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Regulatory Toxicology and Pharmacology 72 (2015) 572–577
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Adverse drug reactions for medicine newly approved in Japan from 1999 to 2013: Syncope/loss of consciousness and seizures/convulsions Takashi Nagayama ⇑ Non-Clinical Development, Science, Services & Planning, UCB Japan Co., Ltd., Shinjuku Grand Tower, 8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023 Japan
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Article history: Received 15 December 2014 Available online 6 June 2015 Keywords: Adverse drug reaction Animal toxicity Medicine Syncope Seizure
a b s t r a c t Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan. Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction A safe medicine is ideally exempt from adverse drug reactions (ADRs), but it is often difficult to distinguish ADR from the intended pharmacological action. During the drug developmental to select a candidate compound, every effort is made to provide safe medicines. In vitro, in vivo and in silico pharmacological studies, pharmacokinetics studies and also many animal toxicity studies are conducted before human use. Some compounds which exhibit unacceptable toxicity are discontinued from development prior to clinical studies. Many medicines on the market are used with their ADR appropriately managed in clinical settings based on the risk:benefit ratio. Unfortunately, there is no medicine without ADR. The aim of this survey was to clarify the correlation between ADR in humans and safety signals observed in animal toxicity studies, in order to contribute to constructing safe drug developmental strategies as well as ensuring the appropriate use of marketed medicines in the clinical setting. As it is difficult to analyze all ADRs, we selected two clinically important ADRs. Selected ADR for our survey were syncope and loss of consciousness,
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seizures and convulsions, hypertension and hypotension, arrhythmia, blood glucose increase and lipid metabolism disorders, changes in the number of leukocytes, dyspnea, hallucination and delusion, vision impairment, hearing impairment, dysgeusia and dysosmia, creatine kinase increase, BUN and creatinine increase, proteinuria and hematuria, dizziness, and vertigo. These parameters are clinically important and significant and some of them showed low translatability from animal toxicity findings. Investigational results for syncope/loss of consciousness and seizures/convulsions have been presented in this paper and investigational results for other ADR will be the subject of a second paper. Due to the difficulty in evaluating the pro-syncope effects in animal models, investigations into the underlying mechanisms such as cerebral circulation insufficiency may be useful. Hypotension, arrhythmia, hypoglycemia and anemia may lead to cerebral circulation insufficiency, finally leading to syncope. On the other hand, pro-seizure effects are frequently evaluated using animal safety pharmacology studies for drug development. Animal models are not perfect; however they can be useful in order to extrapolate pro-seizure effect in humans, especially for CNS targeting drugs. The mechanism of action of a drug is also important; excitatory neuron agonists and inhibitory neuron antagonists may have pro-seizure effects. There is some debate on the necessity and usefulness of animal studies for these kinds of CNS effects. The
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survey results are expected to contribute toward constructing safe drug developmental strategies as well as ensuring the appropriate use of marketed medicines in the clinical setting.
393 medicines in Japan No syncope/loss of consciousness and no seizures/convulsions
247 (62.8%)
2. Methods We reviewed medicines which have been approved in the past 13 years in Japan in terms of (1) what kinds of ADR were observed for each medicine in clinical studies, (2) whether animal toxicity findings that correspond to the concerned ADR were observed or not, (3) how the concerned ADR were predicted before clinical studies or before market distribution in cases where no relevant findings were noted in animal studies, and (4) how the ADR were managed in clinical use. ADR information for 393 human medicines approved for use in Japan as a new drug substances between September 1999 and March 2013 were used for this survey. The ADR described in each package insert were collected. This survey included many ADRs, but only the following are reported in this paper: syncope/loss of consciousness and seizures/convulsions, specifically syncope, loss of consciousness, depressed level of consciousness, consciousness level depression, depressed consciousness, altered state of consciousness, and disturbance of consciousness for syncope/loss of consciousness category and seizures, convulsions, epilepsy, epileptic seizures, petit mal seizures, grand mal seizures and partial seizures for seizures/convulsions category. Comparable animal toxicity findings with ADR were collected by thorough investigation of the review reports and the summary of new drug applications (common technical documents (CTD) Module 2.4 and 2.6) available on the web site of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Survey data was also analyzed for recent trends of syncope/loss of consciousness and seizures/convulsions for recently approved Japanese medicines. In addition, we assessed the correlation with ADR and animal toxicity findings for the medicines. These results suggest improvements in animal and clinical studies to provide safer medicines, and to propose suggestions for clinical use of these medicines to contribute to patient safety. A statistical analysis was not performed in this study. Concordance ratio was used to evaluate translatability of ADR in human patients from animal toxicity findings. The concordance ratio was calculated by the following equation, generally named true positive rate or sensitivity:
Concordance ratioð%Þ ¼ true positive rate ðsensitivityÞ 100 ¼ true positive=ðtrue positive þ false negativeÞ 100
3. Results 3.1. Syncope/loss of consciousness and seizures/convulsions in recently approved Japanese medicines The 393 medicines investigated contained a broad category of medicines for example 50 CNS drugs, 26 cardiovascular drugs, 39 antineoplastics, 50 antibacterial and antiviral agents, 22 monoclonal antibodies, 19 vaccines. According to the search of the package inserts, 101 of 393 medicines (25.7%) showed syncope/loss of consciousness and 105 of 393 medicines (26.7%) showed seizures/convulsions (Fig. 1). A total of 60 medicines (15.3%) have both syncope/loss of consciousness and seizures/convulsions, while 146 medicines (37.2%) showed syncope/loss of consciousness or seizures/convulsions. Our research results showed that more than one third of the recently approved medicines in Japan induce ADR
Syncope/ loss of consciousness
41 (10.4%)
60 (15.3%)
Seizures/ convulsions
45 (11.5%)
Fig. 1. Adverse drug reactions of syncope/loss of consciousness and seizures/convulsions in recently approved 393 Japanese medicines. Adverse drug reaction information for 393 medicines approved for human use in Japan as a new drug substance from September 1999 to March 2013 were used for this survey. 101 (25.7%) medicines showed syncope/loss of consciousness and 105 (26.7%) medicines showed seizures/convulsions. 247 (62.8%) medicines did not show syncope/loss of consciousness nor seizures/convulsions.
such as syncope/loss of consciousness and/or seizures/convulsions directly or affect the metabolic cascade. 3.2. Syncope/loss of consciousness and seizures/convulsions in each class of medicine Evaluated medicines in this study were distributed across a wide range of treatments. In terms of the numbers of medicines in each category, there were 39 antineoplastic agents, 29 anti-virus agents, 26 agents using antibody, 19 vaccines, 19 hormones and hormone analogs, as well as many other categories. The categories with the least number of medicines were synthetic narcotics and agents for otic and nasal use, both of which numbered 3. Syncope/loss of consciousness were reported in many medicines affecting CNS, i.e. all antiparkinsonian agents and 80.0% of psychotropic agents (Fig. 2). Psychotropic agents included 6 antidepressants, 8 antipsychotics and one medicine for attention deficit hyperactivity disorder. Syncope/loss of consciousness was reported in 83.3% of antidepressants and 75.0% of antipsychotics. There are mechanistic associations for syncope/loss of consciousness induction for CNS medicines. Syncope/loss of consciousness was also reported in 80.0% of agents affecting peripheral nervous system (local anesthetics). It was reported in 75.0% of antihypertensives, 62.5% of synthetic antibacterials, and 60.0% of interferons. Seizures/convulsions were reported in many medicines affecting CNS, i.e. 87.6% of psychotropic agents and 66.7% of antiepileptics (Fig. 3). Psychotropic agents were further classified to antidepressants and antipsychotics, with seizures/convulsions reported in 100.0% of antidepressants and 87.5% of antipsychotics. Seizures/convulsions were also reported in 80.0% of agents affecting the peripheral nervous system (local anesthetics) and in 100.0% of interferons, 80.0% of vasoconstrictors, 75.0% of synthetic antibacterials, and 52.6% of vaccines. 3.3. Concordance of human adverse drug reactions with animal toxicity Doses and blood concentration in humans and animals were not directly evaluated in this survey. Whenever the finding was observed in animal studies at any dose used by the sponsor, we evaluated that the toxicity finding as positive in animal studies.
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Overall 393 Oligoneucleode, polysaccharide, and others 9 Hormones and hormone analogs 19 Andotes 5 Agents for osteoporosis 5 Andiabec agents 12 Agents for epidermis 5 Agents affecng respiratory organs 6 Agents for hyperlipidemias 5 Agents for oc and nasal use 3 Agents for not mainly purpose of therapeuc 13 Agents for ophthalmic use 13 Hematopoiec factors, human blood preparaons 11 Vaccines 19 Agents affecng digesve organs 9 Enzyme preparaons 8 Anallergic agents 8 Other cardiovascular agents 8 Other agents affecng metabolism 18 Agents using anbody 26 Vasoconstrictors 5 Anepilepcs 9 Anneoplasc agents 39 Ancoagulants 8 Agents for uro-genital and anal organs 11 Agents against pathologic organisms and parasites 7 An-virus agents 29 Other agents affecng central nervous system 16 Anpyrecs, analgesics and an-inflammatory agents 4 Anbioc preparaons 13 Interferons 5 Synthec anbacterials 8 Synthec narcocs 3 Anhypertensives 8 Agents affecng peripheral nervous system 5 Psychotropic agents 15 Anparkinsonian agents 6
n 0.0%
20.0%
40.0%
60.0%
80.0% 100.0%
Fig. 2. The ratio of medicines showing syncope/loss of consciousness in each class of medicines newly approved in Japan from 1999 to 2013. Horizontal bars indicate the percentage of number of medicines showing syncope/loss of consciousness.
We assumed that the sponsor selected appropriate doses for animal studies reflecting human blood concentration. Animal toxicity concordance ratio with syncope/loss of consciousness is 4.0% (4/101) (Table 1). Only 4 local anesthetics showed syncope/loss of consciousness in animal studies that had been induced by acute toxic reaction. Animal toxicity concordance ratio with seizures/convulsions was only 23.8% (25/105) (Table 1). When seizures/convulsions occurred at any dose in the animal studies, we classified that as concordant findings in this survey. Concordant preclinical findings were observed in safety pharmacology studies for 17 medicines and in repeated administration toxicity studies for 16 medicines
(Table 2). A pro-convulsion study with chemo-convulsants was mainly used for safety pharmacology studies. 3.4. Mechanism of action The 101 medicines which showed syncope/loss of consciousness were classified according to the mechanism of action (Table 3). The mechanism of action for 40 medicines (39.6%) was clearly described in the package insert or CTD. Syncope/loss of consciousness attributed to hypotension is seen in 17 medicines (5.0%), i.e. 5 antiparkinsonian agents, one psychotropic agent, 6 antihypertensives, and one other cardiovascular agent. Syncope/loss of consciousness either
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Overall 393 Oligoneucleode, polysaccharide, and others 9 Hormones and hormone analogs 19 Enzyme preparaons 8 Anhypertensives 8 Andotes 5 Andiabec agents 12 Ancoagulants 8 Agents for uro-genital and anal organs 11 Agents for oc and nasal use 3 Agents for osteoporosis 5 Agents for ophthalmic use 13 Agents for epidermis 5 Agents affecng digesve organs 9 Agents affecng respiratory organs 6 Hematopoiec factors, human blood preparaons 11 Other agents affecng metabolism 18 Agents for not mainly purpose of therapeuc 13 Anparkinsonian agents 6 Agents using anbody 26 Agents for hyperlipidemias 5 Other cardiovascular agents 8 Anpyrecs, analgesics and an-inflammatory agents 4 Agents against pathogenic organisms and parasites 7 Anneoplasc agents 39 An-virus agents 29 Anallergic agents 8 Other agents affecng central nervous system 16 Anbioc preparaons 13 Vaccines 19 Anepilepcs 9 Synthec anbacterials 8 Vasoconstrictors 5 Agents affecng peripheral nervous system 5 Psychotropic agents 15 Synthec narcocs 3 Interferons 5
n 0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Fig. 3. The ratio of medicines showing seizures/convulsions in each class of medicines newly approved in Japan from 1999 to 2013. Horizontal bars indicate the percentage of number of medicines showing seizures/convulsions.
Table 1 Concordance of human adverse drug reaction with animal toxicity finding for medicine newly approved in Japan from 1999 to 2013. Adverse drug reactions
n
True positive (n) Concordance ratio (%)
Syncope/loss of consciousness 101 4 Seizures/convulsions 105 25
4.0 23.8
Concordance ratio (%) = true positive rate (sensitivity) 100 = true positive/(true positive + false negative) 100.
attributed to arrhythmia, hypoglycemia or acute toxic reaction was seen in 5 (5.0%), 4 (4.0%) and 4 (4.0%) medicines respectively. Syncope/loss of consciousness related to hypoglycemia was mainly
Table 2 Classification of animal studies in which seizures/convulsions were observed for 25 medicines. Animal studies
Number of medicines (%)
Repeated-dose toxicity studies Pro-convulsion studies in the safety pharmacology study Other safety pharmacology studies
16 (64.0)# 10 (40.0)# 7 (28.0)#
# 8 medicines showed seizures/convulsions in both toxicity and safety pharmacology studies.
observed with synthetic antibacterials/antibiotics, and those mediated by acute toxic reactions were observed with 4 local anesthetics.
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Table 3 Classification of mechanism of syncope/loss of consciousness for 101 medicines. Mechanism of syncope/loss of consciousness
Number of medicines (%)
Hypotension Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Arrhythmia Hypoglycemia Acute toxic reaction Hypocalcemia Suppression of noradrenalin release Hypotension or hypoglycemia or arrhythmia Unidentified
17 (16.8) 5 (5.0) 5 (5.0) 4 (4.0) 4 (4.0) 1 (1.0) 1 (1.0) 3 (3.0) 61 (60.4)
Table 4 Candidate adverse drug reactions which may have some relation with syncope/loss of consciousness for 61 medicines for which mechanism of syncope/loss of consciousness. Adverse drug reactions
Reported number of medicines (%)
Not reported number of medicines (%)
Hypotension Arrhythmia Hypoglycemia Anemia Hypotension or arrhythmia or hypoglycemia or anemia Dizziness or stagger Nausea or vomiting
37 45 13 43 56
24 (39.3) 16 (26.2) 48 (78.7) 18 (29.5) 5 (8.2)
(60.7) (73.8) (21.3) (70.5) (91.8)
52 (85.2) 60 (98.4)
9 (14.8) 1 (1.6)
Syncope/loss of consciousness as the consequence of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was seen in 5 (5.0%), hypocalcemia was observed in one (1.0%), and suppression of noradrenalin release was noted in one medicine (1.0%). It is well known that the mechanisms of syncope/loss of consciousness for other medicines are strongly related to an insufficient cerebral circulation in the context of the systemic circulation, however the specific mechanism was not clearly identified for 61 medicines (60.4%). ADR inducing insufficient cerebral circulation in the context of the systemic circulation may have a relationship with syncope/loss of consciousness. For the 61 medicines which did not have a clearly identified specific mechanism, accompanying ADRs were evaluated in order to speculate on the causality from cerebral circulation insufficiency (Table 4). Hypotension, arrhythmia, hypoglycemia and anemia were reported in many medicines: 91.8% of medicines showed one of these ADR which suggests some mechanistic relationship with syncope/loss of consciousness. Dizziness or stagger was reported in 85.2% of medicines and nausea or vomiting was reported in 98.4%. Mechanisms of seizures/convulsions for 105 medicines were investigated (Table 3). Four local anesthetics (3.8%) were considered to be mediated by acute toxic reaction. Mechanism of seizures/convulsions for the other 101 medicines (96.2%) was not identified by thorough investigation of the review reports and the summary of new drug applications.
4. Discussion There are many publications for case reports and epidemiological researches on ADR; however research for specific ADR covering all medicines is rare. This survey using the package insert may be useful to understand the entire and/or categorized group of potential risks of syncope/loss of consciousness and seizures/convulsions for recently approved medicines. Syncope/loss of consciousness and seizures/convulsions are one of the clinically important drug-induced ADR. Drug-induced syncope appears relatively common (Lemonick, 2010). In the study of Duke University’s Syncope Clinic, 13% of the patients were rated
as having probable drug-induced syncope (Hanlon et al., 1990). Our survey results for syncope/loss of consciousness emphasizes the importance for physicians to pay attention to the occurrence of this significant ADR for agents affecting CNS, local anesthetics, antihypertensives, synthetic narcotics, synthetic antibacterials, interferons and antibiotic preparations. Our result highlights the difficulty in evaluating pro-syncope potency with preclinical studies, which may be related to physiological differences between human and animals (van Dijk, 2003). It is important to understand the pharmacological mechanism behind syncope/loss of consciousness. Pro-syncope medicine that commonly lead to effects on blood pressure, arrhythmias, or glycemia, may have a potency to induce syncope in human (Lionte, 2009). We also investigated the mechanism underlying syncope/loss of consciousness; mechanisms of action for 40 of the 101 medicines were identified and the results showed some relation with hypotension, SIADH, arrhythmia or hypoglycemia (Table 3). It is considered that the principal mechanism of syncope/loss of consciousness is sudden cerebral perfusion decrease induced by hypotension, SIADH, arrhythmia or hypoglycemia (Lionte, 2009; Tyagi et al., 2009; Hadjikoutis et al., 2004). Antiparkinsonian agents show syncope/loss of consciousness by mediated hypotension through a peripheral D2 dopaminergic mechanism. Cholinesterase inhibitors can provoke symptomatic bradycardia which shows some relation with syncope/loss of consciousness (Gill et al., 2009). Syncope/loss of consciousness induced by psychotropic agent (antidepressant and antipsychotics) is mainly considered to be mediated through SIADH, arrhythmia or hypotension inhibiting cardiac or vascular Na+, Ca2+ or K+ channels (Pacher and Kecskemeti, 2004; Piepho, 2002; Vieweg et al., 2009). The evidence suggests that pharmacological action may have some relation with syncope/loss of consciousness for most of CNS affecting agents, mainly on/off target on unintended organs. Syncope/loss of consciousness induced by synthetic antibacterials is considered to be related to hypoglycemia. We did not identify syncope/loss of consciousness mediated through anemia, but some examples were reported (Tyagi et al., 2009). Usually many medicines have some ADR, such as hypotension, arrhythmia, hypoglycemia and anemia. It is difficult to evaluate syncope/loss of consciousness in animal studies, but it may be useful to investigate closely adverse effects which have some relation with syncope in animal studies. ADR management in the clinic is important, but there is no standard strategy for all medicines. Orthostatic hypotension is common in Parkinson’s disease patients where the prevalence of symptomatic orthostatic hypotension may be as high as 20–50% (Pathak and Senard, 2006; Senard et al., 2001; Perez-Lloret et al., 2013). Parkinson’s disease is a cause of primary autonomic failure with an involvement of the peripheral autonomic system (Senard et al., 2001). Our survey showed all antiparkinsonian agents show syncope/loss of consciousness. The mechanism of syncope for 5/6 medicines is by mediated hypotension through a peripheral D2 dopaminergic mechanism. There are some reviews that described the relationship between orthostatic hypotension and the current treatments employed in Parkinson’s disease (Sánchez-Ferro et al., 2013; Milazzo et al., 2012). This use of antiparkinsonian agents, taking into consideration the risks vs. benefits, is an interesting example for controlling ADR in clinic. Numerous medicines have been reported to be associated with the occurrence of seizures (Murphy and Delanty, 2000; Thundiyil et al., 2007; Delanty et al., 1998; Pesola and Avasarala, 2002; Behnoush et al., 2012; Thundiyil et al., 2011). Drug-induced complicated seizures can result in hyperthermias, acidosis, anoxic brain injury and up to 2% mortality (Thundiyil et al., 2007; Isbister et al., 2004). Our survey results showed that many medicines have seizures/convulsions induction potencies especially the following category of medicines agents affecting CNS, local anesthetics,
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vasoconstrictors, antineoplastic agents, antibiotic preparations, synthetic antibacterials, anti-virus agents, interferons, vaccines and agents using antibodies. The incidence of drug-induced seizures is unknown, but estimated to be around 6% of new onset seizures (Pesola and Avasarala, 2002). There are primary and secondary mechanisms of seizure. Primary mechanisms refer to the properties of a substance that directly affects CNS. Secondary seizures occur as a result of impaired substrate availability: hypoxia, reduced oxygen carriage, lack of energy, or disturbances of glucose and electrolyte metabolism (Delanty et al., 1998). With the exception of 4 local anesthetics (bupivacaine hydrochloride hydrate, levobupivacaine hydrochloride, lidocaine and ropivacaine hydrochloride hydrate), the mechanism of seizures/convulsions for the reviewed medicines was not identified in our survey. It is reported that the mechanism behind the seizures/convulsions is rarely known and is difficult to determine (Elander, 2013), but seizure risk association with neuroactive medicines has been reported (Kumlien and Lundberg, 2010; Lertxundi et al., 2013). Our survey results indicate that most of seizures/convulsions for medicines were not observed in animals, suggesting that it is difficult to evaluate pro-convulsion activity in animal studies. Löscher (2009), Bankstahl et al. (2012) showed that using only one seizure threshold model during preclinical drug development raises the risk that potential pro-convulsant activity of an investigational drug is overlooked. They concluded that a battery of different tests, such as a combination with timed intravenous pentylenetetrazole (PTZ) infusion seizure test and kindled rats or epilepsy-prone rodents can provide complete and more reliable conclusions about the pro-convulsant potential of an investigational drug. Dürmüller et al. (2007) proposed that the dog EEG is included as part of safety pharmacology studies. Performing a battery of tests using different models, different species and different methodologies should improve the accuracy of the prediction of drug toxicity. Additionally a clear mechanistic understanding of drug toxicity and the corresponding risk factors should also improve prediction of drug toxicity in the human population from experimental findings (Li, 2004; Guengerich, 2011). In summary, using a different methodology from standard epidemiological studies, the ADR (syncope and seizures) profile for each category of medicines approved in Japan in recent year is shown in this paper. Our aim was to promote this kind of survey to understand the nature of ADR for recently approved medicines in Japan, and to be helpful in avoiding unnecessary ADR in the clinical setting. Though evaluating pro-syncope effects in animals is difficult, through investigation of the underlying mechanism of syncope/loss of consciousness, such as hypotension, arrhythmia, hypoglycemia and anemia in animal studies, it may help us to avoid introducing pro-syncope medicines on to the market. For seizures/convulsions evaluation, a battery of different animal tests can provide complete and more reliable conclusions about the pro-convulsant potential of an investigational drug before clinical studies. Conflicts of interest The author has no conflict of interest. No funding was provided for this survey. Transparency Document The Transparency document associated with this article can be found in the online version. Acknowledgments The author thanks Dr. François-Xavier Mathy for his scientific advice for this survey and for his editorial contributions to this
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manuscript. We also thank Dr. Christopher Peters and Mr. Simeon Allan for their editorial contributions to this manuscript. References Bankstahl, M., Bankstahl, J.P., Bloms-Funke, P., Löscher, W., 2012. Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models. Neurotoxicology 33 (1), 127–137. Behnoush, B., Taghadosinejad, F., Arefi, M., Shahabi, M., Jamalian, M., Kazemifar, A.M., 2012. Prevalence and complications of drug-induced seizures in Baharloo Hospital, Tehran, Iran. Iran. J. Toxicol. 6 (16), 588–593. Delanty, N., Vaughan, C.J., French, J.A., 1998. Medical causes of seizures. Lancet 352 (9125), 383–390. Dürmüller, N., Guillaume, P., Lacroix, P., Porsolt, R.D., Moser, P., 2007. The use of the dog electroencephalogram (EEG) in safety pharmacology to evaluate proconvulsant risk. J. Pharmacol. Toxicol. Methods 56 (2), 234–238. Elander, M., 2013. Drug-induced convulsions in nonclinical safety studies: implication for clinical development. Drug Dev. Res. 74, 155–161. Gill, S.S., Anderson, G.M., Fischer, H.D., Bell, C.M., Li, P., Normand, S.L., Rochon, P.A., 2009. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch. Intern. Med. 169 (9), 867–873. Guengerich, F.P., 2011. Mechanisms of drug toxicity and relevance to pharmaceutical development. Drug Metab. Pharmacokinet. 26 (1), 3–14. Hadjikoutis, S., O’Callaghan, P., Smith, P.E., 2004. The investigation of syncope. Seizure 13 (8), 537–548. Hanlon, J.T., Linzer, M., MacMillan, J.P., Lewis, I.K., Felder, A.A., 1990. Syncope and presyncope associated with probable adverse drug reactions. Arch. Intern. Med. 150 (11), 2309–2312. Isbister, G.K., Downes, F., Sibbritt, D., Dawson, A.H., Whyte, I.M., 2004. Aspiration pneumonitis in an overdose population: frequency, predictors, and outcomes. Crit. Care Med. 32 (1), 88–93. Kumlien, E., Lundberg, P.O., 2010. Seizure risk associated with neuroactive drugs: data from the WHO adverse drug reactions database. Seizure 19 (2), 69–73. Lemonick, D.M., 2010. Evaluation of syncope in the emergency department. Am. J. Clin. Med. 7 (1), 11–19. Lertxundi, U., Hernandez, R., Medrano, J., Domingo-Echaburu, S., García, M., Aguirre, C., 2013. Antipsychotics and seizures: higher risk with atypicals? Seizure 22 (2), 141–143. Li, A.P., 2004. Accurate prediction of human drug toxicity: a major challenge in drug development. Chem. Biol. Interact. 150 (1), 3–7. Lionte, C., 2009. Toxic and drug-induced syncope in medical practice. Ther. Pharm. Clin. Toxicol. 13 (4), 400–408. Löscher, W., 2009. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur. J. Pharmacol. 610 (1–3), 1–11. Milazzo, V., Stefano, C.D., Servo, S., Crudo, V., Fulcheri, C., Maule, S., Veglio, F., 2012. Drugs and orthostatic hypotension: evidence from literature. J. Hypertens. 1, 104. http://dx.doi.org/10.4172/2167-1095.1000104. Murphy, K., Delanty, N., 2000. Drug-induced seizures: general principles in assessment, management and prevention. CNS Drugs 14 (2), 135–146. Pacher, P., Kecskemeti, V., 2004. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr. Pharm. Des. 10 (20), 2463– 2475. Pathak, A., Senard, J.M., 2006. Blood pressure disorders during Parkinson’s disease: epidemiology, pathophysiology and management. Expert Rev. Neurother. 6 (8), 1173–1180. Perez-Lloret, S., Rey, M.V., Traon, A.P.L., Rascol, O., 2013. Orthostatic hypotension in Parkinson’s disease. Neurodegen. Dis. Manage. 3 (4), 363–377. http://dx.doi.org/ 10.2217/nmt.13.30. Pesola, G.R., Avasarala, J., 2002. Buproprion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J. Emerg. Med. 22 (3), 235–239. Piepho, R.W., 2002. Cardiovascular effects of antipsychotics used in bipolar illness. J. Clin. Psychiatry 63 (Suppl. 4), 20–23. Sánchez-Ferro, A., Benito-León, J., Gómez-Esteban, J.C., 2013. The management of orthostatic hypotension in Parkinson’s disease. Front. Neurol. 4 (64), 2013. http://dx.doi.org/10.3389/fneur.2013.00064 (eCollection). Senard, J.M., Brefel-Courbon, C., Rascol, O., Montastruc, J.L., 2001. Orthostatic hypotension in patients with Parkinson’s disease: pathophysiology and management. Drugs Aging 18 (7), 495–505. Thundiyil, J.G., Kearney, T.E., Olson, K.R., 2007. Evolving epidemiology of drug induced seizures reported to a poison control center system. J. Med. Toxicol. 3 (1), 15–19. Thundiyil, J.G., Rowley, F., Papa, L., Olson, K.R., Kearney, T.E., 2011. Risk factors for complications of drug-induced seizures. J. Med. Toxicol. 7 (1), 16–23. Tyagi, L.K., Singh, V., Gaur, K., Tyagi, S.N., Chaurasiya, S.K., Kori, M.L., 2009. Epidemiology, pathophysiology and treatment of different types of syncope: a review. Global J. Pharmacol. 3 (3), 166–170. van Dijk, J.G., 2003. Fainting in animals. Clin. Auton. Res. 13 (4), 247–255. Vieweg, W.V., Wood, M.A., Fernandez, A., Beatty-Brooks, M., Hasnain, M., Pandurangi, A.K., 2009. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging 26 (12), 997– 1012.
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Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
Adverse drug reactions for medicine newly approved in Japan from 1999 to 2013: Syncope/loss of consciousness and seizures/convulsions Takashi Nagayama ⇑ Non-Clinical Development, Science, Services & Planning, UCB Japan Co., Ltd., Shinjuku Grand Tower, 8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023 Japan
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Article history: Received 15 December 2014 Available online 6 June 2015 Keywords: Adverse drug reaction Animal toxicity Medicine Syncope Seizure
a b s t r a c t Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan. Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction A safe medicine is ideally exempt from adverse drug reactions (ADRs), but it is often difficult to distinguish ADR from the intended pharmacological action. During the drug developmental to select a candidate compound, every effort is made to provide safe medicines. In vitro, in vivo and in silico pharmacological studies, pharmacokinetics studies and also many animal toxicity studies are conducted before human use. Some compounds which exhibit unacceptable toxicity are discontinued from development prior to clinical studies. Many medicines on the market are used with their ADR appropriately managed in clinical settings based on the risk:benefit ratio. Unfortunately, there is no medicine without ADR. The aim of this survey was to clarify the correlation between ADR in humans and safety signals observed in animal toxicity studies, in order to contribute to constructing safe drug developmental strategies as well as ensuring the appropriate use of marketed medicines in the clinical setting. As it is difficult to analyze all ADRs, we selected two clinically important ADRs. Selected ADR for our survey were syncope and loss of consciousness,
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seizures and convulsions, hypertension and hypotension, arrhythmia, blood glucose increase and lipid metabolism disorders, changes in the number of leukocytes, dyspnea, hallucination and delusion, vision impairment, hearing impairment, dysgeusia and dysosmia, creatine kinase increase, BUN and creatinine increase, proteinuria and hematuria, dizziness, and vertigo. These parameters are clinically important and significant and some of them showed low translatability from animal toxicity findings. Investigational results for syncope/loss of consciousness and seizures/convulsions have been presented in this paper and investigational results for other ADR will be the subject of a second paper. Due to the difficulty in evaluating the pro-syncope effects in animal models, investigations into the underlying mechanisms such as cerebral circulation insufficiency may be useful. Hypotension, arrhythmia, hypoglycemia and anemia may lead to cerebral circulation insufficiency, finally leading to syncope. On the other hand, pro-seizure effects are frequently evaluated using animal safety pharmacology studies for drug development. Animal models are not perfect; however they can be useful in order to extrapolate pro-seizure effect in humans, especially for CNS targeting drugs. The mechanism of action of a drug is also important; excitatory neuron agonists and inhibitory neuron antagonists may have pro-seizure effects. There is some debate on the necessity and usefulness of animal studies for these kinds of CNS effects. The
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survey results are expected to contribute toward constructing safe drug developmental strategies as well as ensuring the appropriate use of marketed medicines in the clinical setting.
393 medicines in Japan No syncope/loss of consciousness and no seizures/convulsions
247 (62.8%)
2. Methods We reviewed medicines which have been approved in the past 13 years in Japan in terms of (1) what kinds of ADR were observed for each medicine in clinical studies, (2) whether animal toxicity findings that correspond to the concerned ADR were observed or not, (3) how the concerned ADR were predicted before clinical studies or before market distribution in cases where no relevant findings were noted in animal studies, and (4) how the ADR were managed in clinical use. ADR information for 393 human medicines approved for use in Japan as a new drug substances between September 1999 and March 2013 were used for this survey. The ADR described in each package insert were collected. This survey included many ADRs, but only the following are reported in this paper: syncope/loss of consciousness and seizures/convulsions, specifically syncope, loss of consciousness, depressed level of consciousness, consciousness level depression, depressed consciousness, altered state of consciousness, and disturbance of consciousness for syncope/loss of consciousness category and seizures, convulsions, epilepsy, epileptic seizures, petit mal seizures, grand mal seizures and partial seizures for seizures/convulsions category. Comparable animal toxicity findings with ADR were collected by thorough investigation of the review reports and the summary of new drug applications (common technical documents (CTD) Module 2.4 and 2.6) available on the web site of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Survey data was also analyzed for recent trends of syncope/loss of consciousness and seizures/convulsions for recently approved Japanese medicines. In addition, we assessed the correlation with ADR and animal toxicity findings for the medicines. These results suggest improvements in animal and clinical studies to provide safer medicines, and to propose suggestions for clinical use of these medicines to contribute to patient safety. A statistical analysis was not performed in this study. Concordance ratio was used to evaluate translatability of ADR in human patients from animal toxicity findings. The concordance ratio was calculated by the following equation, generally named true positive rate or sensitivity:
Concordance ratioð%Þ ¼ true positive rate ðsensitivityÞ 100 ¼ true positive=ðtrue positive þ false negativeÞ 100
3. Results 3.1. Syncope/loss of consciousness and seizures/convulsions in recently approved Japanese medicines The 393 medicines investigated contained a broad category of medicines for example 50 CNS drugs, 26 cardiovascular drugs, 39 antineoplastics, 50 antibacterial and antiviral agents, 22 monoclonal antibodies, 19 vaccines. According to the search of the package inserts, 101 of 393 medicines (25.7%) showed syncope/loss of consciousness and 105 of 393 medicines (26.7%) showed seizures/convulsions (Fig. 1). A total of 60 medicines (15.3%) have both syncope/loss of consciousness and seizures/convulsions, while 146 medicines (37.2%) showed syncope/loss of consciousness or seizures/convulsions. Our research results showed that more than one third of the recently approved medicines in Japan induce ADR
Syncope/ loss of consciousness
41 (10.4%)
60 (15.3%)
Seizures/ convulsions
45 (11.5%)
Fig. 1. Adverse drug reactions of syncope/loss of consciousness and seizures/convulsions in recently approved 393 Japanese medicines. Adverse drug reaction information for 393 medicines approved for human use in Japan as a new drug substance from September 1999 to March 2013 were used for this survey. 101 (25.7%) medicines showed syncope/loss of consciousness and 105 (26.7%) medicines showed seizures/convulsions. 247 (62.8%) medicines did not show syncope/loss of consciousness nor seizures/convulsions.
such as syncope/loss of consciousness and/or seizures/convulsions directly or affect the metabolic cascade. 3.2. Syncope/loss of consciousness and seizures/convulsions in each class of medicine Evaluated medicines in this study were distributed across a wide range of treatments. In terms of the numbers of medicines in each category, there were 39 antineoplastic agents, 29 anti-virus agents, 26 agents using antibody, 19 vaccines, 19 hormones and hormone analogs, as well as many other categories. The categories with the least number of medicines were synthetic narcotics and agents for otic and nasal use, both of which numbered 3. Syncope/loss of consciousness were reported in many medicines affecting CNS, i.e. all antiparkinsonian agents and 80.0% of psychotropic agents (Fig. 2). Psychotropic agents included 6 antidepressants, 8 antipsychotics and one medicine for attention deficit hyperactivity disorder. Syncope/loss of consciousness was reported in 83.3% of antidepressants and 75.0% of antipsychotics. There are mechanistic associations for syncope/loss of consciousness induction for CNS medicines. Syncope/loss of consciousness was also reported in 80.0% of agents affecting peripheral nervous system (local anesthetics). It was reported in 75.0% of antihypertensives, 62.5% of synthetic antibacterials, and 60.0% of interferons. Seizures/convulsions were reported in many medicines affecting CNS, i.e. 87.6% of psychotropic agents and 66.7% of antiepileptics (Fig. 3). Psychotropic agents were further classified to antidepressants and antipsychotics, with seizures/convulsions reported in 100.0% of antidepressants and 87.5% of antipsychotics. Seizures/convulsions were also reported in 80.0% of agents affecting the peripheral nervous system (local anesthetics) and in 100.0% of interferons, 80.0% of vasoconstrictors, 75.0% of synthetic antibacterials, and 52.6% of vaccines. 3.3. Concordance of human adverse drug reactions with animal toxicity Doses and blood concentration in humans and animals were not directly evaluated in this survey. Whenever the finding was observed in animal studies at any dose used by the sponsor, we evaluated that the toxicity finding as positive in animal studies.
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Overall 393 Oligoneucleode, polysaccharide, and others 9 Hormones and hormone analogs 19 Andotes 5 Agents for osteoporosis 5 Andiabec agents 12 Agents for epidermis 5 Agents affecng respiratory organs 6 Agents for hyperlipidemias 5 Agents for oc and nasal use 3 Agents for not mainly purpose of therapeuc 13 Agents for ophthalmic use 13 Hematopoiec factors, human blood preparaons 11 Vaccines 19 Agents affecng digesve organs 9 Enzyme preparaons 8 Anallergic agents 8 Other cardiovascular agents 8 Other agents affecng metabolism 18 Agents using anbody 26 Vasoconstrictors 5 Anepilepcs 9 Anneoplasc agents 39 Ancoagulants 8 Agents for uro-genital and anal organs 11 Agents against pathologic organisms and parasites 7 An-virus agents 29 Other agents affecng central nervous system 16 Anpyrecs, analgesics and an-inflammatory agents 4 Anbioc preparaons 13 Interferons 5 Synthec anbacterials 8 Synthec narcocs 3 Anhypertensives 8 Agents affecng peripheral nervous system 5 Psychotropic agents 15 Anparkinsonian agents 6
n 0.0%
20.0%
40.0%
60.0%
80.0% 100.0%
Fig. 2. The ratio of medicines showing syncope/loss of consciousness in each class of medicines newly approved in Japan from 1999 to 2013. Horizontal bars indicate the percentage of number of medicines showing syncope/loss of consciousness.
We assumed that the sponsor selected appropriate doses for animal studies reflecting human blood concentration. Animal toxicity concordance ratio with syncope/loss of consciousness is 4.0% (4/101) (Table 1). Only 4 local anesthetics showed syncope/loss of consciousness in animal studies that had been induced by acute toxic reaction. Animal toxicity concordance ratio with seizures/convulsions was only 23.8% (25/105) (Table 1). When seizures/convulsions occurred at any dose in the animal studies, we classified that as concordant findings in this survey. Concordant preclinical findings were observed in safety pharmacology studies for 17 medicines and in repeated administration toxicity studies for 16 medicines
(Table 2). A pro-convulsion study with chemo-convulsants was mainly used for safety pharmacology studies. 3.4. Mechanism of action The 101 medicines which showed syncope/loss of consciousness were classified according to the mechanism of action (Table 3). The mechanism of action for 40 medicines (39.6%) was clearly described in the package insert or CTD. Syncope/loss of consciousness attributed to hypotension is seen in 17 medicines (5.0%), i.e. 5 antiparkinsonian agents, one psychotropic agent, 6 antihypertensives, and one other cardiovascular agent. Syncope/loss of consciousness either
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Overall 393 Oligoneucleode, polysaccharide, and others 9 Hormones and hormone analogs 19 Enzyme preparaons 8 Anhypertensives 8 Andotes 5 Andiabec agents 12 Ancoagulants 8 Agents for uro-genital and anal organs 11 Agents for oc and nasal use 3 Agents for osteoporosis 5 Agents for ophthalmic use 13 Agents for epidermis 5 Agents affecng digesve organs 9 Agents affecng respiratory organs 6 Hematopoiec factors, human blood preparaons 11 Other agents affecng metabolism 18 Agents for not mainly purpose of therapeuc 13 Anparkinsonian agents 6 Agents using anbody 26 Agents for hyperlipidemias 5 Other cardiovascular agents 8 Anpyrecs, analgesics and an-inflammatory agents 4 Agents against pathogenic organisms and parasites 7 Anneoplasc agents 39 An-virus agents 29 Anallergic agents 8 Other agents affecng central nervous system 16 Anbioc preparaons 13 Vaccines 19 Anepilepcs 9 Synthec anbacterials 8 Vasoconstrictors 5 Agents affecng peripheral nervous system 5 Psychotropic agents 15 Synthec narcocs 3 Interferons 5
n 0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Fig. 3. The ratio of medicines showing seizures/convulsions in each class of medicines newly approved in Japan from 1999 to 2013. Horizontal bars indicate the percentage of number of medicines showing seizures/convulsions.
Table 1 Concordance of human adverse drug reaction with animal toxicity finding for medicine newly approved in Japan from 1999 to 2013. Adverse drug reactions
n
True positive (n) Concordance ratio (%)
Syncope/loss of consciousness 101 4 Seizures/convulsions 105 25
4.0 23.8
Concordance ratio (%) = true positive rate (sensitivity) 100 = true positive/(true positive + false negative) 100.
attributed to arrhythmia, hypoglycemia or acute toxic reaction was seen in 5 (5.0%), 4 (4.0%) and 4 (4.0%) medicines respectively. Syncope/loss of consciousness related to hypoglycemia was mainly
Table 2 Classification of animal studies in which seizures/convulsions were observed for 25 medicines. Animal studies
Number of medicines (%)
Repeated-dose toxicity studies Pro-convulsion studies in the safety pharmacology study Other safety pharmacology studies
16 (64.0)# 10 (40.0)# 7 (28.0)#
# 8 medicines showed seizures/convulsions in both toxicity and safety pharmacology studies.
observed with synthetic antibacterials/antibiotics, and those mediated by acute toxic reactions were observed with 4 local anesthetics.
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Table 3 Classification of mechanism of syncope/loss of consciousness for 101 medicines. Mechanism of syncope/loss of consciousness
Number of medicines (%)
Hypotension Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Arrhythmia Hypoglycemia Acute toxic reaction Hypocalcemia Suppression of noradrenalin release Hypotension or hypoglycemia or arrhythmia Unidentified
17 (16.8) 5 (5.0) 5 (5.0) 4 (4.0) 4 (4.0) 1 (1.0) 1 (1.0) 3 (3.0) 61 (60.4)
Table 4 Candidate adverse drug reactions which may have some relation with syncope/loss of consciousness for 61 medicines for which mechanism of syncope/loss of consciousness. Adverse drug reactions
Reported number of medicines (%)
Not reported number of medicines (%)
Hypotension Arrhythmia Hypoglycemia Anemia Hypotension or arrhythmia or hypoglycemia or anemia Dizziness or stagger Nausea or vomiting
37 45 13 43 56
24 (39.3) 16 (26.2) 48 (78.7) 18 (29.5) 5 (8.2)
(60.7) (73.8) (21.3) (70.5) (91.8)
52 (85.2) 60 (98.4)
9 (14.8) 1 (1.6)
Syncope/loss of consciousness as the consequence of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was seen in 5 (5.0%), hypocalcemia was observed in one (1.0%), and suppression of noradrenalin release was noted in one medicine (1.0%). It is well known that the mechanisms of syncope/loss of consciousness for other medicines are strongly related to an insufficient cerebral circulation in the context of the systemic circulation, however the specific mechanism was not clearly identified for 61 medicines (60.4%). ADR inducing insufficient cerebral circulation in the context of the systemic circulation may have a relationship with syncope/loss of consciousness. For the 61 medicines which did not have a clearly identified specific mechanism, accompanying ADRs were evaluated in order to speculate on the causality from cerebral circulation insufficiency (Table 4). Hypotension, arrhythmia, hypoglycemia and anemia were reported in many medicines: 91.8% of medicines showed one of these ADR which suggests some mechanistic relationship with syncope/loss of consciousness. Dizziness or stagger was reported in 85.2% of medicines and nausea or vomiting was reported in 98.4%. Mechanisms of seizures/convulsions for 105 medicines were investigated (Table 3). Four local anesthetics (3.8%) were considered to be mediated by acute toxic reaction. Mechanism of seizures/convulsions for the other 101 medicines (96.2%) was not identified by thorough investigation of the review reports and the summary of new drug applications.
4. Discussion There are many publications for case reports and epidemiological researches on ADR; however research for specific ADR covering all medicines is rare. This survey using the package insert may be useful to understand the entire and/or categorized group of potential risks of syncope/loss of consciousness and seizures/convulsions for recently approved medicines. Syncope/loss of consciousness and seizures/convulsions are one of the clinically important drug-induced ADR. Drug-induced syncope appears relatively common (Lemonick, 2010). In the study of Duke University’s Syncope Clinic, 13% of the patients were rated
as having probable drug-induced syncope (Hanlon et al., 1990). Our survey results for syncope/loss of consciousness emphasizes the importance for physicians to pay attention to the occurrence of this significant ADR for agents affecting CNS, local anesthetics, antihypertensives, synthetic narcotics, synthetic antibacterials, interferons and antibiotic preparations. Our result highlights the difficulty in evaluating pro-syncope potency with preclinical studies, which may be related to physiological differences between human and animals (van Dijk, 2003). It is important to understand the pharmacological mechanism behind syncope/loss of consciousness. Pro-syncope medicine that commonly lead to effects on blood pressure, arrhythmias, or glycemia, may have a potency to induce syncope in human (Lionte, 2009). We also investigated the mechanism underlying syncope/loss of consciousness; mechanisms of action for 40 of the 101 medicines were identified and the results showed some relation with hypotension, SIADH, arrhythmia or hypoglycemia (Table 3). It is considered that the principal mechanism of syncope/loss of consciousness is sudden cerebral perfusion decrease induced by hypotension, SIADH, arrhythmia or hypoglycemia (Lionte, 2009; Tyagi et al., 2009; Hadjikoutis et al., 2004). Antiparkinsonian agents show syncope/loss of consciousness by mediated hypotension through a peripheral D2 dopaminergic mechanism. Cholinesterase inhibitors can provoke symptomatic bradycardia which shows some relation with syncope/loss of consciousness (Gill et al., 2009). Syncope/loss of consciousness induced by psychotropic agent (antidepressant and antipsychotics) is mainly considered to be mediated through SIADH, arrhythmia or hypotension inhibiting cardiac or vascular Na+, Ca2+ or K+ channels (Pacher and Kecskemeti, 2004; Piepho, 2002; Vieweg et al., 2009). The evidence suggests that pharmacological action may have some relation with syncope/loss of consciousness for most of CNS affecting agents, mainly on/off target on unintended organs. Syncope/loss of consciousness induced by synthetic antibacterials is considered to be related to hypoglycemia. We did not identify syncope/loss of consciousness mediated through anemia, but some examples were reported (Tyagi et al., 2009). Usually many medicines have some ADR, such as hypotension, arrhythmia, hypoglycemia and anemia. It is difficult to evaluate syncope/loss of consciousness in animal studies, but it may be useful to investigate closely adverse effects which have some relation with syncope in animal studies. ADR management in the clinic is important, but there is no standard strategy for all medicines. Orthostatic hypotension is common in Parkinson’s disease patients where the prevalence of symptomatic orthostatic hypotension may be as high as 20–50% (Pathak and Senard, 2006; Senard et al., 2001; Perez-Lloret et al., 2013). Parkinson’s disease is a cause of primary autonomic failure with an involvement of the peripheral autonomic system (Senard et al., 2001). Our survey showed all antiparkinsonian agents show syncope/loss of consciousness. The mechanism of syncope for 5/6 medicines is by mediated hypotension through a peripheral D2 dopaminergic mechanism. There are some reviews that described the relationship between orthostatic hypotension and the current treatments employed in Parkinson’s disease (Sánchez-Ferro et al., 2013; Milazzo et al., 2012). This use of antiparkinsonian agents, taking into consideration the risks vs. benefits, is an interesting example for controlling ADR in clinic. Numerous medicines have been reported to be associated with the occurrence of seizures (Murphy and Delanty, 2000; Thundiyil et al., 2007; Delanty et al., 1998; Pesola and Avasarala, 2002; Behnoush et al., 2012; Thundiyil et al., 2011). Drug-induced complicated seizures can result in hyperthermias, acidosis, anoxic brain injury and up to 2% mortality (Thundiyil et al., 2007; Isbister et al., 2004). Our survey results showed that many medicines have seizures/convulsions induction potencies especially the following category of medicines agents affecting CNS, local anesthetics,
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vasoconstrictors, antineoplastic agents, antibiotic preparations, synthetic antibacterials, anti-virus agents, interferons, vaccines and agents using antibodies. The incidence of drug-induced seizures is unknown, but estimated to be around 6% of new onset seizures (Pesola and Avasarala, 2002). There are primary and secondary mechanisms of seizure. Primary mechanisms refer to the properties of a substance that directly affects CNS. Secondary seizures occur as a result of impaired substrate availability: hypoxia, reduced oxygen carriage, lack of energy, or disturbances of glucose and electrolyte metabolism (Delanty et al., 1998). With the exception of 4 local anesthetics (bupivacaine hydrochloride hydrate, levobupivacaine hydrochloride, lidocaine and ropivacaine hydrochloride hydrate), the mechanism of seizures/convulsions for the reviewed medicines was not identified in our survey. It is reported that the mechanism behind the seizures/convulsions is rarely known and is difficult to determine (Elander, 2013), but seizure risk association with neuroactive medicines has been reported (Kumlien and Lundberg, 2010; Lertxundi et al., 2013). Our survey results indicate that most of seizures/convulsions for medicines were not observed in animals, suggesting that it is difficult to evaluate pro-convulsion activity in animal studies. Löscher (2009), Bankstahl et al. (2012) showed that using only one seizure threshold model during preclinical drug development raises the risk that potential pro-convulsant activity of an investigational drug is overlooked. They concluded that a battery of different tests, such as a combination with timed intravenous pentylenetetrazole (PTZ) infusion seizure test and kindled rats or epilepsy-prone rodents can provide complete and more reliable conclusions about the pro-convulsant potential of an investigational drug. Dürmüller et al. (2007) proposed that the dog EEG is included as part of safety pharmacology studies. Performing a battery of tests using different models, different species and different methodologies should improve the accuracy of the prediction of drug toxicity. Additionally a clear mechanistic understanding of drug toxicity and the corresponding risk factors should also improve prediction of drug toxicity in the human population from experimental findings (Li, 2004; Guengerich, 2011). In summary, using a different methodology from standard epidemiological studies, the ADR (syncope and seizures) profile for each category of medicines approved in Japan in recent year is shown in this paper. Our aim was to promote this kind of survey to understand the nature of ADR for recently approved medicines in Japan, and to be helpful in avoiding unnecessary ADR in the clinical setting. Though evaluating pro-syncope effects in animals is difficult, through investigation of the underlying mechanism of syncope/loss of consciousness, such as hypotension, arrhythmia, hypoglycemia and anemia in animal studies, it may help us to avoid introducing pro-syncope medicines on to the market. For seizures/convulsions evaluation, a battery of different animal tests can provide complete and more reliable conclusions about the pro-convulsant potential of an investigational drug before clinical studies. Conflicts of interest The author has no conflict of interest. No funding was provided for this survey. Transparency Document The Transparency document associated with this article can be found in the online version. Acknowledgments The author thanks Dr. François-Xavier Mathy for his scientific advice for this survey and for his editorial contributions to this
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manuscript. We also thank Dr. Christopher Peters and Mr. Simeon Allan for their editorial contributions to this manuscript. References Bankstahl, M., Bankstahl, J.P., Bloms-Funke, P., Löscher, W., 2012. Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models. Neurotoxicology 33 (1), 127–137. Behnoush, B., Taghadosinejad, F., Arefi, M., Shahabi, M., Jamalian, M., Kazemifar, A.M., 2012. Prevalence and complications of drug-induced seizures in Baharloo Hospital, Tehran, Iran. Iran. J. Toxicol. 6 (16), 588–593. Delanty, N., Vaughan, C.J., French, J.A., 1998. Medical causes of seizures. Lancet 352 (9125), 383–390. Dürmüller, N., Guillaume, P., Lacroix, P., Porsolt, R.D., Moser, P., 2007. The use of the dog electroencephalogram (EEG) in safety pharmacology to evaluate proconvulsant risk. J. Pharmacol. Toxicol. Methods 56 (2), 234–238. Elander, M., 2013. Drug-induced convulsions in nonclinical safety studies: implication for clinical development. Drug Dev. Res. 74, 155–161. Gill, S.S., Anderson, G.M., Fischer, H.D., Bell, C.M., Li, P., Normand, S.L., Rochon, P.A., 2009. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch. Intern. Med. 169 (9), 867–873. Guengerich, F.P., 2011. Mechanisms of drug toxicity and relevance to pharmaceutical development. Drug Metab. Pharmacokinet. 26 (1), 3–14. Hadjikoutis, S., O’Callaghan, P., Smith, P.E., 2004. The investigation of syncope. Seizure 13 (8), 537–548. Hanlon, J.T., Linzer, M., MacMillan, J.P., Lewis, I.K., Felder, A.A., 1990. Syncope and presyncope associated with probable adverse drug reactions. Arch. Intern. Med. 150 (11), 2309–2312. Isbister, G.K., Downes, F., Sibbritt, D., Dawson, A.H., Whyte, I.M., 2004. Aspiration pneumonitis in an overdose population: frequency, predictors, and outcomes. Crit. Care Med. 32 (1), 88–93. Kumlien, E., Lundberg, P.O., 2010. Seizure risk associated with neuroactive drugs: data from the WHO adverse drug reactions database. Seizure 19 (2), 69–73. Lemonick, D.M., 2010. Evaluation of syncope in the emergency department. Am. J. Clin. Med. 7 (1), 11–19. Lertxundi, U., Hernandez, R., Medrano, J., Domingo-Echaburu, S., García, M., Aguirre, C., 2013. Antipsychotics and seizures: higher risk with atypicals? Seizure 22 (2), 141–143. Li, A.P., 2004. Accurate prediction of human drug toxicity: a major challenge in drug development. Chem. Biol. Interact. 150 (1), 3–7. Lionte, C., 2009. Toxic and drug-induced syncope in medical practice. Ther. Pharm. Clin. Toxicol. 13 (4), 400–408. Löscher, W., 2009. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur. J. Pharmacol. 610 (1–3), 1–11. Milazzo, V., Stefano, C.D., Servo, S., Crudo, V., Fulcheri, C., Maule, S., Veglio, F., 2012. Drugs and orthostatic hypotension: evidence from literature. J. Hypertens. 1, 104. http://dx.doi.org/10.4172/2167-1095.1000104. Murphy, K., Delanty, N., 2000. Drug-induced seizures: general principles in assessment, management and prevention. CNS Drugs 14 (2), 135–146. Pacher, P., Kecskemeti, V., 2004. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr. Pharm. Des. 10 (20), 2463– 2475. Pathak, A., Senard, J.M., 2006. Blood pressure disorders during Parkinson’s disease: epidemiology, pathophysiology and management. Expert Rev. Neurother. 6 (8), 1173–1180. Perez-Lloret, S., Rey, M.V., Traon, A.P.L., Rascol, O., 2013. Orthostatic hypotension in Parkinson’s disease. Neurodegen. Dis. Manage. 3 (4), 363–377. http://dx.doi.org/ 10.2217/nmt.13.30. Pesola, G.R., Avasarala, J., 2002. Buproprion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J. Emerg. Med. 22 (3), 235–239. Piepho, R.W., 2002. Cardiovascular effects of antipsychotics used in bipolar illness. J. Clin. Psychiatry 63 (Suppl. 4), 20–23. Sánchez-Ferro, A., Benito-León, J., Gómez-Esteban, J.C., 2013. The management of orthostatic hypotension in Parkinson’s disease. Front. Neurol. 4 (64), 2013. http://dx.doi.org/10.3389/fneur.2013.00064 (eCollection). Senard, J.M., Brefel-Courbon, C., Rascol, O., Montastruc, J.L., 2001. Orthostatic hypotension in patients with Parkinson’s disease: pathophysiology and management. Drugs Aging 18 (7), 495–505. Thundiyil, J.G., Kearney, T.E., Olson, K.R., 2007. Evolving epidemiology of drug induced seizures reported to a poison control center system. J. Med. Toxicol. 3 (1), 15–19. Thundiyil, J.G., Rowley, F., Papa, L., Olson, K.R., Kearney, T.E., 2011. Risk factors for complications of drug-induced seizures. J. Med. Toxicol. 7 (1), 16–23. Tyagi, L.K., Singh, V., Gaur, K., Tyagi, S.N., Chaurasiya, S.K., Kori, M.L., 2009. Epidemiology, pathophysiology and treatment of different types of syncope: a review. Global J. Pharmacol. 3 (3), 166–170. van Dijk, J.G., 2003. Fainting in animals. Clin. Auton. Res. 13 (4), 247–255. Vieweg, W.V., Wood, M.A., Fernandez, A., Beatty-Brooks, M., Hasnain, M., Pandurangi, A.K., 2009. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging 26 (12), 997– 1012.