Jean-Pierre Blayac

Adverse Drug Events Associated with Hospital Admission

OBJECTIVE To increase the knowledge base on the frequency, causality, and avoidability of adverse drug events (ADEs) as a cause for admission in internal medicine or when occurring during hospitalization. METHODS A prospective study was performed for 6 periods of 8 days each. Epidemiologic data (e.g., age, gender, medical history), drug utilization, and adverse drug reactions on patients hospitalized during these periods were collected by a pharmacy student. RESULTS A total of 156 patients (70 men and 86 women) were included in the study. The patients’ mean age ± SD was 66.5 ± 18.1 years and mean length of stay was 13.2 ± 9 days. Renal and hepatic insufficiency and previous history of drug intolerance were observed in 17.9%, 10.2%, and 2% of the hospitalized patients, respectively. Thirty-eight ADEs occurred in 32 patients; in 15 cases, ADEs were identified as the reason for admission, 10 cases occurred during hospitalization, and 13 cases were present at admission, but were not the cause of admission. The most frequent ADEs involved the neurologic (23.6%), renal (15.7%), and hematologic (13.1%) systems. Among these 38 ADEs, 22 were considered avoidable (57.9%); 20 of these were associated with therapeutic errors (inappropriate administration, drug–drug interactions, dosage error, drug not stopped despite the onset of ADEs). Patients with ADEs stayed longer in the hospital and took more drugs both before and during their hospital stay (p < 0.05). CONCLUSIONS Most of the ADEs observed in this study were avoidable. The risk/benefit ratio of administered drugs could be improved with better knowledge of the patients’ medical history and the risk factors of ADEs.

Antipsychotics‐induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database

First‐ and second‐generation antipsychotics commonly cause mild gastrointestinal hypomotility. Intestinal necrosis may be a consequence of such gastrointestinal perturbations.

Methadone Withdrawal Symptoms with Nevirapine and Efavirenz

within the first month of therapy, which is in accordance with the current l i t e r a t u r e .1 , 2 It must be noted that the only fatal event concerned a patient treated for coronary stenting who also consumed acetylsalicylic acid chronically, and paracetamol during the four days preceding the adverse reaction. The available data do not allow a definitive causality assessment due to the aspirin and paracetamol involvement. The other three cases involved patients treated for other thrombotic arteriopathies. We conclude that sending a “Dear Health Professional” letter led to a clear increase in the number of spontaneous hematologic adverse reaction reports for ticlopidine, probably due to the interest raised. However, it is not possible to establish from our data, which derive only from spontaneous monitoring, if earlier diagnosis and a reduction in mortality were effectively achieved in patients with TTP.

Multiple Congenital Malformations Associated with Topical Tretinoin

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Effects of α-adrenoceptor agonists and antagonists on insulin secreting cells and pancreatic blood vessels: comparative study

The effects of alpha-adrenergic drugs were studied on glucose-induced insulin secretion and effluent flow rate on the same preparation: the isolated perfused rat pancreas. An alpha 1-adrenoceptor agonist, phenylephrine 0.05 microM slightly decreased insulin secretion (-25%); this inhibition was counteracted by an alpha 2-adrenoceptor antagonist, yohimbine 0.6 microM. Phenylephrine evoked a fall in liquid flow rate (-13%) which was reversed by an alpha 1-adrenoceptor antagonist, prazosin 6 microM, but not by yohimbine. An alpha 2-adrenoceptor agonist, clonidine 0.01 and 0.05 microM decreased insulin secretion (-80%). This inhibition was reversed by yohimbine 0.6 and 6 microM respectively. Only the concentration of 0.05 microM clonidine evoked a fall (-25%) in liquid flow rate; this fall was counteracted by yohimbine 0.6 microM. In conclusion our results show that adrenergic inhibition of insulin secretion is mediated only by alpha 2-receptors whereas both types of adrenoceptors are implicated in the vasoconstrictor effect. The insulin inhibitory effect of adrenoceptor agonists is not related to vasoconstriction.

Hepatitis After Intravenous Injection of Sublingual Buprenorphine in Acute Hepatitis C Carriers: Report of Two Cases of Disappearance of Viral Replication After Acute Hepatitis

Objective To report 2 cases of acute hepatitis related to intravenous administration of buprenorphine in hepatitis C–infected patients. Case Summary Two patients, aged 33 and 50 years, respectively, who were hepatitis C virus (HCV) carriers were treated with sublingual buprenorphine 8 mg/day for addiction. Several years after initiation of buprenorphine, they were hospitalized because of clinical hepatitis with jaundice that developed after intravenous injection of buprenorphine. Serum alanine aminotransferase rose to 100 times the upper limit of normal (ULN) in the first patient and to 21 times the ULN in the second. As cofactors, the first patient had consumed alcohol, and the second patient took aspirin 600 mg in addition to the injection of buprenorphine 20 mg 4 days before the onset of jaundice. After stopping the intravenous injections, both patients continued sublingual buprenorphine therapy, with no relapse of hepatitis. Interestingly, in these 2 patients, buprenorphine-induced hepatitis was followed by the disappearance of HCV RNA. Discussion Most cases of hepatotoxicity related to buprenorphine have occurred in hepatitis C–infected patients. The main mechanism for buprenorphine-induced hepatitis is a mitochondrial defect, exacerbated by cofactors with additional potential to induce mitochondria dysfunction (eg, HCV, alcohol, concomitant medications). According to the Naranjo probability scale, buprenorphine was found to be the probable cause of acute hepatitis in both patients. In addition, we assessed the relationship between intravenous buprenorphine and acute hepatitis using 2 scales for causality assessment of hepatotoxicity (the Council for International Organizations of Medical Sciences scale and the Maria & Victorino scale). The diagnosis of intravenous buprenorphine-induced hepatitis was classified as probable in both cases. In addition, these 2 cases illustrate that acute hepatitis in a carrier of chronic HCV may occasionally facilitate the clearance of virus. Conclusions Although buprenorphine is well tolerated when used at recommended sublingual doses, patients should be informed about the risk of acute hepatitis with misuse of the drug by the intravenous route. These cases illustrate that, in carriers of chronic HCV, acute hepatitis may modify the hosts immunotolerance and facilitate clearance of the virus.

Optimal Management of Methotrexate Intoxication in a Child with Osteosarcoma

OBJECTIVE To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with osteosarcoma treated with high-dose MTX. CASE SUMMARY During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations, acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2 and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient. Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations observed. DISCUSSION According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo probability scale indicated a probable relationship between the complications and MTX. CONCLUSIONS This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be considered.

Slow-Release Oral Morphine Sulfate Abuse: Results of the Postmarketing Surveillance Systems for Psychoactive Prescription Drug Abuse in France

Background: Few data are available concerning the diversion and abuse of morphine sulfate. In France, morphine sulfate abuse is currently investigated by the health authorities. The aim of our study was to provide data on morphine sulfate abuse in France, collected during the period 1996–2011. Methods: The French monitoring system for psychoactive medication abuse collected data from several sources: spontaneous reporting of cases of abuse or dependence (NotS; ‘Notifications Spontanées’), specific periodic surveys from specialized care centers (OPPIDUM; ‘Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse’), and community pharmacists (OSIAP; ‘Ordonnances Suspectes Indicateur d’Abus Possible’). Results: A total of 649 cases (75% men, median age: 34 years) were spontaneously reported: 578 cases of abuse and 71 cases of use as opiate maintenance treatment. The medication formulation was Skenan® (614 cases), and Moscontin® (35 cases). All surveys (NotS, OPPIDUM, and OSIAP) showed an overrepresentation of Skenan® (87.9–94.6% of cases) that was intravenously injected in 60.4–61.2% of the cases. Data analysis showed that patients abusing morphine sulfate have a long history of drug abuse and a history of polydrug use. Conclusion: All the data presented in this study highlight the level of morphine sulfate abuse, specify the modalities of use (intravenous route), and show the risks associated with abuse (infectious diseases). This study outlines the usefulness of our epidemiological tools, and provides evidence supporting intensive surveillance.

Carboxypeptidase G2 rescue in delayed methotrexate elimination in renal failure.

We report here the case of a 68-year-old woman who presented severe renal failure following the first cycle of high dose methotrexate (HDMTX) for the treatment of a cerebral malignant lymphoma. Before HDMTX administration, serum creatinine value was normal and three days after HDMTX, it reached 457 μmol/ L. Leucovorin rescue, hemodialysis and cholestyramine did not increase MTX clearance. Because of the persistence of renal failure, and the high risk of important hematological side-effects associated with high MTX plasma levels, the patient received carboxypeptidase G2 (CPDG2). This allowed MTX plasma levels to decrease by 80% in 15 minutes. No side effects were observed and renal function normalized rapidly. In some patients, when high-dose leucovorin associated with hemodialysis and cholestyramine are unable to restore normal MTX clearance, CPDG2 should be considered because it may represent a safe and efficient alternative for the management of MTX intoxication.

Neurotoxicity Related to Valganciclovir in a Child with Impaired Renal Function: Usefulness of Therapeutic Drug Monitoring

Objective: To report a case of neurotoxicity related to antiviral drugs, discuss the involvement of concomitant medications, and document the pharmacokinetics of ganciclovir (administered as valganciclovir) in a child with impaired renal function. Case Summary: A 13-year-old boy with acute lymphoblastic leukemia was treated for cytomegalovirus retinitis with valganciclovir 450 mg every 2 days in the course of hematopoietic stem cell transplantation. Concomitant medication included omeprazole, furosemide, and acetaminophen. During treatment, when creatinine clearance decreased to 20 mL/min, the child presented with acute neurotoxicity, consisting of mental confusion and hallucinations, which resolved when all medications were stopped. Valganciclovir therapeutic monitoring showed high ganciclovir concentrations in the plasma (3.85 μg/mL) and cerebrospinal fluid (2.6 μg/mL) 48 hours after the last valganciclovir dose. After recovery of neurologic function, valganciclovir was resumed at a lower dosage (225 mg twice a week) with therapeutic drug monitoring and was well tolerated. However, the cytomegalovirus infection was not resolved. The leukemia relapsed, and the patient had terminal renal failure and died. The Naranjo probability scale indicated a probable relationship between valganciclovir and neurotoxicity. Discussion: Drugs taken by this child (acyclovir, valganciclovir, omeprazole) have been reported to induce neurotoxicity, with the pharmacokinetics of the first 2 being altered by renal failure. At the time when acyclovir was first administered, symptoms of neurotoxicity were already apparent. Moreover, plasma concentrations of ganciclovir were very high during the course of the neurotoxicity. Thus, the adverse effects seemed related to an overdosage of valganciclovir and were worsened by the addition of acyclovir. Conclusions: This case is informative because few clinical and pharmacokinetic data are available concerning the use of valganciclovir in children. A study should be performed to determine the proper pediatric dose of valganciclovir with and without renal impairment to prevent the occurrence of adverse effects.