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Joseph D. Kay, MD, FACC
Gabapentin and pregabalin are in part absorbed and transported via the large neutral amino acid carrier (system L) (10) natural pet medicine 8 mg ondansetron with visa, but it is unclear whether mutations in this carrier affect absorption (11) symptoms 2016 flu discount ondansetron 4mg overnight delivery. P-glycoprotein expression increase has been well described in epileptic human and animal tissue (18 medicine zyprexa generic ondansetron 8 mg on-line,22) treatment of diabetes buy ondansetron 8mg. Despite the statistical association, the authors cautioned that this polymorphism may not be causal. The warning is appropriate for many reasons including, but not limited to , the fact that the polymorphism itself does not alter the amino acid sequence (30) and is within an extensive block of linkage dysequilibrium that spans most of the gene. Other polymorphisms that may also play a role are 2677G T and 1236C T and some association studies analyzed these together with the 3435C T haplotype (31,35,37,41,42). This polymorphism consists of a C T transversion at position 3435 in exon 26; it is silent, not altering the amino acid sequence (14). Similarly, high levels of expression were found in brain tissues resected from a 4-month-old female with tuberous sclerosis and treatment-resistant epilepsy (58) and in a postmortem examination of a patient who died in status epilepticus (59). Evidence exists that carbamazepine, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate, and valproic acid are substrates for multidrug transporters in the brain (11, 12, 53). The subunit is the pharmacogenetic focus because the subunits only modulate properties of the channel and are not required for its functioning. When alanine was substituted for certain amino acids in these transmembrane regions, the affinity of phenytoin and lamotrigine decreased two- to eightfold (69,70). Subsequently, a small human tissue electrophysiologic study suggested that sodium channels may exhibit different properties in patients with pharmacoresistant epilepsy as evidenced by different response to carbamazepine (72). Few published human studies have since examined the relationship between response to therapy and presence of polymorphisms in these genes. Results could not be confirmed by the same researchers in a smaller study in Chinese patients (75). However, this study revealed a marginal effect on phenytoin pharmacodynamics and was therefore interpreted as a potential confirmation by the authors (75). Voltage-dependent calcium channels in the human brain are multimeric complexes of 1, and subunit is expressed only in skele2 subunits (78,79); the tal muscle. Its 10 members (1A to 1I and 1S) encode six functionally distinct calcium channels (types P, Q, L, N, T, and R). Significant homology is seen in the membrane-spanning segments coded for by each of these genes. No polymorphisms (either naturally occurring or by site-specific mutagenesis) that alter drug binding have been described. Genetic variability in phase I metabolizing enzymes can alter pharmacokinetic profiles and subsequently drug toxicity. Advancing the medical management of epilepsy: disease modification and pharmacogenetics. Sequence similarities have been used to devise a standardized nomenclature for categorizing the P450 proteins into families and subfamilies (89,91). P450 proteins are in the same family if they exhibit more than 40% similarity in protein sequence; within the same family, proteins that have more than 55% sequence homology are in the same subfamily (91). Both alleles together can explain all Asian and approximately 80% of whites poor metabolizers (106). Individuals with at least one of these variant alleles are poor metabolizers, exhibiting a reduced ability to metabolize phenytoin and requiring lower-than-average doses to decrease the incidence of concentration-dependent adverse effects (113,116). In an African American woman with signs of neurotoxic phenytoin reactions, clearance was 17% of that in normal patients. In another Japanese study (110), predicted plasma concentrations with a phenytoin dose of 5 mg/kg/day were 18. Following a single 300 mg dose of phenytoin, 96 healthy Turkish volunteers underwent genotyping and analyses of plasma levels of phenytoin and its metabolites (111). Carriers of one or two alleles required a 13% and 30% lower dose of phenytoin, respectively (73). Attempts to clarify the metabolism of phenobarbital in two clinical studies from the same Japanese group reported inconsistent results (123,124). One year later, this group administered phenobarbital 30 mg daily for 14 days to 10 healthy volunteers: 5 extensive metabolizers (*1 *1) and 5 poor metabolizers (*2 *2 and *3 *3) (125). In a separate study of 21 healthy Chinese males (131), serial blood samples were obtained up to 24 days after a single 5-mg oral dose of diazepam. Plasma elimination half-lives of the drug and its metabolite were significantly longer (both P 0. In vitro, this variant showed a lower intrinsic clearance for nifedipine than the wild type but was not significantly different for testosterone 6 -hydroxylation. Measurement of the ratio of morning spot urinary 6 -hydroxycortisol to free cortisol in persons with these mutations suggests that these alleles may have a decreased activity compared with the wild type. Expression is variable, with reported rates in 10% to 29% of livers to at least trace presence in all liver samples, depending on the detection method used (144147). The frequency of this mutation varies from 27% in African Americans to 75% in Asians and 95% in whites (135,150). These three mutations exhibited decreased enzymatic activity for testosterone clearance and nifedipine oxidation, compared with the wild-type allele (150). This enzyme catalyzes the conversion of epoxides to less toxic trans-dihydrodiols that can subsequently be conjugated with glucuronic acid or glutathione and excreted. This detoxification is critical during the metabolism of phenytoin and phenobarbital (that both form arene oxide intermediates) and carbamazepine (that forms a 10,11-carbamazepine epoxide). It has a frequency of approximately 30% to 40% in whites, African Americans, and Hispanics, and up to 15% in Asians (159). Ethnicity is important, as carbamazepine-induced StevensJohnson syndrome was not seen in Caucasians (174). In lamotrigine-induced idiosyncratic drug reactions T-cell receptor polymorphisms may play a similar role, but no polymorphisms have been described to date (11). The patients showed more frequent polymorphisms, but no consistent single polymorphism or pattern was detected. Vigabatrin-Associated Visual Field Defects Visual field constriction occurs in up to 40% of patients taking Vigabatrin. No risk factors for visual field loss and no definite genetic predictors have been identified. Teratogenicity Neural tube defects in children after maternal valproic acid treatment may be related to genetic and environmental influences. Genetic influences are supported by occurrence of neural tube defects in siblings, even despite folate supplementation, and conception of a healthy child after valproic acid discontinuation in one of these mothers (186190). Results could not be reproduced using chorionic villi sampling due to local enzyme variability (194). In many phenotypic correlation studies, a single polymorphism may not be easily detectable because of possible interactions with other polymorphisms that may also influence the risk (198). Additional research is needed into the cost-effectiveness of pharmacogenetic testing and the educational needs of clinicians who must incorporate these test results into actual practice. Additionally, pharmacogenetic and pharmacogenomic characterization of risk profiles and medical intractability may also offer additional treatment approaches, that is, as seen in P-polyglycan inhibitors that may reduce pharmacologic intractability (199). Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Mediation of highly concentrative uptake of pregabalin by L-type amino acid transport in Chinese hamster ovary and Caco-2 cells. In a few cases, the impact of allelic variations in one gene is large enough to alter a phenotype in an easily recognizable fashion. Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.
Somerfeld-Ziskind and Ziskind (43) randomized 100 patients with epilepsy to phenobarbital or ketogenic diet symptoms of colon cancer 8 mg ondansetron fast delivery. Phenobarbital controlled seizures better symptoms 7dpo buy ondansetron 4 mg with visa, but no differences were reported on limited neuropsychological testing symptoms 24 hour flu ondansetron 4 mg amex. Errors in experimental design include subject selection bias medications not to take after gastric bypass discount 8mg ondansetron otc, nonequivalence of clinical variables, and nonequivalence of dependent variables. Selection bias is a problem when subjects are not randomly assigned to a treatment group or inadequately matched, or if the sample size is inadequate for a parallel-group design. Examples of nonequivalence of clinical variables include the failure to control for anticonvulsant blood levels or seizure frequency. Nonequivalence of dependent measures may occur when there is no assurance that treatment groups performed similarly on dependent measures prior to treatment. Additional design issues include sample size, testretest effects, characteristics of behavioral tests, and effects of changes in seizures. Issues related to statistical analysis and interpretation include type I error, use of inappropriate statistics, nonorthogonal contrasts, and comparison of studies with nonequivalent designs/statistics. Furthermore, the cognitive effects may be partially offset by the reduction in seizures. However, the best drug regimen for an individual patient is the one that best controls seizures with the fewest side effects, and for some patients this regimen may involve polytherapy. Review of Selected Studies of Older Antiepileptic Drugs Dodrill and Troupin (46) compared the cognitive effects of carbamazepine and phenytoin in patients with epilepsy using a double-blind, randomized, crossover, monotherapy design. When they reanalyzed controlling for anticonvulsant blood levels, no differences were observed (47). Meador and associates (48) also found no cognitive differences between carbamazepine and phenytoin in patients with epilepsy, but evidence of worse performance with phenobarbital. In another study (49), 32% of the variables were significantly worse with phenobarbital than with phenytoin or valproate, with the latter two agents being similar to each other, and about half of all variables significantly worse than nondrug condition. Other studies comparing carbamazepine and phenytoin have described modest negative effects on cognition with both agents, but few differential effects (5254). A possible criticism of some of the crossover studies described above might be the relatively short duration of treatment. Dodrill and Wilensky (55) addressed this issue in a study that examined neuropsychological performance over 5 years in patients with epilepsy. Greater electroencephalographic slowing and more frequent cognitive complaints were reported with carbamazepine in adults (58), and better overall tolerability was seen with gabapentin in healthy elderly adults (59). In contrast, gabapentin can produce irritability, hyperactivity, and agitation in children (60,61). Lamotrigine An adjunctive therapy study in patients with epilepsy found no cognitive effects with lamotrigine versus placebo on a limited neuropsychological battery (62). A double-blind, randomized, crossover design, with two 10-week treatment periods, in healthy adults revealed significantly better performance for lamotrigine versus carbamazepine on more than half of the variables. Other studies with healthy adults demonstrated fewer cognitive side effects with lamotrigine compared with carbamazepine, diazepam, phenytoin, placebo, and valproate (6365). In clinical trials, lamotrigine was better tolerated than carbamazepine and phenytoin (6669). Lamotrigine has positive psychotropic properties as evidenced in bipolar disorder patients and epilepsy patients with severe cognitive impairment (7173). Significantly more improvements in mood occurred with lamotrigine compared to levetiracetam in a double-blind, randomized, parallel, adjunctive therapy study in epilepsy patients (74). Levetiracetam A double-blind, randomized, crossover healthy volunteer study with eight treatments arms found significantly less neuropsychological effects of levetiracetam versus carbamazepine on 44% of variables (75). Felbamate Given the restrictions imposed by the systemic toxic effects of felbamate, there are no systematic investigations of cognition, but anecdotally, it is reported to be alerting and can even produce insomnia. Gabapentin Studies of add-on gabapentin in patients with epilepsy report subjective improvements in well being (56). When comparing gabapentin with placebo in patients with partial epilepsy, using a double-blind, dose-ranging (1200 to 2400 mg/day), add-on, crossover design, Leach and coworkers (57) found one positive effect and no negative effects, except for more subjective drowsiness. A double-blind, randomized, crossover study of healthy volunteers (37) compared gabapentin and carbamazepine during two 5-week treatment periods. Significantly better performance was seen with gabapentin versus carbamazepine on 26% of the variables, carbamazepine was worse than nondrug on 48% of the variables, and gabapentin was worse than nondrug on 19% of the variables. Although both agents produced some effects, significantly fewer untoward cognitive effects were seen with gabapentin compared with carbamazepine. These results have Rufinamide A double-blind, randomized, parallel, placebo-controlled, multidose study found no statistically significant cognitive changes for any of the doses of rufinamide (82). No significant cognitive effects were reported in a small, low-dose, add-on study (83) and in a large, randomized, double-blind, add-on, placebocontrolled, parallel-group, doseresponse study in patients with epilepsy (84). The increased susceptibility of the elderly to the cognitive effects of a variety of agents is attributable to both pharmacokinetic and pharmacodynamic factors. For example, it is well established that the elderly are at increased risk for untoward cognitive effects from benzodiazepines (100). Similar to studies in younger adults, one study (101) reported comparable cognitive effects of phenytoin and valproate in elderly patients. This finding was predominately a result of side effects that were least likely with lamotrigine, intermediate with gabapentin, and worse with carbamazepine. Topiramate In clinical trials, topiramate produced somnolence, psychomotor slowing, memory difficulties, and language problems. Factors affecting these adverse effects include titration rate, maintenance time, dose, polytherapy, and individual susceptibility. In a singleblind, randomized, parallel-group study in healthy volunteers (85), topiramate was associated with more adverse cognitive effects than gabapentin and lamotrigine at 1 month, but the topiramate titration rate was faster than recommended. In a study of 38 patients with epilepsy tested on/off or off/on topiramate, declines in verbal fluency, attention, processing speed, and working memory, but not retention, were associated with topiramate use (86). A double-blind, randomized, placebo-controlled, 12-week treatment, parallel-group study in healthy adults found that gabapentin had less adverse effects on 50% of the variables compared to topiramate (89). A double-blind, randomized, crossover study in healthy adults with 12-week treatment arms noted worse effects for topiramate on 88% of variables compared to lamotrigine (39). Similarly, a multicenter, double-blind, randomized, adjunctive therapy reported more adverse neuropsychological effects for topiramate versus lamotrigine (90). A double-blind, randomized, crossover, monotherapy study (106) conducted in children with epilepsy, found performance on phenobarbital was worse than valproate. Adverse cognitive effects of phenobarbital have also been found in placebo-controlled, parallel-group studies of children with febrile convulsions (107,108). Similar to the outcomes of adult studies, comparisons of carbamazepine, phenytoin, and valproate in children have yielded few differences (109112). A single-dose study in healthy volunteers showed less impairment than lorazepam (95), and vigabatrin produced fewer adverse effects than carbamazepine in a small, open-label, randomized, parallel-group study of patients with epilepsy (96). Zonisamide Zonisamide appears to have a wide therapeutic index, but can cause sedation. Phenobarbital produces neuronal deficits, reduces brain weight, and impairs development of reflexes, open-field activity, schedule-controlled behavior, and brain levels of catecholamines in mice (120124). Prenatal phenytoin produces dose-dependent, long-lasting impaired coordination and learning in rats (125132). Significant, but less striking, neurobehavioral effects are seen with trimethadione and valproate (127,131,133,134). Disparities across studies are partly a result of differences in methodology and patient populations. In many prospective studies, follow-up began postnatally rather than during pregnancy. In many studies, the influences of possible confounding factors have not been addressed in an empirical fashion. The majority of investigations report an increased risk for developmental delay in children of mothers with epilepsy (2,139152), although a few studies (153155) found no delays. The incidence of mental retardation is increased in children of mothers with epilepsy versus children of mothers without epilepsy, but not in children of fathers with epilepsy versus controls (148,156). Hattig and colleagues (165) reported greater cognitive impairment with polytherapy compared with monotherapy and with valproate as monotherapy.
Actavis develops treatment 4 high blood pressure 4mg ondansetron otc, manufactures medicine symbol buy 8mg ondansetron otc, markets medications vs grapefruit discount 4mg ondansetron with amex, sells doctor of medicine order 4 mg ondansetron with visa, and distributes branded, generic, branded generic, biosimilar, and over-the-counter pharmaceutical products. Currently, Actavis offers forty-five branded pharmaceutical products and approximately 250 generic pharmaceutical product lines in the United States. In that circumstance, the Commission may appoint a trustee to divest the Products if the parties fail to divest them as required. The Order requires Valeant and Precision to take all action to maintain the economic viability, marketability, and competitiveness of the products to be divested until such time that they are transferred to Commission-approved acquirers. The Order also requires that Valeant and Precision transfer all confidential business information, including customer information related to the divestiture products, to Actavis and Matawan Pharmaceuticals. The complaint alleges that Respondent represented that some of its benches and tables are all, or virtually all, recycled plastic, but that these products contained substantially less recycled plastic than claimed. The consent order prohibits Respondent from making representations regarding the recycled content or the environmental benefit of any product or package unless they are true, not misleading, and substantiated by competent and reliable evidence. Respondent has advertised, offered for sale, sold, and distributed plastic lumber products, including picnic tables and benches. The acts and practices of Respondent alleged in this complaint have been in or affecting commerce, as "commerce" is defined in Section 4 of the Federal Trade Commission Act. Since at least June 2011, Respondent has disseminated one or more advertisements and promotional materials for plastic lumber products, including but not necessarily limited to the attached Exhibits A and B. In connection with the advertising, promotion, offering for sale, or sale of plastic lumber products, Respondent has represented, directly or indirectly, expressly or by implication, that its Eco, Hexagonal, and Perennial Tables and its Garden, Geneva, Sports, and Trailside Benches are all or virtually all recycled plastic. The representations set forth in Paragraph 7 are false or misleading, or were not substantiated at the time the representations were made. The recycled content of any product or package; or the environmental benefit of any product or package; C. For any representation that a product or package contains recycled content, such evidence must show that any recycled content in such product or package is composed of materials that have been recovered or otherwise diverted from the waste stream. Provided, however, that, with respect to any proposed change in the corporation about which respondent learns less than thirty (30) days prior to the date such action is to take place, respondent shall notify the Commission as soon as is practicable after obtaining such knowledge. Within ten (10) days of receipt of written notice from a representative of the Commission, respondent shall submit additional true and accurate written reports. This order will terminate on August 20, 2034, or twenty years from the most recent date that the United States or the Federal Trade Commission files a complaint (with or without an accompanying consent decree) in federal court alleging any violation of the order, whichever comes later; provided, however, that the filing of such a complaint will not affect the duration of: A. The complaint also alleges that these products contained substantially less recycled plastic than Respondent represented. The proposed consent order contains several provisions designed to prevent Respondent from engaging in similar acts and practices in the future. Part I prohibits Respondent from making representations regarding the recycled content or the environmental benefit of any product or package unless they are true, not misleading, and substantiated by competent and reliable evidence. Part I further provides that if, in general, experts in the relevant scientific field would conclude it necessary, such evidence must be competent and reliable scientific evidence. The purpose of this analysis is to aid public comment on the proposed consent order. Alifraghis sent messages proposing that all three competitors raise their prices to meet the higher prices charged by another competitor. The consent order prohibits Respondent from entering into, participating in, maintaining, organizing, implementing, enforcing, inviting, offering, or soliciting an agreement with any competitor to divide markets, to allocate customers, or to fix prices. Alifraghis invited two of his closest competitors, Nationwide Barcode ("Nationwide") and Competitor A, to join with Instant in a collusive scheme to raise and fix prices for barcodes. Alifraghis, including the acts and practices alleged herein, are in commerce or affect commerce, as "commerce" is defined in Section 4 of the Federal Trade Commission Act, 15 U. Instant, Nationwide, and Competitor A are three of the largest sellers of barcodes in the United States. Competition between and among Instant, Nationwide, and Competitor A has driven down the prices for barcodes charged by each of these sellers. This message contained an explicit invitation to raise and fix prices of barcodes. The email stressed that all three firms had to act in concert or the plan would not succeed. The problem is that his prices were lower than yours which I knew you would lower yours once again, it was only a matter of time. I can even assure you right now, that I will never lower my prices under yours, I will only match your prices. If you do not decide you want to match the prices of [Competitor B], I will match your prices upon receiving your reply or within 48 hours, whichever comes first, this will make [Competitor A] obviously change his prices as well and we will all be at a lower price. We need to all work together on this to bring the prices back up to where they should be. I am not going to change my quantity breakdowns, but will meet those prices (I might stay higher in a few areas where it makes sense to me) but for all intent and purpose, the prices will be the same or higher. Alifraghis and Competitor A trying to overcome what he perceived as an impasse in the planning to coordinate an increase in prices. It seems that none of us really trust one another and the issue of "price fixing" with someone who is nameless becomes a sticking point. Alifraghis feared that Competitor A was not ready and willing to cooperate with the proposal to raise prices. I am a man of my word and I reached out to you which means I take this business very seriously. Alifraghis and Competitor A asking each of them to confirm their "intentions" with regard to the price-fixing scheme under discussion. Until [Competitor A] agrees to change all of his prices, I will not change mine first. On August 11, the price increase discussed by the barcode competitors in multiple email messages failed to materialize. Peretz implored his competitors to continue their dialogue and to take the opportunity presented to raise prices. I can care less if you match my prices, that would be a smart move for you at this point. As set forth in Paragraphs 8 through 21 above, Respondent invited his competitors to collude with Instant to raise prices for barcodes in violation of Section 5 of the Federal Trade Commission Act, as amended. The acts, policies and practices of Respondent, as alleged herein, constitute unfair methods of competition in or affecting commerce in violation of Section 5 of the Federal Trade Commission Act, as amended. Such acts, policies and practices of Respondent will continue or recur in the absence of appropriate relief. Alifraghis, an individual, (hereinafter referred to as "Respondent"), and Respondent having been furnished thereafter with a copy of the draft of Complaint that counsel for the Commission proposed to present to the Commission for its consideration and which, if issued by the Commission, would charge Respondent with violations of Section 5 of the Federal Trade Commission Act, as amended, 15 U. The Federal Trade Commission has jurisdiction over the subject matter of this proceeding and of 2. Alifraghis; all businesses, partnerships, joint ventures, subsidiaries, divisions, groups, affiliates and websites controlled by Jacob J. Entering into, attempting to enter into, adhering to , participating in, maintaining, organizing, implementing, enforcing, inviting, encouraging, offering or soliciting any agreement or understanding, express or implied, between or among Respondent and any Competitor: 1. Exhorting, requesting, suggesting, urging, advocating, encouraging, advising, or recommending to any Competitor, either publicly or privately, that it: 1. Set, change, reduce, limit, maintain, or reduce its service terms or service levels. Any other change in Respondent including, but not limited to , assignment and the creation or dissolution of subsidiaries, if such change might affect compliance obligations arising out of this Order. Access, during office hours and in the presence of counsel, to all facilities and access to inspect and obtain copies of relevant books, ledgers, accounts, correspondence, memoranda and all other records and documents in the possession or under the control of Respondent relating to compliance with this Order, which copying services shall be provided by Respondent at the request of the authorized representative(s) of the Commission and at the expense of Respondent; and the opportunity to interview Respondent, or officers, directors, or employees of Respondent, who may have counsel present, related to compliance with this Order. After 30 days, the Commission will review the Consent Agreements again and the comments received, and will decide whether it should withdraw from the Consent Agreements or make final the accompanying Decisions and Orders ("Proposed Orders"). It is not intended to constitute an official interpretation of the proposed Consent Agreements and the accompanying Proposed Orders or in any way to modify their terms. The Consent Agreements are for settlement purposes only and do not constitute an admission by Respondents that the law has been violated as alleged in the Complaints or that the facts alleged in the Complaints, other than jurisdictional facts, are true.
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A framework to manage the operation of the legislation medications vaginal dryness order 4 mg ondansetron with visa, including the development of a paediatric committee is also addressed symptoms cervical cancer buy ondansetron 4mg on line. This guidance addresses the conduct of pharmacovigilance for medicines used by the paediatric population and is aimed at both the pharmaceutical industry and national competent authorities (19) schedule 6 medications generic 4mg ondansetron fast delivery. A further draft guideline (20) (Commission Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies) has been issued by the European Commission for a period of consultation symptoms influenza cheap ondansetron 8 mg with mastercard. Safety concerns warranting new labelling or further study were expressed for some products. These reviews are in addition to the routine pharmacovigilance activities for all products in all populations and have helped to focus on safety issues that may present in paediatric patients. Other areas There appears to be an absence of formal frameworks in other areas, highlighting the need for developments. This led Harry Shirkey in 1963 to state that children constitute therapeutic orphans. However, children have therapeutic needs which probably cannot be met if medicines representing major therapeutic advances in adults are not tested and labelled for paediatric use. Once a medicine becomes available on the market for adults, it is possible to use it in children in an off-label way. Thus use of unlicenced and off-label medicines for children has been common practice for decades; this does not offer children the same quality, safety and efficacy of medicines as adults. From the practical point of view this means that for the physician: No information is available on effective and safe dosing regimens (dose range, frequency of administration and duration of therapy). Therefore it is not surprising that paediatric patients are exposed to a rate of potentially dangerous medication errors three times higher than that for adult patients (23). No assessment of the treatment is, however, possible without safety data and knowledge. The "trial and error" principle is not acceptable in an extremely vulnerable population. Preclinical investigations on reproductive toxicology, mutagenicity and carcinogenicity are mandatory. Special consideration must be given to the long-term follow-up on skeletal, neural, behavioural, sexual and immunological maturation and development in toxicology studies in juvenile animals. The predictive value of such studies in relation to effects in the paediatric population is however uncertain. Clinical investigations include pharmacodynamic, pharmacokinetic and efficacy studies. Such studies may be performed using different methodological approaches, which are dependent on the type of safety parameters, and the practical, clinical and economic circumstances. A new conceptual model has been developed, which calls for pharmacovigilance processes to be involved earlier in the life-cycle of a medicine (24). The safety specification addresses the populations potentially at risk (where the product is likely to be used) such as children, and outstanding safety questions which warrant further investigation to further the understanding of the benefit-risk profile during the post-approval period. The pharmacovigilance plan provides details of planned pharmacoepidemiological studies. Serious adverse events are often rare, and are generally not observed in a paediatric clinical trial programme, particularly if there is a lag period before onset or a trigger such as changes in growth and development. Additional reasons for monitoring post-marketing medicine safety in children include the following: the use of unlicenced and off-label medicines is highly prevalent in children (see above). A good example for this kind of poisoning is the life-threatening gasping syndrome seen in infants exposed to benzyl alcohol (26). This may expose the patient to increased risk of medicine toxicity and adverse events. Benzyl alcohol is widely used as a preservative in allergenic extracts for scratch and intracutaneous testing, and can lead to false-positive results (29). The content of benzyl alcohol in many injectable pharmaceutical preparations should be considered carefully. Unfortunately many countries still take the view that the identity of the additives and excipients in medicines is a trade secret, and this attitude must be deplored. The duty to declare the additives and excipients is only realized in some countries. Deaths in neonates have been associated with administration of 99234 mg/kg/day benzyl alcohol in large-volume parenteral solutions or endotracheal solutions. The toxic effects of benzyl alcohol, which include respiratory vasodilatation, hypertension, convulsions and paralysis, have been known for years. However, little is known about the toxic effects or levels of benzyl alcohol and the metabolic acidosis caused by accumulation of the metabolite, benzoic acid, in neonates, especially in sick premature infants. Its effect is mainly related to an excessive body burden relative to body weight, so that the load of this metabolite may exceed the detoxification capacity of the immature liver and kidneys. It is therefore necessary to identify indications for which medicines are actually used in paediatrics, as well as the dosage forms. Effectiveness studies are necessary to determine the results in real-life clinical situations, and then to match evidence of harm to effectiveness, by age group. Actual measurement of benefit-to-risk balances is not an easy task, and is the subject of much research, but as a minimum, there is a need to gather the information suggested above, wherever possible. The phrase "medical error" is an umbrella term covering all errors that occur within the health-care system. Medication errors are probably one of the most common types of medical error, as medication is the most common health-care intervention. While the majority of all errors (61%) originated in medication order writing, most serious errors (58%) originated in the prescribing decision. Several published reports confirm that medication errors are not uncommon in paediatrics; one significant study has shown that potentially harmful medication errors may be three times more common in the paediatric population than in adults (32). This in turn indicates that the epidemiological characteristics of medication errors may differ between adults and children. For potent drugs, when only a small fraction of the adult dose is required for children, it becomes very easy to cause dosing errors of 10-fold or greater because of miscalculation or misplacement of the decimal point. As discussed above, many drugs used to treat children are either not licenced (unlicenced) or are being prescribed outside the terms of the product licence (offlabel prescribing) (36). This poses an additional risk to children from medication errors as doses must be calculated on an individual patient basis, often in the absence of appropriate dosing information from the pharmaceutical manufacturer. In addition, adult dosage formulations often have to be manipulated at ward level by nursing staff, or suitable products prepared extemporaneously in the pharmacy, to meet the need for small doses in paediatric patients. Such manipulations may involve, for example, cutting or grinding up tablets or dispersing or mixing drugs with such agents as food or drinks before administration. These practices are associated with a high risk of errors as the bioavailability of the drugs following such manipulations is often unknown and unpredictable. An example is the case of a child who received his regular supplies of diazoxide suspension made as an extemporaneously prepared suspension at 10 mg/ml, from a local community pharmacy. His parents did not read the label and gave the same volume of the suspension resulting in a five times overdose. This is also true for offlabel use, which ranges between 50 and 90% in the paediatric population in most countries, as demonstrated by hospital-based surveys. The medicine regulatory agencies and the medicine manufacturers must take the responsibility whenever they receive feedback from the health professionals. These professionals-if they are trained adequately-are the ones who are able to observe reactions and events associated with a new medicine on the market, when it is introduced into a quite heterogeneous population with different ages, sex, co-morbidity and polypharmacotherapy. It has been recognized that the current system of medicine regulation in western countries does have some serious drawbacks (39). As the medicine regulatory agency has been responsible for the authorization process at the beginning of the medicine life-cycle, there is a need for a reform of the system to reduce the influence of conflict of interest in the evaluation of the postmarketing events. It is important that drug manufacturers follow up on adverse reactions to their products once they are well-established on the market. However, spontaneous reporting is expected to be of only limited value in the safety monitoring of paediatric medicines, unless the notorious underreporting among health professionals including paediatricians can be overcome. There have been repeated reports of fatalities caused by accidental contamination of medicines with this substance, most commonly in cough syrups used mainly by children (46). The advantages of this approach are that: One has the ability to focus on specific areas of importance for the reallife assessment of medicine safety. In addition, retrospective and prospective monitoring from computerized medical records, requiring a more or less passive role of the health professionals, is timeefficient compared with other intensive surveillance systems. It will probably improve spontaneous reporting of pharmacological, unpredictable and not dose-related reactions and the much more common, and in part preventable, dose-related reactions to a medicine. As long as comprehensive, but at the same time, simple and clear clinical documentation in medical records-such as the problem-oriented medical record-is available, the same approach can be applied manually in less developed countries with simple protocols.