BSP :: Current Drug Safety Home Page

Contents

Antimalarial Drugs in Pregnancy: A Reviews Pp.1-15
François Nosten, Rose McGready, Umberto d’Alessandro, Ana Bonell, Francine Verhoeff, Clara Menendez, Thenonest Mutabingwa & Bernard Brabin
[Abstract]  [Full Text Article]

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy Pp.17-24
Carlos De las Cuevas & Emilio J. Sanz
[Abstract]  [Full Text Article]

The Safety of Medications for the Treatment of Bipolar Disorder During Pregnancy and the Puerperium Pp.25-33
Seetal Dodd & Michael Berk
[Abstract]  [Full Text Article]

The Role of Growth Factors in the Prevention and Treatment of Chemotherapy-Induced Peripheral Neurotoxicity Pp.35-42
Guido Cavaletti & Paola Marmiroli
[Abstract]  [Full Text Article]

Headache: One of the Most Common and Troublesome Adverse Reactions to Drugs Pp.43-58
Anna Ferrari
[Abstract]  [Full Text Article]

SSRIs, Suicide and Violent Behavior: Is there a Need for a Better Definition of the Depressive State? Pp.59-62
Chantal Henry & Jacques Demotes-Mainard
[Abstract]  [Full Text Article]

Hypnotics and Driving Safety: Meta-Analyses of Randomized Controlled Trials Applying the on-the-Road Driving Test Pp.63-71
Joris C. Verster, Dieuwke S. Veldhuijzen, Alain Patat, Berend Olivier & Edmund R. Volkerts
[Abstract]  [Full Text Article]

Tolerability of Amine Uptake Inhibitors in Urologic Diseases Pp.73-85
Martin C. Michel, Henricus G. Ruhe, Annemieke A. de Groot, Ramiro Castro & Matthias Oelke
[Abstract]  [Full Text Article]

Role of Vitamin K₂ in the Treatment of Postmenopausal Osteoporosis Pp.87-97
Jun Iwamoto, Tsuyoshi Takeda & Yoshihiro Sato
[Abstract]  [Full Text Article]

The Clinical Development of γ-Hydroxybutyrate (GHB) Pp.99-106
Gregory P. Wedin, Carl S. Hornfeldt & Lisa M. Ylitalo
[Abstract]  [Full Text Article]

Host Pharmacogenetics in the Treatment of HIV and Cancer Pp.107-116
Alan Winston, Eleftheria Hatzimichael, Vanessa Marvin, Justin Stebbing & Mark Bower
[Abstract]  [Full Text Article]

How Vaccine Safety can Become Political – The Example of Polio in Nigeria Pp.117-119
Christopher J. Clements, Paul Greenough & Diana Shull
[Abstract]  [Full Text Article]

Informing People about the Risks and Benefits of Medicines: Implications for the Safe and Effective Use of Medicinal Products Pp.121-126
Dianne C. Berry
[Abstract]  [Full Text Article]

Abstracts

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Antimalarial Drugs in Pregnancy: A Reviews
François Nosten, Rose McGready, Umberto d’Alessandro, Ana Bonell, Francine Verhoeff, Clara Menendez, Thenonest Mutabingwa & Bernard Brabin

[Full Text Article]

In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of antimalarial treatments in pregnancy, including artemisinin based combination therapies.

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Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy
Carlos De las Cuevas & Emilio J. Sanz

[Full Text Article]

Psychiatric treatment with selective serotonin reuptake inhibitors (SSRIs) may be desirable or necessary during pregnancy; however, the benefit of these treatments must balance the benefits to the mother with any risk to the developing foetus. At the present time, the role of serotonin in normal central nervous system development, as well as the effects of altering serotonin transmission at critical periods of embryo development, remains to be further clarified.

Depression has a high prevalence in pregnant women (around 10%) and approximately one-half of the pregnancies are unplanned, making necessary that physicians have to know the risks associated with the decision to use this kind of antidepressants during pregnancy.

The effects of antidepressants in pregnancy could be classified in several main categories: the teratogenic possible effects; the effects on the normal development of the brain and neuropsychological functions; the effects on birth weight and/or early delivery; the risk of increased bleeding on the mother during delivery; the neuropsychological behaviour and adaptation after delivery, including not only neonatal withdrawal syndromes but also pain reactivity and increased parasympathetic cardiac modulation during recovery after an acute noxious event and in a wide range of neurobehavioural outcomes; and medium- to long-term effects in neurocognitive functions in those children.

These areas are reviewed according to the most recent published cohort-controlled studies and prospective surveys regarding SSRIs use in pregnancy. The review tries to clarify the blurred aspects of the use of SSRI during pregnancy and to give sensible and up-to-dated guidelines for the treatment of psychiatric disorders with SSRI during pregnancy.

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The Safety of Medications for the Treatment of Bipolar Disorder During Pregnancy and the Puerperium
Seetal Dodd & Michael Berk

[Full Text Article]

Risks associated with pharmacological treatment of bipolar disorder are heightened during reproductive events. Treatments need to be planned with the mutual agreement of both the treating physician and the patient and tailored to the needs of the individual so as to minimise risk while providing adequate treatment. Conventional treatments have all been associated with teratogeny in first trimester exposure, lithium with cardiac malformation and valproate and carbamazepine with neural tube malformations. There have been an insufficient number of first trimester exposures to the newer anticonvulsant mood stabilisers, lamotrigine and oxcarbazepine, to determine whether there is a safety advantage in switching to these agents. Increasingly, atypical antipsychotics are being suggested as useful agents for the treatment of bipolar disorder. While not known to be teratogenic, there are other reproductive safety concerns associated with these agents. Bipolar disorder patients may be prescribed antidepressants, and many of these agents are associated with a low safety risk during reproductive events, however data regarding use of these agents are currently equivocal. Adverse outcomes from inadequate pharmacological prophylaxis have been documented for both the mother and the baby. Risks and benefits need to be carefully balanced based on an accurate review of the evidence.

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The Role of Growth Factors in the Prevention and Treatment of Chemotherapy-Induced Peripheral Neurotoxicity
Guido Cavaletti & Paola Marmiroli

[Full Text Article]

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem since it is the dose-limiting side effect of a significant number of antineoplastic drugs. The incidence of CIPN varies depending on the conditions, but severe neuropathy can occur in up to 40% of patients undergoing a polichemotherapy regimen.

Moreover, even when CIPN is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. Currently, no treatment is available which can significantly improve the clinical signs and symptoms of CIPN. In recent years, new agents have been proposed as neuroprotectants, and some of them have been more specifically studied for CIPN. So far, the most interesting results for future applications have been obtained in the pre-clinical studies involving cytokines and growth factors. For several of these drugs, in fact, sound hypotheses have been formulated to support the idea of a protective role on selected neuronal targets. However, this theoretical basis has frequently failed to lead to consistent results in pre-clinical and clinical applications. We will review the state-of-the-art of CIPN treatment with growth factors and focus on the future prospects opened up by the most recent pre-clinical and clinical studies.

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Headache: One of the Most Common and Troublesome Adverse Reactions to Drugs
Anna Ferrari

[Full Text Article]

It is difficult to attribute the diagnosis of adverse drug reaction to a condition which is also a common symptom. The decision might be arduous in the case of headache, because this disorder is very frequent in the general population. The drugs that more frequently induce headache belong to a variety of therapeutic classes with different mechanisms of action and different toxicity. In the majority of cases the headache has not a typical feature, it is dosedependent, and is associated to other symptoms of neurotoxicity. Some drugs cause, instead, a specific headache: this is the case of NO donors, which are also used in experimental studies in order to induce headache.

This review describes the classes of drugs which induce headache, analyzes the frequency of headache induction among the drugs of the same class, and discusses the possible mechanisms underlying headache induction. It is to be hoped that a better awareness of this issue would help the physician to consider it in the differential diagnosis of a recent-onset or changed headache and to avoid prescription of drugs known to cause headache to patients already suffering from this disorder.

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SSRIs, Suicide and Violent Behavior: Is there a Need for a Better Definition of the Depressive State?
Chantal Henry & Jacques Demotes-Mainard

[Full Text Article]

To what extent do SSRIs increase the risk of suicide or violent behavior? Recent data indicate that some SSRIs lack a favorable 'risk–benefit' profile for treating childhood and adolescent depression. In addition, certain recent documents have cast doubt on previous conclusions dissociating antidepressant from violence.

Beyond the debate on the need for improved transparency in clinical studies, this controversy raises other critical issues of SSRI use that merit our consideration.

Firstly, is there an overuse of antidepressants, and does the risk of suicide increase with the prescription of antidepressants in the whole population? Secondly, is the response to antidepressants modified during adolescence? If so, by what mechanisms? We know that SSRI treatment can trigger mood changes in undiagnosed young bipolar patients resulting in agitation and disinhibition, and such effects may lead to suicide and violence.

Thirdly, recent extensive literature has shown that some cases of depression are worsened by antidepressants and new data has suggested that bipolar depression can be improved by atypical antipsychotics. Finally, current criteria defining the depressive state are very similar to those employed during the 19^th century, a pre-therapeutic period. Currently, while it is recognised that depressive mood is a very broad construct, there is still only one definition in international classifications to describe a major depressive episode. There is a clear need to develop an evidence-based approach to psychiatry aiming at delineating diagnostic categories predictive of the response to treatments.

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Hypnotics and Driving Safety: Meta-Analyses of Randomized Controlled Trials Applying the on-the-Road Driving Test
Joris C. Verster, Dieuwke S. Veldhuijzen, Alain Patat, Berend Olivier & Edmund R. Volkerts

[Full Text Article]

Background: Many people who use hypnotics are outpatients and are likely to drive a car the day after drug intake. The purpose of these meta-analyses was to determine whether or not this is safe.

Methods: Placebo-controlled, randomized, double-blind trials were selected if using the on-the-road driving test to determine driving ability the day following one or two nights of treatment administration. Primary outcome measure of the driving test was the Standard Deviation of Lateral Position (SDLP); i.e., the weaving of the car. Fixed effects model meta-analyses were performed. Effect size (ES) was computed using mean standardized (weighted) difference scores between treatment and corresponding placebo SDLP values.

Results: Ten studies, published from 1984 to 2002 (207 subjects) were included in the meta-analyses. The morning following bedtime administration, i.e. 10-11 hours after dosing, significant driving impairment was found for the recommended dose of various benzodiazepine hypnotics (ES=0.42; 95% Confidence Interval (CI)=0.14 to 0.71). Twice the recommended dose impaired driving both in the morning (ES=0.68;CI=0.39 to 0.97) and afternoon, i.e. 16-17 hours after dosing (ES=0.57, CI=0.26 to 0.88). Zopiclone 7.5 mg also impaired driving in the morning (ES=0.89;CI=0.54 to 1.23). Zaleplon (10 and 20 mg) and zolpidem (10 mg) did not affect driving performance the morning after dosing. Following middle-of-the-night administration, significantly impaired driving performance was found for zopiclone 7.5 mg (ES=1.51, CI=0.85 to 2.17), zolpidem 10 mg (ES=0.66, CI=0.13 to 1.19) and zolpidem 20 mg (ES=1.16, CI=0.60 to 1.72). Zaleplon (10 and 20 mg) did not affect driving performance.

Conclusions: The analyses show that driving a car the morning following nocturnal treatment with benzodiazepines and zopiclone is unsafe, whereas the recommended dose of zolpidem (10 mg) and zaleplon (10 mg) do not affect driving ability.

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Tolerability of Amine Uptake Inhibitors in Urologic Diseases
Martin C. Michel, Henricus G. Ruhe, Annemieke A. de Groot, Ramiro Castro & Matthias Oelke

[Full Text Article]

Inhibitors of serotonin (5-HT) and/or noradrenaline (NA) reuptake have been developed for pharmacological treatment of major depressive disorder. Insights in the role of 5-HT and NA in the neurological control of the lower urinary tract have also lead to their application in common urological conditions such as stress urinary incontinence (SUI), nocturnal enuresis and ejaculatory disorders.

The European approval of the 5-HT and NA reuptake inhibitor (SNRI) duloxetine for treatment of SUI underlines the importance of a new approach in SUI, but has also given rise to questions about the safety of antidepressants in urology. This paper reviews the safety of 5-HT and NA reuptake inhibitors in their on-and off-label use in urology. A systematic Medline search was performed for randomised controlled trials, meta-analyses and practice guidelines dealing with antidepressants in urology. The safety profiles of the drugs in the urological population were compared with data from psychiatric populations.

Tricyclic antidepressants are associated with serious cardiovascular side effects. In addition, anticholinergic and antihistaminic side effects are common. Although recently questions have been raised regarding the cardiovascular safety profile of venlafaxine, most selective 5-HT reuptake inhibitors and SNRI have not been associated with serious cardiovascular effects. Their most common side effect is nausea. However, nausea tends to be mild and, importantly, transient. Patient counselling about side effects and up-titrating doses may be useful strategies for minimising discomfort and withdrawals.

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Role of Vitamin K2 in the Treatment of Postmenopausal Osteoporosis
Jun Iwamoto, Tsuyoshi Takeda & Yoshihiro Sato

[Full Text Article]

Vitamin K2, raloxifene, and bisphosphonates, such as etidronate, alendronate, and risedronate, are widely used in the treatment of postmenopausal osteoporosis in Japan. A meta-analysis study has demonstrated the efficacy of anti-resorptive agents: raloxifene and etidronate have been shown to reduce the incidence of vertebral fractures, and alendronate and risedronate have been shown to reduce the incidence of both vertebral and hip fractures. Furthermore, a report of the World Health Organization (WHO) has provided evidence from a randomized controlled trial suggesting that vitamin K2, which may stimulate bone formation via γ-carboxylation of osteocalcin and/or steroid and xenobiotic receptors (SXRs), reduces the incidence of vertebral fractures, despite having only modest effects on the bone mineral density (BMD). Based on the weight of the currently available evidence, it i s recommended that alendronate and risedronate, rather than vitamin K2, should be chosen initially for the treatment of postmenopausal osteoporosis, because these agents have been shown to be the most efficacious for reducing the incidence of both vertebral and hip fractures among the current range of commercially available agents. However, the more potent anti-fracture efficacy of combined treatment with the anti-resorptive and commercially available anabolic agents may need to be established. Some studies have shown that combined treatment with a bisphosphonate and vitamin K2 may be more effective than treatment with a bisphosphonate alone in preventing vertebral fractures. On the other hand, the results of a preclinical study do suggest the possible efficacy of combined treatment with vitamin K2 and raloxifene in the prevention of vertebral and hip fractures in postmenopausal women, although no clinical studies have reported on the effects of combined treatment with vitamin K2 and raloxifene in postmenopausal women with osteoporosis. Vitamin K deficiency, as indicated by high serum levels of undercarboxylated osteocalcin, has been shown to contribute to the occurrence of hip fractures in elderly women. Thus, we propose that the important role of vitamin K2 used in combination with bisphosphonates or raloxifene should not be underestimated in the prevention of fractures in postmenopausal women with osteoporosis with vitamin K deficiency.

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The Clinical Development of γ-Hydroxybutyrate (GHB)
Gregory P. Wedin, Carl S. Hornfeldt & Lisa M. Ylitalo

[Full Text Article]

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980’s while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990’s. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem® (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

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Host Pharmacogenetics in the Treatment of HIV and Cancer
Alan Winston, Eleftheria Hatzimichael, Vanessa Marvin, Justin Stebbing & Mark Bower

[Full Text Article]

Physicians prescribing drugs are routinely confronted with the balance between efficacy and toxicity. Pharmacogenetics involves the study of how inheritance influences response to drugs, and its goal is to enable the appropriate selection of these individuals, thus eliminating unpredictable responses. Pharmacogenetics can be used to identify target populations that either will have minimal benefit or a better outcome including better survival or improvement in surrogate end points. As we move towards common use of targeted therapies, the future of medicine will involve an examination of the interplay between multiple genetic factors, as the response to drugs is likely to be complex and polyfactorial especially in chronic diseases. There has already been some success in situations where single genes play a large role in the overall drug response, and this is discussed with reference to commonly used cytotoxics and antiretrovirals, encompassing the major principles of pharmacogenetics.

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How Vaccine Safety can Become Political – The Example of Polio in Nigeria
Christopher J. Clements, Paul Greenough & Diana Shull

[Full Text Article]

Vaccine safety is increasingly a major aspect of immunization programmes. Parents are becoming more aware of safety issues relating to vaccines their babies might receive. As a consequence, public health initiatives have had to take note of pressures brought to bear by individual parents and groups. Now we document a new phase in vaccine safety where it has been used to achieve political objectives. In 1988, the World Health Assembly declared its intention to eradicate poliomyelitis from the globe by the year 2000. This goal had to be postponed to 2005 for a number of reasons. Although the progress has been spectacular in achieving eradication in almost all nations and areas, the goal has been tantalizingly elusive.

But arguably the most difficult country from which to eradicate the virus has been Nigeria. Over the past two years, tension has arisen in the north against immunizing against polio using the oral polio vaccine (OPV). Although this vaccine has been used in every other country in the world including other Muslim states, some religious leaders in the north found reason in August 2003 to advise their followers not to have their children vaccinated with OPV. Subsequent to this boycott, which the Kano governor had endorsed for a year and then ended in July 2004, cases of polio occurred in African nations previously free of the virus, and the DNA finger-print of the virus indicated it had came from Nigeria. In other words, Nigeria became a net exporter of polio virus to its African neighbours and beyond. Now the disease has spread to about a dozen formerly polio-free countries, including Sudan and Indonesia. We show that, while the outward manifestations of the northern Nigerian intransigence were that of distrust of vaccine, the underlying problem was actually part of a longstanding dispute about political and religious power vis a vis Abuja. It is unlikely that polio transmission will be interrupted by 2005 if this dispute is allowed to run its course.

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Informing People about the Risks and Benefits of Medicines: Implications for the Safe and Effective Use of Medicinal Products
Dianne C. Berry

[Full Text Article]

Providing effective information about drug risks and benefits has become a major challenge for health professionals, as many people are ill equipped to understand, retain and use the information effectively. This paper reviews the growing evidence that people’s understanding (and health behaviour) is not only affected by the content of medicines information, but also by the particular way in which it is presented. Such presentational factors include whether information is presented verbally or numerically, framed positively or negatively, whether risk reductions are described in relative or absolute terms (and baseline information included), and whether information is personalised or tailored in any way. It also looks at how understanding is affected by the order in which information is presented, and the way in which it is processed. The paper concludes by making a number of recommendations for providers of medicines information, about both the content and presentation of such information, that should enhance safe and effective medicines usage.