Joaquín Borrás-Blasco

Acute Seizures Due to a Probable Interaction between Valproic Acid and Meropenem

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic—clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 μg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 μg/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic—clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 μg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 μg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 μg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem—valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

Adverse Cutaneous Reactions Induced by TNF-α Antagonist Therapy

Objective: To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-&agr;) antagonist therapy. Methods: A literature search was performed using PubMed (1996–March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. Results: Since the introduction of TNF-&agr; antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-&agr; antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-&agr; antagonists for a variety of rheumatologic conditions. TNF-&agr; antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-&agr; antagonists. Conclusions: As the use of TNF-&agr; antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-&agr; antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

Optic Neuritis with Concurrent Etanercept and Isoniazid Therapy

OBJECTIVE To report a case of optic neuritis associated with concurrent etanercept and isoniazid therapy. CASE SUMMARY A 55-year-old man diagnosed as having rheumatoid arthritis had received treatment with nonsteroidal anti-inflammatory drugs, sulfasalazine, oral methotrexate, leflunomide, and deflazacort. Four months prior to admission, he had a Disease Activity Score of 6.06; treatment with etanercept was considered. Three months prior to admission, because of evidence of latent tuberculosis, isoniazid 300 mg once daily and pyridoxine 50 mg once daily were prescribed. Treatment with subcutaneous etanercept 25 mg twice weekly was started 5 days after isoniazid was initiated. Two weeks prior to admission, the patient developed blurred vision in his left eye. Ten days later, his vision worsened and he was hospitalized. The visual acuity in both eyes was 0.7, and a campimetric examination was compatible with optic neuritis. Magnetic resonance imaging of the brain revealed lesions suggesting demyelinating lesions. The clinical course was consistent with bilateral optic neuritis. Etanercept was stopped, and isoniazid was replaced with rifampin 600 mg once daily. The patient was treated with intravenous methylprednisolone hemisuccinate 1 g/day for 5 days followed by oral prednisolone, resulting in a minor subjective improvement in left eye visual acuity. He then received oral prednisone for 3 weeks, slowly tapering to discontinuation. DISCUSSION No physiologic factors could have predisposed this patient to develop optic neuritis. He was not diagnosed with a demyelinating disease or underlying systemic condition. The optic neuritis was unlikely to be an early manifestation of multiple sclerosis based on the clinical course and the negative results of the imaging tests. Furthermore, there was a close temporal correlation between the drug exposure and the onset of symptoms. After discontinuation of etanercept and isoniazid therapy, the patients general condition improved. Use of the Naranjo probability scale indicated a possible relationship between optic neuritis and combined etanercept–isoniazid therapy. CONCLUSIONS Patients initiated on etanercept and isoniazid should be closely monitored for the development of adverse neurologic signs and effects. If optic neuritis is determined, etanercept and isoniazid should be discontinued immediately.

Acenocoumarol-Induced Henoch-Schönlein Purpura

OBJECTIVE To report a probable case of Henoch-Schönlein purpura associated with acenocoumarol therapy. CASE SUMMARY A 76-year-old white woman was prescribed acenocoumarol for chronic atrial fibrillation. Two months after starting therapy, the patient came to our hospitals emergency department because of abdominal pain associated with vomiting. Physical examination revealed multiple round, confluent, purpuric lesions with some vesicles and an area of residual pigmentation. Lesions were present predominantly on the legs and gluteus, and also on the abdomen and arms. Skin biopsy of the lesions was compatible with leukocytoclastic vasculitis with deposition of immunoglobulin A. An upper intestinal endoscopy was done and identified purpuric mucosal lesions in the fundus, body, and antrum of the stomach and the duodenal bulb. Renal function was not affected, although proteinuria (1.26 g/day) was found and microscopic hematuria was observed. DISCUSSION The most likely cause of the Henoch–Schönlein purpura in this case was considered to be acenocoumarol because of the close temporal relationship between exposure to the drug and onset of symptoms, as well as the rapid resolution of the symptoms and signs after acenocoumarol was discontinued. The oral anticoagulant was the only identifiable precipitant that the patient encountered before the Henoch–Schönlein purpura developed. An objective causality assessment revealed that the adverse drug event was probable. CONCLUSIONS This case report illustrates a probable association between Henoch–Schönlein purpura and acenocoumarol. As of December 2003, this reaction had not been previously reported. Clinicians should be aware of this potential adverse effect of a widely used drug.

Burning mouth syndrome due to efavirenz therapy.

1. Rarnbeck B, Kurlemann G, Stodieck SR,MayTW,Jurgens U.Concentrations of lamotrigine ina mother on lamotrigine treatment andhernewbornchild.EurJ ClinPharmacoll997;51:481-4. 2. Tomson T,OhmanI, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997;38:1039-41. 3. OhmanI, VitolsS, Tomson T. Lamotrigine in pregnancy: pharmacokineticsduring delivery,in the neonate,and during lactation.Epilepsia 2000;41:709-13. 4. Gentile S. Lamotrigine in pregnancy and lactation. ArchWomens Ment Health 2005;8:57-8. 5. Begg EJ, DuffullSB, HackettLP,lIett KF.Studyingdrugs in human milk: timeto unifythe approach. J HumLact2002;18:319-28. 6. Mikati MA,FayadM, Koleilat M,et aI. Efficacy, tolerability, andkineticsof lamotrigine in infants. J Pediatr2002;141:31-5. Burning Mouth Syndrome Due to Efavirenz Therapy

Recombinant Factor VIIa is an Effective Therapy for Abdominal Surgery and Severe Thrombocytopenia: A Case Report

A 50-year-old woman was admitted to the emergency room. An appendectomy was done. On the sixth day the patient’s general state deteriorated and she became somnolent with jaundice due to distal obstructive choledocholithiasis. The results of laboratory tests were platelets 12 x 109/L, prothrombin time 13 seconds, international normalized ratio 1.19, activated partial thromboplastin time 31.8 seconds, and fibrinogen 8.78 g/L. There was no evidence of disseminated intravascular coagulation. In view of the patient’s clinical condition, surgery was considered to be indicated. Because it was a life-threatening situation and at the time there was no platelet concentrate available for immediate transfusion, she was treated with a single dose of recombinant factor VIIa (rFVIIa) (60 μg/kg).The dose of 60 μg/kg was selected on the basis of experience with rFVIIa in the treatment of hemophilic patients. In this case, use of rFVIIa was a valid alternative to control the bleeding in a patient with thrombocytopenia. However, despite the efficacy of the treatment, it should not be forgotten that it was used because of the unavailability of platelets and that we were dealing with a life-threatening situation. Clinical trials should be carried out to verify the safety, effectiveness, and efficiency of rFVIIa in these cases.

Photo-Induced Stevens–Johnson Syndrome Due to Sulfasalazine Therapy

OBJECTIVE: To report a case of photo-induced Stevens–Johnson Syndrome (SJS) due to sulfasalazine therapy. CASE SUMMARY: Photo-induced SJS associated with sulfasalazine therapy occurred in a 34-year-old white man diagnosed as having seronegative symmetrical polyarthritis with no predisposing factors. According to his medical record, the patient had received methotrexate, levofolinate calcium, deflazacort, and diclofenac sodium as needed. Two months prior to admission, methotrexate and diclofenac sodium were suspended and treatment with sulfasalazine was started. The patient presented to our emergency department because of severe erythema confined to sun-exposed areas; annular lesions on the extremities and the mucosa were affected. Nikolskys sign was present. A skin biopsy was compatible with SJS, and the clinical diagnosis was SJS induced by sulfasalazine. Administration of sulfasalazine was suspended, which resulted in an improvement in the skin lesions and general state of health. The patient was discharged without further symptoms. DISCUSSION: The observed reaction to sulfasalazine was considered phototoxic, as lesions appeared like a burn rash reaction in sun-exposed areas when sulfasalazine treatment was started and the reaction progressed to SJS. It seems that there was a correlation between the time course of the reaction and the administration of sulfasalazine. An objective causality assessment revealed that the adverse effect was possible. CONCLUSIONS: To our knowledge, this is the first report of photo-induced SJS due to sulfasalazine therapy. Clinicians should be aware of this infrequent but severe reaction. If clinical evaluation leads to the suspicion of SJS, sulfasalazine should be discontinued immediately.

Clinical and economic impact of the use of etanercept 25 mg once weekly in rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis patients

Objective: To determine the clinical and economic impact of etanercept 25 mg/week (ETN25) on rheumatoid arthritis (RA), psoriatic arthropathy (PA) and ankylosing spondylitis (AS) patients in sustained clinical remission. Methods: Observational, retrospective cohort of patients treated with etanercept 50 mg/week (ETN50) who achieved and maintained clinical remission (Disease Activity Score 28 < 2.6 or BASDAI < 2) over a period of 1 year and had slow worsening of structural changes were enrolled in an off-label program (January 2006 to June 2013) to switch from ETN50 to ETN25. Economic impact was assessed using Enbrel® official prices for Spain. Results: From 1 January 2006 to 1 June 2013, 98 RA, 40 PA and 47 AS patients were treated with ETN50; 39 (24%) patients (20 women; age = 53 ± 7 years; 24 RA, 7 PA, 8 AS) received ETN25 for at least 0.5 years (2.6 ± 2.0 years; range = 0.5 – 7.3 years). As of 1 June 2013, 29 (74%) patients continued on ETN25. RA patients: 17 patients continued on ETN25, 5 patients discontinued use due to reactivation of RA (4 switched back to ETN50 and 1 switched to adalimumab; all regained clinical remission) and 2 patients discontinued use due to adverse reactions. PA patients: four patients continued on ETN25, two patients discontinued use due to reactivation of PA (switched back to ETN50, regaining clinical remission) and one patient discontinued use due to adverse reaction. All AS patients continued on ETN25. The total savings associated with ETN25 over the 7-year observation period were €622,073, resulting in the ability to treat 52 additional patients with ETN50 for one year without increasing total ETN costs. Conclusion: ETN25 produces cost savings while maintaining clinical response in a high proportion of patients after at least one year under clinical remission with ETN50. At a time when the cost of therapy is an unavoidable component of healthcare treatment decisions, ETN25 could be a cost-effective option for selective RA, PA and AS patients.

Urticaria due to etanercept in a patient with psoriatic arthritis.

A 50-year-old woman was referred to our emergency room because of urticaria. Eleven days after etanercept therapy was started, the patient developed an urticarial rash of the trunk and face. A diagnosis of generalized urticaria was made. Etanercept treatment was suspended. Treatment was started with methylprednisolone and dexchlorpheniramine. The patients condition improved and she was discharged. In this case, the most probable cause of urticaria was considered to be etanercept because of the temporal relationship between exposure to the drug and the onset of symptoms. The adverse reaction could be considered probable. Although the overall risk of skin adverse events associated with etanercept appears low, clinicians should be aware of this reaction.

Parapharyngeal Abscess in a Patient Receiving Etanercept

Objective: To report a case of parapharyngeal abscess associated with Streptococcus viridans in a patient with rheumatoid arthritis receiving treatment with etanercept. Case Summary: A 40-year-old man diagnosed with rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, methotrexate, and deflazacort. Six months prior to admission, the patient had a Disease Activity Score of 3.4; clinicians decided to start treatment with etanercept. Chest X-rays were normal and the tuberculin skin test was negative. Treatment with etanercept plus methotrexate was started. Three months later, methotrexate was discontinued. Six months after etanercept therapy was started, the patient presented to our emergency department with a swelling of his neck, odynophagia, otalgia, and trismus. The clinical course was consistent with parapharyngeal abscess. Etanercept treatment was suspended. The parapharyngeal abscess was drained and intravenous methylprednisolone, amoxicillin/clavulanic acid, and clindamycin were administered. The parapharyngeal abscess secretion culture was positive for S. viridans and Bacteroides spp. The patients condition improved with antibiotic therapy; he was discharged 5 days after admission. Discussion: Tumor necrosis factor-α plays an essential role in the immune-mediated response to infection. In our patient, the most possible cause of parapharyngeal abscess was considered to be etanercept because of the temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the abscess developed. Based on the Naranjo probability scale, an association between etanercept and the adverse reaction could be considered possible. Conclusions: Patients initiated on etanercept therapy should be closely monitored for the development of tuberculosis and other infections. During treatment, all febrile or novel illnesses should be evaluated promptly. If clinical evaluation leads to the suspicion of tuberculosis and other infections associated with etanercept, it should be discontinued immediately.