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Doxazosin in a gastrointestinal therapeutic system formulation.

A new formulation of doxazosin, the gastrointestinal therapeutic system (GITS), has been developed to change the drug delivery rate and the pharmacokinetic profile of the drug, allowing a more gradual absorption of doxazosin, thus reducing the plasma doxazosin trough-to-peak ratio and minimizing the need for titration. In patients with hypertension or symptomatic benign prostatic hypertrophy, doxazosin GITS is efficacious as doxazosin standard formulation but has better tolerance and eliminates the need for titration.

Journal Article↗

General pharmacology of gemcitabine hydrochloride in animals.

Gemcitabine (2',2'-difluorodeoxycytidine monohydrochloride, LY188011 hydrochloride, CAS 122111-03-9) is a nucleoside analog with a broad spectrum of antitumor activity in murine models and is currently undergoing clinical evaluation. The profile of the pharmacological effects of this agent was assessed in studies evaluating the cardiovascular and respiratory systems, renal function, the gastrointestinal system, the central nervous system, and the autonomic nervous system. In vivo doses ranged from 0.15 to 300 mg/kg given by the intravenous route, while in vitro concentrations up to 1 x 10-3 mol/l were used. Gemcitabine was inactive in the autonomic nervous system, gastrointestinal function, and central nervous system studies. Only minimal changes were seen in the cardiovascular and respiratory study, with a slight decrease in pulmonary arterial pressure at the mid dose and a stroke volume increase at the high dose. In the renal function studies, a slight decrease in the urine pH at the high dose and decreased serum creatinine at the mid dose levels were observed. In summary, gemcitabine had minimal effect in these pharmacodynamic studies. These results indicate that gemcitabine has a low potential to produce adverse pharmacologic effects.

Animals↗

SISCOPE: a multiuser information system for gastrointestinal endoscopy.

SISCOPE is an integrated data management system for use in gastrointestinal endoscopy units which operates in the multiuser mode on UNIX minicomputers or MS-DOS personal computers and can be used for patient bookings, endoscopic data entry and retrieval, and automatic report generation in upper gastrointestinal endoscopy, proctologic examinations, colonoscopy and peritoneoscopy. The description of endoscopic findings is remarkably detailed and data entry very rapid due to an advanced design of input screens that incorporates several recent concepts, including windows, menu bars and pull-down menus; typing is eliminated as data is entered with a mouse by pointing at options within menus. Endoscopic findings can be described under eight headings: morphology, topography, qualifiers, modifiers, signs of bleeding, endoscopic diagnosis, pathological diagnosis and etiology. Terminology is based strictly 3on the OMED system. SISCOPE also allows recording of details on endoscopic procedures, indications for the examination, preparation, premedication, complications and late entry of pathology reports. After entering all data, a report in natural language is produced automatically, the entire process taking one minute on average. Data retrieval programs give on-line access to previous examinations of a given patient and automatically generate activity reports. A formal language allows direct queries to the database and transfer of data for statistical analysis or other data processing. The system is simple to learn and use because operation is intuitive and all endoscopic techniques share the same basic menu structure and screen design.

Computer Systems↗

Morning versus evening administration of nifedipine gastrointestinal therapeutic system in the management of essential hypertension.

The nifedipine gastrointestinal therapeutic system (GITS) is a recently developed controlled-release formulation for once-a-day dosing. We evaluated the influence of morning versus evening administration of the drug in a randomized double-blind cross-over study including 15 essential hypertensives. Five patients had to be excluded from blood pressure analysis because of noncompliance (three cases) or intolerable side effects (two cases). To assess the exact duration of the antihypertensive efficacy noninvasive automatic ambulatory blood pressure monitoring was performed. After a placebo period patients were given 30 mg nifedipine GITS either at 1000 or 2200 hours. Twenty-four-hours systolic and diastolic blood pressure profiles documented a sustained antihypertensive effect of both nifedipine regimens throughout the whole period without affecting the circadian rhythm. Statistical analysis revealed no significant difference between morning and evening administration. Two patients stopped their medication because of intolerable side effects (fatigue and muscle cramps, respectively). Two more cases suffered from mild reversible headache which provoked no discontinuation of the drug. In conclusion our results document a sustained antihypertensive efficacy of 30 mg nifedipine GITS in patients with moderate essential hypertension. Time of administration has no impact on day- and nighttime blood pressure control.

Aged↗

Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris. The Netherlands Working Group on Cardiovascular Research (WCN).

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the beta-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 +/- 117s, time to onset of pain from 619 s by 56 +/- 120 s, and total exercise time from 685 s by 40 +/- 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 +/- 129 s, time to onset of pain from 572 s by 57 +/- 118 s, and total exercise time from 653 s by 33 +/- 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise (P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly (P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Administration, Oral↗

Systemic and gastrointestinal candidiasis of infant mice as model for antifungal therapy.

Systemic and gastrointestinal infection was established in infant (15-19 days old) mice after oral-intragastric challenge with Candida albicans. All survivors retained high levels of organisms in the liver, kidney, spleen, stomach and intestine up to the 24th post infection day. These animals with persistent infections were used to study the efficacy of short term antifungal therapy. Drug treatment was initiated on 13th day for a two week period, treatment with fluconazole was compared with amphotericin B, and 5 fluorocytosine. The results suggest that fluconazole is a useful drug in the treatment of gastrointestinal candidiasis.

Amphotericin B↗

Intestinal response in aging: changes in reserve capacity.

In contrast to the cardiovascular system, the gastrointestinal tract in old age does not reveal the marked structural and functional deteriorations that might be expected to arise from the body's aging process. Besides preserving an active mass of functional tissue, the intestinal regulatory mechanisms show a precise and functional response to the changing circumstances of aging. With regard to the aging processes, therefore, the relative physiological stability of the gastrointestinal system is very important. A possible cause of the maintenance of its functional capacity may be the processes involved in the cellular aging and rapid turnover of the gastrointestinal epithelium. This part of the gut remains practically unchanged and may continue its growth processes almost up to the point of death. Thus, intestinal functions do not seem to deteriorate even in late age. Kinetic studies indicate that the intestinal response in senescense to secure normal absorption processes occurs through an adaptation of transfer (carrier mediated) mechanisms. Such model studies have suggested that with age the affinity of the intestinal carrier mechanisms for the absorption of glucose and neutral amino acids are diminished. Appropriate changes in absorption occur i.e. in the young a faster rate of absorption is achieved at low luminal concentration than in the old. The amounts and activities of many essential intestinal enzymes have been observed to be reduced with age. This too may lead to a slower rate of absorption. In old age therefore it is the rate of intestinal absorption that undergoes a significant change rather than an overall deterioration in absorptive ability. Our present knowledge indicates that there are at least two important regulatory mechanisms that enable the aged gastrointestinal tract to adapt itself to its altered functional capacity. On the one hand, the response of the intestinal epithelium mediated by the various rapid repair processes for the uptake of substances needed by the organism, and, on the other hand, the existence of the current load in the luminal environment controlling the intestinal metabolism and homeostasis in a normal way during aging. An analysis of the close relationship that exists between structure and function in the gastrointestinal tract during aging, in particular the reasons for the observed alterations of the absorptive surfaces, will undoubtedly be useful in the practical elucidation of such problems as mucosal injuries, resection and malabsorption therapy.

Aged↗

Bioavailability of D-penicillamine in a patient with gastrointestinal progressive systemic sclerosis.

D-penicillamine pharmacokinetics were studied in a patient with gastrointestinal progressive systemic sclerosis possibly complicated by malabsorption. D-penicillamine bioavailability was examined after oral, duodenal, intravenous and rectal administration. No D-penicillamine was detectable in plasma after administration to the gastrointestinal tract. The pharmacokinetics after intravenous administration agreed closely with the corresponding situation in healthy volunteers.

Administration, Oral↗

Blood pressure control in patients with mild to moderate essential hypertension switched from nifedipine gastrointestinal therapeutic system (GITS) 30 mg to nifedipine GITS 20 mg.

BACKGROUND: Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides sustained plasma nifedipine concentrations throughout the 24-hour dosing interval. OBJECTIVE: This study was undertaken to determine if adult patients with mild to moderate essential hypertension whose blood pressure had been controlled for > or = 3 months with nifedipine GITS 30 mg could be successfully switched to a 20-mg daily dose with continued antihypertensive efficacy. METHODS: This was a randomized, double-blind, parallel-group study. Patients entered a 1-week run-in period during which they continued to receive their usual antihypertensive medication, including nifedipine GITS 30 mg. After baseline assessment, patients entered a 6-week treatment period during which they were randomly assigned to receive nifedipine GITS 30 or 20 mg. Men and women were eligible to participate if they were > or = 55 years of age, had received a diagnosis of mild to moderate essential hypertension (sitting diastolic blood pressure [DBP] 95-114 mm Hg), and had exhibited good blood pressure control (sitting DBP < or = 90 mm Hg) while taking nifedipine GITS 30 mg once daily for > or = 3 months. Systolic blood pressure (SBP), DBP, and heart rate were recorded at baseline and after 1, 3, and 6 weeks of treatment. Adverse events were reported by patients. The responder rate was defined as the percentage of patients whose sitting DBP was < 95 mm Hg at the final study assessment. Results were based on the intent-to-treat analyses, which included data for all patients who received > or = 1 dose and had 1 postbaseline blood pressure assessment. Statistical significance was set at P < 0.05. RESULTS: Seventy-five patients entered the 1-week run-in period; 71 patients (94.7%) were randomized to treatment. Twenty-four patients received nifedipine GITS 30 mg for 43.0 +/- 3.3 days, and 47 patients received nifedipine GITS 20 mg for 42.5 +/- 6.7 days. Both groups exhibited a sustained decrease in blood pressure throughout the study; minor variations were not statistically significant. End-point SBP and DBP for the 30- and 20-mg groups were 135.5 +/- 9.8/81.7 +/- 5.4 mm Hg and 138.6 +/- 11.8/82.9 +/- 7.6 mm Hg, respectively. Changes from baseline in end-point SBP and DBP did not differ significantly between groups. At the end of treatment, goal DBP (< 95 mm Hg) was achieved by 24 of 24 patients (100%) receiving the 30-mg dose and 45 of 47 patients (95.7%) receiving the 20-mg dose. Blood pressure control (sitting DBP < 90 mm Hg) was achieved by 21 of 24 (87.5%) patients in the 30-mg group and 35 of 47 (74.5%) patients in the 20-mg group. The most commonly reported adverse event was headache; 2 patients discontinued the study because of adverse events. Overall, 9 of 24 patients (37.5%) in the 30-mg group and 14 of 47 patients (29.8%) in the 20-mg group experienced > or = 1 treatment-related adverse event. CONCLUSIONS: Patients whose mild to moderate essential hypertension is controlled with nifedipine GITS 30 mg once daily may be able to switch to 20 mg once daily with continued antihypertensive efficacy. In addition to safety and economic advantages, such a switch may be a reasonable alternative in patients with lower body weight or as an adjunct to existing antihypertensive therapy.

Aged↗

Effectiveness of nifedipine gastrointestinal therapeutic system for treatment of hypertension: results of the MATH Trial.

Nifedipine gastrointestinal therapeutic system (GITS), a controlled-release delivery system given once a day, was evaluated in a multisite study of mild-to-moderate hypertensive subjects, seated diastolic pressure between 95 and 110 mm Hg, on placebo. Of 1,666 subjects enrolled, 69% were eligible to begin treatment. Therapy with nifedipine GITS was started at 30 mg daily and increased by 30 mg/day each week until there was a response (seated diastolic pressure < 90 mm Hg and a reduction of > or = 10 mm Hg) or until a maximum dose of 180 mg/day was reached. After titration, responders were kept on active treatment for 12 more weeks. Seventy-six percent of those treated responded, and 88% of the responders completed the 12-week phase. Comparisons were made among relevant subgroups. Elderly patients (age > or = 65 years) had a significantly higher response rate at a lower average daily dose, compared with younger subjects. Response rates were > 70% and relatively similar in (a) white and black patients, (b) diabetic and nondiabetic patients, (c) men and women, and (d) normal-weight, over-weight, and obese patients. Nifedipine GITS had no significant effect on fasting serum glucose or cholesterol fractions. Edema and headache were the most often observed adverse effects during treatment. Incidence of the former was related to dose but occurred without evidence of fluid retention (average body weight fell significantly by 1% during treatment). As antihypertensive monotherapy given once a day, nifedipine GITS is effective and well tolerated for a wide spectrum of hypertensive patients.

Administration, Oral↗

Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma).

Gastrointestinal dysmotility in systemic sclerosis (scleroderma) is prevalent in 90% of patients, increasing morbidity and in some cases mortality. The resultant gastrointestinal complications are usually extensive, involving many regions of the gut from the oesophagus to the anus. Collagen replacement of vascular and enteric smooth muscle results in hypomotility, lumen dilatation, tensile rigidity and eventual loss of organ functions. The aim of this paper is to provide an overview of systemic sclerosis-related gastrointestinal dysmotility and available/potential therapeutic options. We evaluated published data on the pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis patients using the MEDLINE database for English and non-English articles from 1966 to July 2005. Based on this systematic review, lifestyle and medical therapy approaches are preferred as they often improve and/or ameliorate symptoms. Surgery is only recommended with serious, rare complications such as bowel perforation or ischaemia. Alternative therapies such as acupuncture-based therapies are well tolerated, with clinical improvement and may be of potential therapeutic benefit for systemic sclerosis gastrointestinal dysmotility. Further elucidation of initiating and persistent mechanisms of systemic sclerosis-related gastrointestinal dysmotility will optimize the development of a multidisciplinary and more directed treatment regimen.

Colon↗

Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles.

Delta-Notch signalling regulates cell-fate decisions in a variety of tissues in diverse organisms, through cell-to-cell interactions. Here, we report the expression pattern of a Delta gene family member, Delta-like 4 (Dll4). Dll4 expression was analyzed in mouse embryos and selected adult organs by monitoring beta-galactosidase (beta-gal) expression from a lacZ reporter cassette inserted downstream of the Dll4 promoter, which allowed for high sensitivity and single cell resolution. Expression was detected in several tissues where Notch signalling is known to control cell-fate decisions, like the vascular system, the nervous system, the gastrointestinal system, and the thymus. Throughout embryonic cardiovascular development, Dll4 expression was seen only on endocardial cells and endothelial cells of the arteries, arterioles, and capillaries, being absent from vascular smooth muscle cells and veins. In the nervous system, expression was detected in the brain, neural tube, retina, and, for the first time, in the olfactory epithelium, vomeronasal organs and para-aortic bodies. Extensive Dll4 expression was also observed in the gut. This detailed expression analysis reveals new clues for both endothelial and non-endothelial Dll4 function in different organs.

Animals↗

Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management.

Opioid tolerance and withdrawal have been challenges for decades. The neurochemical mechanisms of tolerance and dependence are clinically important only because they can affect weaning schedules and the adjustment of doses for neonates. Analgesic effects are characterized by an increased depolarization threshold for the neuron, shorter duration of the action potential generated, and reduced release of neurotransmitters. Tolerance and withdrawal are associated with the reversal of these cellular effects. Adverse clinical effects associated with the use of opioids in neonates include respiratory depression, chest wall rigidity, urinary retention, and decreased gastrointestinal motility. The physiological systems most prominently affected by opioid withdrawal include the central nervous system, gastrointestinal system, and the autonomic nervous system. Opioid withdrawal symptoms in neonates can be assessed by using easily available scoring systems, although these need to be validated for different populations. Management of opioid withdrawal includes the use of other opioids, benzodiazepines and alpha-2 adrenergic receptor antagonist, clonidine. Careful titration of opioids with attention given to appropriate weaning schedules can reduce the incidence of withdrawal in neonates.

Drug Tolerance↗

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain.

BACKGROUND: Introduced in 1997, the combination of hydrocodone and ibuprofen is the only fixed-dose combination analgesic containing an opioid and ibuprofen that has been approved by the US Food and Drug Administration. OBJECTIVE: This study compared the efficacy and tolerability of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HC/IB) with those of combination oxycodone 5 mg and acetaminophen 325 mg (OX/AC) in the treatment of moderate or severe acute low back pain. METHODS: This was a multicenter, randomized, double-blind, parallel-group, repeat-dose study lasting up to 8 days. The recommended dosing of the study medications was 1 tablet every 4 to 6 hours, not to exceed 5 tablets per day. If adequate pain relief was not obtained, patients were permitted to take up to 4 doses per day of supplemental analgesic medication-the nonopioid component of the assigned study medication (ibuprofen 200 mg or acetaminophen 325 mg). Measures of efficacy included mean daily pain relief scores (0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good relief, and 4 = complete relief), mean daily number of tablets and doses of study medication, mean daily number of tablets and doses of supplemental analgesic medication, global evaluation (poor, fair, good, very good, or excellent), and results on the modified 36-item Short-Form Health Survey (SF-36). All efficacy measures were analyzed on an intent-to-treat basis. Tolerability was evaluated based on adverse events reported spontaneously or elicited by the in vestigators using nonsuggestive questioning, as well as on the number of patients discontinuing treatment because of adverse events. RESULTS: The study enrolled 147 patients (75 HC/IB, 72 OX/AC). The most common cause of low back pain was muscular/ligamentous injury (97/147; 66.0%), followed by degenerative disk disease (27/147; 18.4%). At baseline, 80 patients (54.4%) reported experiencing moderate pain, and 67 patients (45.6%) reported experiencing severe pain. There were no significant differences between HC/IB and OX/AC with regard to mean ( +/- SD) daily pain relief scores (2.40 +/- 1.06 vs 2.50 +/- 1.01, respectively), mean daily number of tablets of study medication (1.80 +/- 1.70 vs 2.20 +/- 1.60), mean daily number of doses of study medication (1.80 +/- 1.65 vs 2.10 +/- 1.58), mean daily number of tablets of supplemental analgesic medication (0.60 +/- 1.13 vs 0.50 +/- 0.99), mean daily number of doses of supplemental analgesic medication (0.60 +/- 1.07 vs 0.50 +/- 0.90), global evaluations, or mean scores on the modified SF-36. In addition, there were no significant differences in the proportion of patients experiencing adverse events with HC/IB (47; 62.7%) and OX/AC (45; 62.5%). Adverse events were consistent with those generally associated with the component analgesics and predominantly involved the central nervous system and gastrointestinal system. CONCLUSIONS: The results of this study suggest that HC/IB and OX/AC are similarly effective and tolerable in relieving moderate or severe acute low back pain. Additional controlled longitudinal trials are necessary to evaluate the clinical utility of HC/IB in treating acute low back pain.

Acetaminophen↗

Intensive care: cost and benefit.

This study presents a review of 961 patients treated in the general intensive care unit (ICU) of Akershus Central Hospital (ACH) from 1978 to 1981, including also a follow-up study of the 419 patients treated in 1978 and 1979 who were observed for an average period of 20 months after admittance to the ICU. The ICU patients represented 1.7% of all the patients admitted to the referring departments. Approximately 2/3 (67.3%) of the patients were surgical patients, representing 2.9% of the patients treated in that department, 19.6% were medical patients, and 8.6% came from the department of pediatrics. Surgery was the main reason for ICU admittance in 48.1% of the patients; in 70% of these, surgery by itself made postoperative intensive care necessary. Acute or chronic cardiovascular or respiratory disorders caused or contributed to ICU admittance in 78% of the patients; disorders of the nervous system (29.0%), gastrointestinal system (25%), and severe infections (28%) came next. The average stay in the ICU was 6.2 days. The patient's need for observation, nursing and therapy was assessed daily according to a care grade scale from 1 to 5, with 5 as maximum effort. The average care grade during the stay, multiplied by the duration of stay in days, gave the care product, which was used as an expression of the patient's need for ICU resources. The sum of care products for all the patients through 1 year thus expressed the total work load on the ICU. The ICU budget for 1 year, divided by the total care product for the same year, and thereafter multiplied by the care product for single patients or patient groups, was used as the basis for calculation of ICU costs. Patients receiving mechanical ventilation required 95% of the total work load in the ICU, and 66.3% of these efforts were directly associated with the ventilator treatment period as judged by the care product. Complications to treatment were recorded in 7.3% of the patients, and four of these patients dies of such complications. Improvement by intensive care was achieved in 81.4% of the patients, 5.2% were unchanged, and 13.4% died while in the ICU. Mortality was 9.5% below and 19.3% above the age of 60 years. Of the 419 patients who were followed for an average period of 20 months after admittance to the ICU, 56 died in the ICU, 28 died later during the same stay in ACH, and another 47 died after discharge from ACH, whereas 288 (68.7%) were still alive.(ABSTRACT TRUNCATED AT 400 WORDS)

Cost-Benefit Analysis↗

Medicinal plants popularly used in the Xingó region - a semi-arid location in Northeastern Brazil.

The aim of this study was to identify plant species among the diverse flora of the caatinga ecosystem that are used therapeutically. Research was undertaken in the municipalities of Piranhas and Delmiro Gouveia, in the Xingó region (state of Alagoas, NE Brazil). In order to identify the medicinal plants used in this region, semi-structured questionnaires were applied. The species cited were collected and sent to the Xingó Herbarium for taxonomic analysis. The relative importance (RI) of each species cited was calculated to verify their cultural importance. The therapeutic indications attributed to the species were classified under 16 body systems. A total of 187 medicinal species were cited, from 64 families and 128 genera. The main indications for medicinal plant use were against common colds, bronchitis, cardiovascular problems, kidney problems, inflammations in general, and as tranquilizers. Approximately 16% (30 plant species) were versatile in relation to their use, with an Relative Importance value over 1, having been indicated for up to nine body systems. The body systems that stood out the most were: the respiratory system, the gastrointestinal system, and infectious diseases. Most cited plant parts used for medicinal purposes were flowers, leaves, and inner stem bark.

Adult↗

[Adverse drug reactions in a Suba hospital of Bogotá].

OBJECTIVE: This study was carried out in order to identify, document and assess suspect of Adverse Drug Reactions (ADR) that are report to pharmacovigilance program of Suba Hospital. METHODOLOGY: It was carried out an observational, descriptive and longitudinal study, in all the patients that consulted to the services of Urgencies and External Consultation, in the Hospital of Suba of the Bogotá city. RESULTS: During the period of study 46 reports of suspicion of ADR were received, from those which 26 (56,6 %) corresponded to consultation reason, the 20 remaining it was indoor patient . In the classification for Organ-System, the gastrointestinal system presents the highest percentage of reports (30,4 %), followed by the cardiovascular (17,4 %), nervous central system (13 %), Skin (13 %), Obstetric (10,9 %), renal system (4,3 %). The therapeutic Groups with more reported percentages of suspicion of ADR were Antipsychotic (30,4 %), Nutritional Supplements (17,4 %), Anti-infective (10,9 %), the other pharmacological groups present similar or inferior percentages to those mentioned previously. The incidence of ADR as consultation reason was 3 ADR consultation reason/10,000 consultations / month. CONCLUSIONS: It was identify to pregnant, children and young people as a risk group to development an ADR. A low proportion it was clasificated as a serious and less than half as a possible according World Health Organization algoritm.

Adolescent↗