ABSTRACT
Oseltamivir is contraindicated for people aged 10-19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First, the importance of animal models and the concept of human equivalent dose (HED) is summarized. Second, the specific condition for oseltamivir use, influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular level of evidence (channels, receptors and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA , GABAB and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic), respectively.
Subject(s)
Antiviral Agents/adverse effects , Central Nervous System/drug effects , Drug-Related Side Effects and Adverse Reactions , Oseltamivir/adverse effects , Receptors, Nicotinic , Animals , Antiviral Agents/metabolism , Central Nervous System/metabolism , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/metabolism , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/metabolism , Humans , Influenza, Human/drug therapy , Influenza, Human/metabolism , Oseltamivir/metabolism , Receptors, Nicotinic/metabolism , Respiratory Insufficiency/chemically induced , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/metabolismABSTRACT
Gorham disease (GD) is a rare osteolytic condition of unknown etiology that causes spontaneous, progressive bone resorption. The maxillofacial area is one of the regions most frequently involved in this disease. GD is characterized by its aggressiveness and rarity; therefore, the treatment modalities remain controversial, and no specific treatment method has been proved effective. The present report describes a case of GD with massive craniofacial bone involvement that was treated effectively using a combination of 5-fluorouracil and cisplatin, with 10 years of follow-up.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/administration & dosage , Fluorouracil/administration & dosage , Jaw Diseases/drug therapy , Orbital Diseases/drug therapy , Osteolysis, Essential/drug therapy , Adolescent , Biopsy , Female , Follow-Up Studies , Humans , Jaw Diseases/diagnostic imaging , Orbital Diseases/diagnostic imaging , Osteolysis, Essential/diagnostic imaging , Radiography, Panoramic , Skull/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
The effects of itopride hydrochloride, a new drug used to regulate motility in the gastrointestinal tract, on the delayed rectifier K+ current (I(K)) and the L-type Ca2+ current (I(Ca)) were evaluated in guinea-pig ventricular myocytes at concentrations of 1, 10 and 100 microM to determine whether the drug has a proarrhythmic effect through blockade of I(K). Itopride did not affect I(K) at concentrations of 100 microM or less, and no significant effects of 1, 10 or 100 microM itopride were observed on the inward rectifier K+ current (I(K1)) responsible for the resting potential and final repolarization phase of the action potential. We next investigated the effects of itopride on L-type Ca2+ current (I(Ca)). Significant inhibition of I(Ca) was observed at itopride concentrations greater than 10 microM. These results suggested that itopride hydrochloride has an inhibitory effect on I(Ca) at concentrations much higher than those in clinical use.
Subject(s)
Benzamides/pharmacology , Benzyl Compounds/pharmacology , Calcium Channels, L-Type/drug effects , Potassium Channels, Voltage-Gated , Potassium Channels/drug effects , Ventricular Function , Action Potentials/drug effects , Animals , Delayed Rectifier Potassium Channels , Electric Conductivity , Guinea Pigs , Heart Ventricles/drug effects , Male , Myocardium/cytologySubject(s)
Adverse Drug Reaction Reporting Systems , Drug-Related Side Effects and Adverse Reactions , Ribonucleosides/toxicity , Animals , Anti-Arrhythmia Agents/adverse effects , Clinical Trials as Topic , Disopyramide/adverse effects , Forecasting , Heart/drug effects , Humans , Japan , Pharmaceutical Preparations/classification , Toxicity TestsSubject(s)
Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/economics , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/economics , Asthma/drug therapy , Administration, Oral , Adult , Child , Clinical Trials, Phase III as Topic , Costs and Cost Analysis , Drug Evaluation/methods , Humans , JapanABSTRACT
Six patients who developed urticaria, dyspnea, and anaphylactic shock due to topical application of chlorhexidine gluconate solution are described. Chlorhexidine gluconate was confirmed as the causative agent of type I hypersensitivity by intradermal, scratch, and epicutaneous tests. To prevent life-threatening adverse reactions, it seems important to use chlorhexidine gluconate on wound surfaces at a concentration of 0.05%, as recommended by the manufacturer; chlorhexidine gluconate may not be suitable for application to mucous membranes.
