Efficacy and safety of potassium clavulanate/amoxicillin (CLAVAMOX) dry syrup in children with otitis media

To evaluate the efficacy and safety of CLAVAMOX dry syrup (potassium clavulanate/amoxicillin) in children with otitis media, we conducted a postmarketing surveillance from February to September 2006. The analysis was made on the basis of 470 survey sheets collected from 127 medical institutions, of which we investigated 455 cases for safety, and 433 cases for efficacy. The efficacy was 95.2% in the 433 subjects eligible for the efficacy analysis. The clinical improvement rates for major symptoms (otalgia, otorrhea, flare reaction of drum membrane and fever) were 95% or more.The efficacies for the three major offending bacteria of otitis media (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were between 94.6% and 100%. The efficacies for penicillin-resistant Streptococcus pneumoniae (PRSP) and penicillin intermediate resistant Streptococcus pneumoniae (PISP) were 95% or more. Adverse drug reactions (ADRs) were reported in 106 (23.3%) of the 455 subjects eligible for safety analysis. The major ADRs were diarrhea, of which incident was 22.6% (103 of 455). These ADRs were observed at a higher rate in younger age patients. Most of the diarrhea cases were non-serious, reversible on discontinuation or continuation of the drug. No clinically important serious diarrhea cases such as pseudomembranous colitis or dehydration were observed. Our surveillance results demonstrated that CLAVAMOX dry syrup had excellent efficacy and clinically manageable safety in children with otitis media. These findings indicated that this medicine was clinically-useful in children with otitis media.     

Some studies of the action of betahistine at H1 and H2 receptors for histamine

Betahistine produced a concentration-dependent contraction of the guinea-pig ileum and was about 27 times less active than histamine in this respect. Betahistine induced desensitization of contractile responses to histamine in the guinea-pig ileum. The H1 histamine receptor antagonist mepyramine was a competitive antagonist of the action of betahistine on the guinea-pig ileum. Betahistine caused relaxation of the rat uterus contracted by acetylcholine, and this action of betahistine was blocked by the H2 receptor antagonist cimetidine. Betahistine had a concentration-dependent positive chronotropic action on isolated guinea-pig atria, and in this respect was tenfold less potent than histamine. The action of betahistine on the atria was blocked by the H2 receptor antagonist YM11170. Betahistine caused a concentration-related contraction of the isolated lung parenchymal strip of the guinea-pig, and YM11170 potentiated this effect. Betahistine failed to release histamine from rat peritoneal mast cells at concentrations up to 100 microM and it did not prevent histamine release induced by either substance P or anti-IgE. Betahistine produced a dose-related flare and wheal reaction when injected intradermally into human skin. It is concluded that betahistine has agonist activity at both H1 and H2 receptors for histamine.     

Adverse reactions to new anticonvulsant drugs.

A lack of systematic pharmacoepidemiological studies investigating adverse drug reactions (ADRs) to anticonvulsants makes it difficult to assess accurately the incidence of anticonvulsant-related ADRs. Most of the available information in this regard stems from clinical trial experience, case reports and postmarketing surveillance, sources that are not, by any means, structured to provide precise data on adverse event epidemiology. For various ethical, statistical and logistical reasons, the organisation of structured clinical trials that are likely to provide substantial data on ADRs is extremely difficult. This review concentrates on current literature concerning serious and life-threatening ADRs. As with the older anticonvulsants, the majority of ADRs to newer anticonvulsants are CNS-related, although there are several that are apparently unique to some of these new drugs. Gabapentin has been reported to cause aggravation of seizures, movement disorders and psychiatric disturbances. Felbamate should only be prescribed under close medical supervision because of aplastic anaemia and hepatotoxicity. Lamotrigine causes hypersensitivity reactions that range from simple morbilliform rashes to multi-organ failure. Psychiatric ADRs and deterioration of seizure control have also been reported with lamotrigine treatment. Oxcarbazepine has a safety profile similar to that of carbamazepine. Hyponatraemia associated with oxcarbazepine is also a problem; however, it is less likely to cause rash than carbamazepine. Nonconvulsive status epilepticus has been reported frequently with tiagabine, although there are insufficient data at present to identify risk factors for this ADR. Topiramate frequently causes cognitive ADRs and, in addition, also appears to cause word-finding difficulties, renal calculi and bodyweight loss. Vigabatrin has been reported to cause seizure aggravation, especially in myoclonic seizures. There have been rare reports of other neurological ADRs to vigabatrin, such as encephalopathy, aphasia and motor disturbances. Vigabatrin-induced visual field constriction is the latest and most worrying ADR. Many questions regarding the nature of this potentially serious ADR remain unanswered, as no prospective controlled study examining the phenomenon has been published. Rare cases of behavioural ADRs and IgA and IgG2 deficiency associated with the use of zonisamide have been reported. However, relatively few patients so far have been exposed to this drug, and therefore more postmarketing information is required. The relatively late establishment of aplastic anaemia and hepatic failure as potentially fatal ADRs of felbamate, and of visual field constriction with vigabatrin, should serve as ample reminders that ADRs can appear at any time.     

Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H(1) receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H(1) receptor agonist and H(3) receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H(3) receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H(1) receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.     

Clinical perspectives in drug safety and adverse drug reactions

Adverse drug reactions (ADRs) remain a common clinical problem since they can mimic many diseases and cause significant morbidity and mortality. Judicious prescribing is important to minimize their occurrence. Apart from the recent identification of a few pharmacogenomic biomarkers for serious reactions, many remain unpredictable. Spontaneous reporting continues to play an important role in pharmacovigilance and the value of astute clinical observation and well-documented reports of suspicions of a causal link cannot be underestimated. Many national reporting schemes have developed considerable experience and expertise over many years and have large ADR databases, which are national assets. Despite advances in pharmacovigilance, numerous deficiencies have been identified; postmarketing surveillance remains the weakest link in the regulatory process. Regulatory authorities have tended to act later rather than sooner in response to safety signals, and this, when combined with under-reporting, may have led to exposure of a large number of patients to drug-related harm before restriction or withdrawal. In an attempt to improve vigilance, international surveillance may benefit by moving from its current passive/reactive mode toward active surveillance systems with a prospective, comprehensive and systematic approach to monitoring, collecting, analyzing and reporting data on ADRs. This will include increased pressure on pharmaceutical companies to conduct postmarketing studies. Such an active/proactive approach, while maintaining focus on ADR detection, could also aim to extend knowledge of safety, such that emerging changes in risk–benefit during a drug’s marketed life are effectively communicated to clinicians and patients. Drug safety monitoring and its regulation are now undergoing an overhaul and it is hoped that vigilance, public safety and trust will improve as a result.     

Patient self-monitoring: A challenging approach to pharmacoepidemiology

This paper reports the development over the past 10 years of an innovative patient self-monitoring method of (1) signalling possible adverse drug reactions (ADRs) and unexpected beneficial drug reactions, and (2) providing incidence estimates and relative risks. The system's validity has been well documented in a series of published papers. There is no other existing postmarketing surveillance method that can obtain early reliable and accurate patient reports about possible side-effects. We thought that, having successfully developed and validated the method, both the US Food and Drug Administration (FDA) and the pharmaceutical industry would recognize the need to support its application as an important complementary approach to existing postmarketing surveillance methods. Despite our repeated requests, however, neither FDA nor industry has shown any interest in helping to sustain this research, in part because pharmacoepidemiologists tend to focus on the detection of serious ADRs as defined and diagnosed by physicians, but also because it has become patently clear that the US pharmaceutical industry does not want its new drugs to be monitored for possible ADRs. Thus there is virtually no systematic attention being paid to the possible importance of less serious ADRs as inferred from accurate patient reports of behavioural and subjective symptoms — which, especially with CNS-acting drugs, may often be essential for obtaining reliable ADR profiles.     

药物安全性相关因素分析

目的:探讨影响药物安全性的因素,供药物开发及临床应用参考。方法:复习近年来有关ADRs及药物安全性的研究文献,阐明影响药物安全性的重要因素。结果:药物代谢、遗传药理、病人的年龄、病理生理状况以及联合用药是影响药物安全性不可低估的因素。上市药物监测是保证药物安全性最重要的措施之一,新药上市1~3年是监测的关键时期。结论:在新药研究和开发时,对这些影响因素进行评价和研究,尤其是增加体外药物相互作用的研究项目,可以有效地降低ADRs的发生率,防止不良反应给人体造成的危险,还可以降低新药开发的风险。加强新药上市1~3年内ADRs的监测,正确评临床应用的风险和效益,可以有效地保证新药的安全性。     

Safety,tolerability and pharmacokinetics of 2‐pyridylacetic acid,a major metabolite of betahistine,in a phase 1 dose escalation study in subjects with ADHD

Betahistine, a potent histamine H₃ receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo‐controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2‐pyridylacetic acid (2‐PAA), a major metabolite of betahistine were quantified using a validated LC‐MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in C_max and AUC_0‐4 of 2‐PAA with the betahistine dose (R² 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (C_max) and 1.007 (AUC_0‐4). A population pharmacokinetic model with first‐order absorption of betahistine and metabolism to 2‐PAA, followed by a first‐order elimination of 2‐PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested. Copyright © 2015 John Wiley & Sons, Ltd.     

Randomized, double-blind, placebo-controlled, food allergy challenge to olestra snacks

Following approval of the fat replacer olestra for use in preparing savory snacks, Procter & Gamble implemented a postmarketing surveillance program to monitor marketplace introduction. Three and one-half percent of all health effects reported by consumers to the surveillance toll-free number were allergy-type symptoms (e.g., rash, itching, edema, hives, dyspnea). Because of these reports, we investigated whether olestra or some component of olestra snacks was a likely allergen in some subset of the population. A single center, randomized, double-blind, placebo-controlled, within-subject crossover food challenge study was conducted to confirm or refute the allergenicity of olestra snacks. Of the 65 subjects who reported symptoms consistent with immediate hypersensitivity to olestra's postmarketing surveillance program, 14 men and women traveled to the Arkansas Children's Hospital Research Institute to participate in this study. Each subject underwent a standard skin prick test at the beginning of the study, to help determine what component, if any, of the olestra product was allergenic. Following the skin prick test, subjects ate in random order, olestra-containing potato chips and regular fat-containing potato chips. The dose of potato chips consumed at each challenge was at least the amount alleged to have caused the symptoms that prompted the consumer to phone the postmarketing surveillance toll-free number. No subject experienced an allergic reaction after consuming the olestra-containing chips. Nor did any subject elicit a positive response to olestra following the skin prick testing. Two subjects had positive reactions consistent with immediate hypersensitivity after consuming the regular-fat, placebo potato chips. The results of this study confirm that olestra is unlikely to have an allergenic potential.     

Patient Drug Attributions and Postmarketing Surveillance

Although studies have shown that patients can distinguish probable adverse drug reactions (ADRs) from adverse clinical events (ACEs) caused by other factors, it is not known whether these attribution judgments add any independent validity to other accepted methods of identifying ADRs, such as physician assessments or epidemiologic data. Data from 2487 patients receiving fluoxetine and 815 receiving trazodone were used to see whether such information was redundant when added to standard statistical analysis directed toward detecting ADRs. Relative risk values for 14 trazodone or fluoxetine ADRs were selected because each was significantly identified by an innovative postmarketing surveillance system. In one analysis, all patient reports were used to compute relative risk; in the other, only reports attributed by patients to the study drug were included. Results indicate that taking into account patient attribution judgments results in a consistent, albeit modest, increase in the discriminatory power of this monitoring method.     

Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase

AIM

To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents.

METHODS

Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding.

RESULTS

Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12–17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known.

CONCLUSIONS

Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.     

Postmarketing safety information: how useful are spontaneous reports?

From 1995 until June 1998 123 new chemical entities (NCEs) were launched in Switzerland. In this time period 250 reports of adverse reactions (ADRs) involving 56 different NCEs were reported to the Swiss Drug Monitoring Center SANZ directly by physicians within the voluntary spontaneous reporting scheme (SRS). No cases from observational or clinical postmarketing studies were included. Of the reports 88% were suspected to be drug-related and 20% of them were serious. In 64% the ADRs were unlabelled and not notified to the health professionals. Disorders of the central nervous system (CNS) were reported in 32% and cardiovascular disorders in 26% of the unlabelled and serious cases. The non-serious cases accounted for 80% of the reported NCE-ADRs and 60% of them were unlabelled. Skin reactions were reported most frequently (18%), followed by psychic (15%), gastrointestinal (10%), cardiovascular and CNS disorders (8% each). In the labelled non-serious cases gastrointestinal and skin reactions were reported in 25% and 24% respectively. The other system organ classes were involved to a much smaller extent (<8%). CONCLUSIONS: (1) Spontaneous reports are of great value in optimizing postmarketing safety information. (2) Early reports give rise to a different ADR profile than expected from premarketing safety information. (3) Spontaneous reports have a strong signalling function especially for drugs used by general practitioners. (4) Sensitive signal detection systems are of great value in detecting non-labelled and serious ADRs in an early phase.     

倍他司汀治疗梅尼埃病所致眩晕的疗效观察及护理体会

目的：观察倍他司汀治疗梅尼埃病所致眩晕的疗效、安全性,总结护理体会。方法：将入选的76例梅尼埃病所致眩晕患者随机分成试验组（38例）和对照组（38例）,试验组在常规治疗基础上给予倍他司汀片每次1片,每日3次;对照组仅给予常规治疗。2组疗程均为1周。2组均给予系统护理。比较2组治疗1周后的临床疗效及不良反应。结果与结论：试验组总有效率（92.11%）显著高于对照组（73.68%）,差异有统计学意义（χ2=4.547,P=0.033）;试验组总不良反应发生率（18.42%）与对照组（15.79%）接近,差异无统计学意义（P〉0.05）。系统护理是梅尼埃病患者病情改善的必要条件,在系统护理的基础上给予倍他司汀治疗梅尼埃病所致眩晕具有较好疗效,且安全性较好。     

Postmarketing Drug Safety Surveillance

Postmarketing drug safety surveillance has undergone many changes, especially over the past decade when international harmonization on safety reporting and risk management strategies were adopted by regulators worldwide. It is important for readers in the field to keep abreast of the most recent occurrences and future trends. This review provides an overview of the latest regulatory initiatives in postmarketing drug safety surveillance and outlines major trends observed in three major economic regions (the European Union, Japan, and the US). The report encompasses regulatory developments in safety reporting, safety signal analyses, and risk management strategies. In addition, an overview of other important areas, such as medication errors, pharmacogenomics, and the future of pharmacovigilance, is also included. Overall, the most important initiative is the application of the concept of risk management programs. Regulatory authorities are currently developing guidance to the industry and healthcare providers through various concept papers and workshops. In addition, global harmonization of safety reporting has taken place within regulatory agencies for some time. These initiatives could strengthen the ability of pharmacovigilance organizations to review and monitor the safety of drug products. Furthermore, automated data-mining techniques have been developed and used to systematically screen adverse drug events for early safety signal detection. The future conduct of postmarketing drug safety surveillance is likely to be evidence-based, technology-driven, and patient-focused.     

Postmarketing survey on the clinical use of cefotiam

We performed a survey of clinical experience of cefotiam (CTM: Pansporin) as postmarketing surveillance (PMS), and evaluated the efficacy and safety of CTM in 10,499 cases of data which were collected during the first 2 years after approval. The following results were obtained. The efficacy rate of CTM in the treatment of various infections was 83.2%, which was equal or superior to the clinical results obtained before approval. A total of 472 adverse drug reactions was reported by 10,499 patients (4.50%). The commonest adverse drug reactions was liver function abnormality (230 cases), followed by dermal symptoms (103 cases), gastrointestinal symptoms (53 cases) and renal function abnormality (20 cases) in the order mentioned. All of these adverse drug reactions had already been known for cephem antibiotics, and no remarkable adverse drug reactions specific to CTM was found. The above PMS results indicate the same efficacy of CTM that obtained from premarketing studies. As regards safety, there was no remarkable unexpected adverse drug reaction and their profile was also the same as that found in premarketing studies. Thus, the utility of CTM was confirmed.     

甲磺酸倍他斯汀的合成

目的:合成甲磺酸倍他斯汀.方法:以2-乙烯基吡啶为原料,经加成,成盐两步反应合成甲磺酸倍他斯汀.结果:合成了甲磺酸倍他斯汀,总收率为72%.结论:本方法操作简便,适合工业化生产.     

Effects of betahistine on the spatiotemporal response properties of vestibulospinal neurons to labyrinthine volleys

Betahistine, a drug used in the treatment of vestibular disorders, speeds-up the recovery from hemilabyrinthectomy in experimental animals, likely through the activation of histamine receptors. In order to better understand the mechanism of action of this drug we investigated, in adult, urethane anesthetized rats, whether betahistine modifies the spatial (directional) and temporal response properties of vestibular nuclear neurons to the labyrinthine input, as well as the convergence of different labyrinthine signals on single units. Extracellular single-unit activity was recorded from the caudal, spinal-projecting region of the vestibular nuclei during tilt of the animal, before and after i.p. injection of betahistine. The two orthogonal directions of maximal and minimal response to tilt, as well as the corresponding gains were determined for each neuron. Betahistine reduced the maximal response gain of units showing larger basal values of this parameter and increased it in neurons with smaller basal values, while the minimal response gain was on the average raised. These changes led to a significant decrease in the spatial specificity of the neurons, suggesting that betahistine affects the process of spatiotemporal convergence on vestibular units, likely through a rearrangement of the various inputs. This could be related to the effect of the drug on vestibular compensation.     

The effect of betahistine on gastric acid secretion and mucosal blood flow in conscious dogs

In 3 conscious dogs, betahistine (2-(2'-methyl aminoethyl pyridine)) (80 or 160mug kg(-1) min(-1)) increased acid secretion from Heidenhain pouches to 8.8% and 17.6% respectively of the maximal response to histamine. Betahistine also increased mucosal blood flow (radioactive aniline clearance). The ratio of mucosal blood flow to secretion was greater for betahistine than for histamine but the difference between betahistine and histamine was significant in only one of the dogs.