients (35 vs 45 months, P < .05). Cumulative mean duration of voriconazole therapy at SCC diagnosis was 35 months (range, 7-63 months). A multistep process was noted in 14 of 17 patients: acute phototoxicity during the first year of voriconazole therapy (mean time, 6 months [range, 0-18 months]), actinic keratosis (AK) of the same sun-exposed skin area in the second/third year (mean, 30 months [range, 11-57 months]), followed by SCC during the third year or later. Five cases of AK without SCC and 37 cases of other skin lesions were also reported. CONCLUSIONS: Our results suggest that long-term voriconazole prescription may be associated with a multistep phototoxic process involving acute skin lesions followed by AK then by SCC. Discontinuation of voriconazole should be strongly considered in patients experiencing chronic phototoxicity.

Carbamazepine-induced acute generalized exanthematous pustulosis: a case report.

A 15-year-old adolescent was admitted to the hospital for management of a generalized pruritic skin rash, which had appeared 10 days prior to admission. Carbamazepine (CBZ) and insulin were initiated 44 and 23 days prior to the onset of the skin rash (day 44), respectively. Clinical examination showed bluish lesions on the tongue and bilateral keratoconjunctivitis. His skin was very erythematous and pruritic without edema and covered with hundreds of nonfollicular pustules mainly on the trunk and skin folds. Laboratory assessment revealed leukocytosis, hypereosinophilia, and thrombocytopenia. A sample of superficial pus from a pustule on the trunk showed a significant number of leukocytes as well as a significant number of Staphylococcus aureus and Lancefield Group B ß-hemolytic streptococci strains. An abdominal skin biopsy revealed acute to subacute folliculocentric spongiotic dermatitis with subcorneal pustules. All of these observations were consistent with a diagnosis of acute generalized exanthematous pustulosis (AGEP). Although we could not exclude with certainty the role of insulin initiated on day 21 and discontinued on day 55 with substitution to oral metformin and repaglinide, no cases of AGEP have ever been published with insulin, and skin lesions were not related to injection sites. This article describes a probable case of CBZ-induced acute generalized exanthematous pustulosis in a 15-year-old adolescent.

Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in a diabetic patient.

OBJECTIVE: To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient. CASE SUMMARY: A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale). DISCUSSION: This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia. CONCLUSIONS: This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

[Bisphosphonates-associated osteonecrosis of the jaw: review on reported cases]. / Les ostéonécroses de la mâchoire associées aux biphosphonates: synthèse bibliographique.

Osteonecrosis of the jaws associated with the use of bisphosphonates (alendronate, pamidronate, risedronate et zoledronate) are described as an avascular necrosis. We have listed 184 cases of bisphosphonates-associated osteonecrosis of the maxillary in the literature. Many mechanisms are discussed in bisphosphonates-associated osteonecrosis: a disturbing bone turnover, an accumulation of bone's microdamage or an antiangiogenic effect. Other risk factors seem however to be involved: cancer, chemotherapy, glucocorticoids, infection and renal insufficiency.

Goiter in a newborn exposed to lithium in utero.

OBJECTIVE: To report a case of neonatal goiter and biological hypothyroidism in a newborn exposed to lithium in utero resulting from therapy given to the mother before and during her pregnancy. CASE SUMMARY: A male neonate, born at 37 weeks' gestation, presented with a goiter without other signs of hypothyroidism. His serum thyroid-stimulating hormone concentration was high and unbound tetrathyroxine concentration was low, indicating that chronic exposure to lithium was present. Oral thyroxine treatment was initiated when the infant was 3 days old and continued for 11 weeks. Treatment was effective in reducing the goiter and hormone concentrations, and allowing normal growth and psychomotor development during the following 3.5 months. Other drugs taken by the mother during pregnancy are not known to induce thyroid abnormalities. DISCUSSION: Lithium is used for prophylaxis and treatment of bipolar disorder. Goiter and hypothyroidism in adults have been described in patients treated with lithium; thyroid disorders are reversible if lithium is discontinued. Few cases of goiter and hypothyroidism have been reported in newborns exposed to lithium in utero. In our patient, congenital hypothyroidism required longer thyroxine treatment than lithium-induced thyroid disorders. The delay before improvement seems to be similar to that observed in adults. The Naranjo probability scale indicated that lithium was the probable cause of hypothyroidism resulting from in utero exposure. CONCLUSIONS: Lithium is a well-known goitrogenic agent. Thus, if lithium treatment needs to be continued during pregnancy in women with bipolar disorder, adequate screening for morphology by ultrasonography and systematic hormonal biological control in newborns are recommended.

Nefopam abuse.

OBJECTIVE: To report 3 patients who abused nefopam, a central analgesic that inhibits serotonin, norepinephrine, and dopamine reuptake. CASE SUMMARIES: CASE 1: A 42-year-old white woman with migraines started nefopam therapy about 10 years ago. She now obtains nefopam by prescription forgery and self-administers intramuscular nefopam 300 mg/d. She experiences anticholinergic effects of nefopam and, when attempting withdrawal, depressive symptoms. CASE 2: A 40-year-old white woman with osteoporosis has injected 120 mg of nefopam intramuscularly daily for several years. When she tried to increase doses due to worsening of her symptoms, she experienced tremor, involuntary movements, and dry mouth, and became aggressive. She then resumed the initial doses. She now reports symptoms of depression when attempting withdrawal. CASE 3: A 33-year-old white man, with a history of alcohol and benzodiazepine dependence and ileostomy, and an implanted drug delivery system, has been prescribed nefopam. Fifteen days after therapy was initiated, his daily consumption was 840 mg/d, and further increased to 1840 mg/d. He experienced violent behavior, agitation, facial dysesthesia and myoclonus, tremor of fingers, and sweating. He did not attempt withdrawal. DISCUSSION: The patients described above are drug-dependent according to the Diagnostic and Statistical Manual, 4th Edition. All patients developed a pharmacodynamic tolerance phenomenon, which can develop rapidly. Violent behavior, tremor after massive intake, and depressive symptoms during withdrawal are similar to those reported with psychostimulant abuse. CONCLUSIONS: When abused, nefopam has primarily psychostimulant-like effects, which are probably linked to its dopamine reuptake inhibition properties.