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Anaphylactic Reaction to Drugs
Commonly Used for Gastrointestinal
System Diseases: 3 Case Reports and
Review of the Literature
1 Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey 2 Department of Chest Diseases, Adult Allergy Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey Abstract. Proton pump inhibitors and H receptor antagonists, which are commonly used to treat peptic ulcer and
gastroesophageal reflux diseases, are associated with a low incidence of adverse reactions. We report 3 cases ofanaphylactic reactions induced by lansoprazole or ranitidine diagnosed in a population of 8304 first-referral patientsover a 13-year period. Cutaneous sensitivity to famotidine, ranitidine, omeprazole, pantoprazole, and lansoprazolewas evaluated by skin prick tests with a concentration of 10 mg/mL (at 1:1000, 1:100, 1:10 and 1:1 dilutions), andif they were negative, intradermal skin tests were performed with the same dilutions of the extracts. Single-blind,placebo-controlled oral provocation tests were performed with lansoprazole, omeprazole, famotidine, and ranitidinein 2 cases. One case involved anaphylaxis during an oral provocation test with lansoprazole, and 2 cases wereanaphylactic reactions to ranitidine. In both cases the skin test was positive for ranitidine and in 1 case an oralprovocation test was also positive. The second patient refused that test. Cross reactivity to other H receptor antagonists was not demonstrated and a safe alternative drug was found for all 3 patients. Although incidences ofanaphylactic reactions induced by proton pump inhibitors or H reactions are rare, they can be life threatening.
Key words: Anaphylactic reaction. Proton pump inhibitors. Histamine H antagonists.
Resumen. Los inhibidores de la bomba de protones y los antagonistas de los receptores H , utilizados habitualmente
en el tratamiento de la úlcera péptica y enfermedades por reflujo gastroesofágico, están asociados con una bajaincidencia de reacciones adversas. Se describen 3 casos de reacciones anafilácticas, inducidas por fármacos(lansoprazol y ranitidina) , que se produjeron en la Unidad de Alergia de adultos de nuestro hospital universitariode entre 8.304 pacientes de primera visita durante un período de 13 años. La sensibilidad cutánea a famotidina,ranitidina, omeprazol, pantoprazol y lansoprazol se evaluó mediante pruebas cutáneas (prick) con una concentraciónde 10 mg/ml (a diluciones 1:1000, 1:100, 1:10 y 1:1). En los casos en que las pruebas cutáneas (prick) fueronnegativas, se realizaron pruebas cutáneas intradérmicas con las mismas diluciones de extractos utilizadas en elprick. En dos casos, se llevaron a cabo pruebas de provocación oral controladas con placebo y ciego simple conlansoprazol, omeprazol, famotidina y ranitidina En un caso se desencadenó anafilaxia al realizar la prueba deprovocación oral con lansoprazol. También hubo dos pacientes que experimentaron reacciones anafilácticas debidoa la ranitidina. En uno de ellos, la prueba cutánea para la ranitidina fue positiva, pero puesto que el pacienterechazó la prueba de provocación oral, ésta no se realizó. No se ha demostrado reactividad cruzada con otrosantagonistas de receptores H en estos casos. Se recomendó al menos un fármaco alternativo seguro en los tres pacientes. Aunque las incidencias de reacciones anafilácticas inducidas por IBP y antagonistas de los receptoresH2 son raras, pueden ser responsables de riesgo vital.
Palabras clave: Reacción anafiláctica. Inhibidores de la bomba de protones. Antagonistas de los receptores H .
J Investig Allergol Clin Immunol 2006; Vol. 16(3): 203-209 Anaphylactic Reaction to Gastrointestinal System Drugs Introduction
findings. The patient was admitted to the intensive careunit (ICU) for monitoring and nasal oxygen therapy (4 Proton pump inhibitors and H receptor antagonists, L/min) was provided. An electrocardiogram was normal.
which are commonly used for the treatment of peptic ulcer After 24 hour in the ICU, she was discharged from the and gastroesophageal reflux disease, are associated with hospital with no further complications.
a low incidence of adverse reactions [1, 2]. We report 3 When the patient revisited our clinic to assess skin cases in which 3 such drugs (lansoprazole, famotidine tests for allergy to omeprazole, pantoprazole, and and ranitidine) induced anaphylactic reactions diagnosed lansoprazole, no reaction was seen with omeprazole or in our university hospital adult allergy clinic. The pantoprazole in skin tests. The epidermal tests with diagnoses were made out of a case load of 8304 first- lansoprazole were positive with dilutions 1:10 and 1:1.
referral patients over a 13-year period (January 1991- Her total IgE level was 18 kU/L. No reaction developed December 2003). We also review other reported after oral provocation tests with famotidine or omeprazole.
anaphylactic reactions induced by proton pump inhibitorsand H receptor antagonists in the literature.
Case Descriptions
A 49-year-old man with a history of allergic reactions to ranitidine and famotidine was referred to our clinic for further evaluation. He had experienced localizedangioedema on his hands 15 to 20 minutes after taking a A 54-year-old woman with a 2-year history of multiple 150 mg tablet of ranitidine (Ulcuran®) when he was 42 drug allergies, especially to antibiotics and drugs for years old. Approximately 6 to 7 months later, severe treating gastrointestinal system disease, was admitted to pruritus appeared 30 to 40 minutes after he took 150 mg our clinic to determine safe alternatives. The patient had of another brand of ranitidine (Ranitab®). The episode a history of 3 anaphylactic reactions, 2 of which were resolved within 2 to 3 hours without any intervention.
most likely to lansoprazole or to another drug prescribed Anaphylactic reaction (hypotension, shortness of breath, for gastrointestinal disease. It was not clear from the difficulty in swallowing, edema on hands, and generalized patient’s medication records, however, which drugs had severe pruritus) developed within 5 minutes of taking a triggered the reactions: 5 months earlier, she was admitted 20 mg famotidine tablet when he was 46 years old. As a to a city hospital with an anaphylactic reaction, but as result, he came to the emergency room.
she was taking several medications concurrently, the He has had persistent rhinitis since he was 42 years inducer drug could not be determined. The results of old. He did not have familial history of atopy.
complete blood counts and blood biochemistry tests were Intravenous ranitidine (Ulcuran®) had been within normal ranges during hospitalization. The patient administered (50 mg/8 h) for 3 days with no complications reported various reactions due to different drugs. She had in a general surgery ICU during hospitalization after a experienced faintness and unconsciousness with the use motor vehicle accident when he was 41 years old.
of opipramol, ramipril, amitriptyline, diltiazem, and Thereafter he had received 150 mg/12 h oral ranitidine estrogens; local allergy with etofenamate gel; and acute (Ranitab®) with no adverse reaction.
urticaria with ampicillin. She had a history of a partial Skin tests with famotidine (Nevofam®), ranitidine gastrectomy (at age 34), cholecystectomy (at age 41), (Ranitab®), omeprazole (Losec®), pantoprazole goiter (since age 39), and total abdominal hysterectomy (Pantpas®), and lansoprazole were performed and bilateral salpingo-oophorectomy (at age 51). Her intradermally and epidermally. The patient had only reacted when 0.1 mL of intradermal ranitidine was Oral provocation tests were planned at our clinic for administered at a dose of 0.01 mg/mL. All other skin test the medications (lansoprazole and famotidine) she had results were negative. His total IgE level was 620 kU/L.
been taking before the anaphylactic reaction. Twenty He refused an oral provocation test intended to find a minutes after taking 7.5 mg of lansoprazole, generalized flushing was observed over nearly the patient’s entirebody, and fatigue and nausea developed. Her bloodpressure was 80/50 mm Hg and pulse was 55 beats/min.
Following intravenous (IV) infusion of 500 mL of normalsaline, an IV push of 100 mg of prednisolone, and an IV A 49-year-old woman was admitted to the hospital to push of 91 mg (2 ampoules) of pheniramine, her pulse receive thirteen intravenous immunoglobulin treatments and BP recovered to 100 beats/min and 90/60 mm Hg, for isolated eye vasculitis with uveitis. Prednisolone (25 140/80 mm Hg, and 150/90 mm Hg after 30, 60, 90 mg), ranitidine (50 mg), and pheniramine (45.5 mg) were minutes. She also received nasal oxygen therapy at a rate administered intravenously and a paracetamol tablet (500 of 5 to 10 L/min. After 45 minutes, another IV push of mg) was administered orally as premedication 30 minutes 45.5 mg of pheniramine was administered because of before intravenous immunoglobulin treatment. She had tremors. Neurology consultation revealed no significant symptoms of numbness all over the body, dyspnea, J Investig Allergol Clin Immunol 2006; Vol. 16(3): 203-209 dysphonia, and edema of the face, lips, throat and tongue Single-blind, placebo-controlled oral provocation right after the ranitidine injection, which had followed tests were performed with lansoprazole, omeprazole, the pheniramine injection. There was no change in blood famotidine, and ranitidine at 30-minute intervals in pressure. A 45.5-mg IV push of pheniramine and a 50 mg fractionated dosages until the full therapeutic dose was IV push of prednisolone were injected, in addition to 5 to reached or there was an adverse reaction (hypotension, 6 L/min nasal oxygen therapy. All of the symptoms shortness of breath, difficulty in swallowing, swollen hands, and generalized severe pruritus). The interval During the oral provocation test with 75 mg of between the oral provocation test with each drug was at ranitidine, the patient experienced difficulty in swallowing least 48 hours. Written informed consent was obtained and breathing and throat edema. Physical examination from each patient before challenges. Tests were performed revealed bilateral rhonchi. Also administered were 100 by an allergist in the outpatient clinic where the means to mg IV of prednisolone, 91 mg IV of pheniramine and deal with an emergency were available. During the nebulized salbutamol at a concentration of 2.5 mg/2.5 mL.
procedure blood pressures, peak expiratory flow values and Blood pressure was sustained within normal range.
possible allergic reactions were monitored every 15 minutes Her past medical and surgical history included an up to 3 hours and every hour thereafter for 4 hours [4].
appendectomy (at age 18 years), tonsillectomy (at age Although H receptor antagonists and proton pump 21), coronary angiography (at age 43), lumbar disc hernia inhibitors are widely used for gastrointestinal problems, operation (at age 45), and isolated episodes of ocular anaphylactic reactions have rarely been described.
vasculitis with uveitis. Skin prick tests were not According to the reports in the Uppsala Monitoring Center performed, because the patient had been receiving oral database [5] for May 1999, the frequency of anaphylactic corticosteroids and intravenous immunoglobulin therapy.
reactions out of all reported adverse reactions for H2 Her family history was not remarkable.
receptor antagonists (cimetidine and ranitidine) and proton The patient had received omeprazole during recent pump inhibitors (lansoprazole, omeprazole and and earlier hospital admissions without adverse reactions.
pantoprazole) were between 0.2% and 0.7%. However, Furthermore oral famotidine was well-tolerated when she these percentages are from a database of reports from all types of physicians, not only from allergy clinicphysicians. The previously published cases summarizedin Tables 1 and 2 and the 3 cases we have reported in this Discussion
article (Table 3) were all well-documented life-threateninganaphylactic reactions.
For in vitro and in vivo tests, famotidine, ranitidine, Natsch et al [5] also reported a case of lansoprazole omeprazole, pantoprazole, and lansoprazole were used induced anaphylactic reaction during an oral provocation at a concentration of 10 mg/mL. Drugs used in test test that was similar to our Case 1. We also performed preparations were obtained as pure products from dealers skin tests with lansoprazole, omeprazole, and for the manufacturers. For this purpose, we used injectable pantoprazole, observing positive results only for famotidine (Nevofam®) 20 mg/mL, ranitidine (Ranitab®) lansoprazole. We have not demonstrated cross reactivity 50 mg/mL, omeprazole (Losec®) 40 mg/mL, pantoprazole (Pantpas®) 40 mg/mL, and lansoprazole (Lansor) 30 mg/mL We also report two patients who experienced diluted in phosphate-buffered saline (PBS), pH 7.3.
anaphylactic reactions due to ranitidine and famotidine.
For verifying cutaneous sensitivity to famotidine, In our Case 2, the skin test for ranitidine was positive, ranitidine, omeprazole, pantoprazole, and lansoprazole but since the patient refused the oral provocation test it was used in skin prick tests at a concentration of 10 was not performed. In our Case 3, the oral provocation mg/mL (at 1:1000, 1:100, 1:10 and 1:1 dilutions). Prick test result was positive with ranitidine. We have not and intradermal tests were carried out as described by demonstrated cross reactivity to other H antagonists in Österballe et al [3] by pricking the skin on the volar these cases, and we were able to provide at least one safe surface of the forearm with a special lancet. Histamine alternative drug for all three patients.
and saline were used as positive and negative controls, We searched the English language literature in relation respectively. Resulting wheals were measured after 15 to these 3 cases and summarized all reported anaphylactic minutes. A positive reaction was defined as a wheal with reactions with proton pump inhibitors (10 patients) [5- a geometric mean diameter of at least 3 mm. If the skin 13] and H receptor antagonists (6 patients) [4, 14-18] in prick tests were negative, intradermal skin tests were 2 tables (Tables 1 and 2). Ranitidine was the only H2 performed with the same dilutions of extracts used in the receptor antagonist for which reactions were reported.
skin prick tests. Five normal subjects served as controls According to the majority of cases given in Tables 1 and and all the skin tests performed in these controls were 2, skin prick tests and oral challenge tests were negative to other proton pump inhibitors and H antagonists, Total serum IgE was measured with an enzyme suggesting a pharmacological mechanism was not immune assay kit (Immulite 2000-TIE, Diagnostic implicated. A cross reaction was not present in the Products Corporation, Los Angeles, California, USA) according to manufacturer’s instructions.
According to our literature review, rabeprazole and J Investig Allergol Clin Immunol 2006; Vol. 16(3): 203-209 Anaphylactic Reaction to Gastrointestinal System Drugs Anaphylactic Reactions Induced by Proton Pump Inhibitors * OPZ indicates omeprazole; PPZ, pantoprazole, LPZ, lansoprazole, SBP J Investig Allergol Clin Immunol 2006; Vol. 16(3): 203-209 TN, indicates ranitidine; CTN, cimetidine; NTN, nizatidine; FTN, famotidine; PO, by mouth; IV J Investig Allergol Clin Immunol 2006; Vol. 16(3): 203-209 Anaphylactic Reaction to Gastrointestinal System Drugs esomeprazole are the only proton pumpinhibitors without any anaphylactic reactions reported in the literature. However, rabeprazole marketed. No anaphylactic reaction has been reported with any H receptor antagonist but antagonists are extensively used in clinicalpractice and they are well tolerated by patients.
However, these findings suggest that, although induced by these drugs are low, clinicians should be aware of this possibility of lifethreatening risk. Furthermore, the possibilityof cross reactivity between drugs in the samegroup should be considered.
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LPZ indicates lansoprazole; OPZ, omeprazole; PTZ, pantoprazole; FTN, famotidine; R Ulcuran, a brand name of ranitidine. ‡ Ranitab, a brand name of ranitidine.
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