Higher Adverse Drug Reactions Research Articles

CYP450 and drug efflux transporters polymorphism influence clinical outcomes of Thai osimertinib-treated non-small cell lung cancer patients.

Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.

AN OBSERVATIONAL STUDY TO ASSESS THE ADVERSE DRUG REACTION OF ANTI-ASTHMATIC DRUGS AMONG ADULTS IN WESTERN RAJASTHAN

Background: Asthma is one of the most common chronic illness worldwide. For prevention of exacerbations, patients of bronchial asthma are kept on long-term treatment that is why they are amenable for adverse drug reactions (ADRs). The study was planned to monitor ADRs with intervention of anti-asthmatic drugs in adults visited in medicine outpatient or admitted in inpatient department of a tertiary care teaching hospital. Methods: A cross-sectional study was conducted among 340 asthma patients in collaboration with Department of Medicine for duration of 12 months. Information of patients was collected with the help of semi-structured case record form ADRs along with interventions given that were also recorded. Results: Data analysis was done with the help of SPSS version20.0. Fisher exact test was applied. A total of 340 patients were enrolled in the study. The highest numbers of ADRs were observed with Salbutamol (34.78%). The highest ADRs were noted with Beta2 agonists class of drugs. The main ADRs noted were headache followed by tremors and oral thrush. Statistically significant association was found between presence of ADRs and severity of asthma. Conclusion: Identifying any possible connection between a presenting complaint and drug used is crucial to reduce the risk of ADRs in the future. Appropriate monitoring of ADRs is a key for this. Reduction in ADRs will improve the compliance of patient and ultimately their clinical outcome.

ADVERSE DRUG REACTIONS OF ANTI-EPILEPTIC DRUGS IN PEDIATRIC AGE GROUP IN A TERTIARY CARE TEACHING HOSPITAL; A CROSS-SECTIONAL STUDY

Objectives: In this cross-sectional study, the aims were to analyze the incidence and pattern of adverse drug reactions (ADRs) of antiepileptic drugs in pediatric patient. Most common adverse effect and most common drug causing adverse effect were evaluated. Methods: Study was conducted over 60 Patients for 6 months in out-patient basis pediatric department in Rajindra Hospital associated with GMC, Patiala, a tertiary care teaching hospital in Punjab. The patient diagnosed by the Pediatrician with epilepsy who fulfilling inclusion and exclusion criteria was enrolled after taking informed consent. ADRs were noted using Pediatric Epilepsy Side Effect Questionnaire at clinic visit and any other adverse effects reported by patients. Results: In this study, a total of 60 children were enrolled. The mean age was 10.26±3.70, median were 11.00. 41 (68.33%) patients were boys and 19 (31.67%) were girls. In Cognitive ADRs with anti-epileptic drugs, there were total 17 ADRs reported. Valproate was causing most cognitive ADRs (32.43%). Among all cognitive ADRs, attention difficulty was the commonest complains. There were no motor and behavioral ADRs reported. Total 27 general neurological ADRs reported, which was highest reported ADRs. Among general neurological, Clobazam was causing highest ADRs (55.56%). 10 patients also reported tremor as another ADR and Clobazam causing most (22.22%). Conclusion: In the present study, boys were developing more epilepsy than girls. Valproate was causing most ADRs. Among all cognitive ADRs, attention difficulty was the most common ADR. General neurological ADRs were highest reported ADRs.

Change the preprocedural fasting policy for contrast-enhanced CT: results of 127,200 cases

ObjectivesTo analyze the relationship between the dietary preparation status prior to contrast-enhanced CT (CECT) and adverse drug reactions (ADR) and emetic complications.MethodsNon-emergency adult patients who underwent routine CECT in our hospital from January 2019 to December 2020 were retrospectively analyzed. Stratified dietary preparation regimens were implemented for different clinical scenarios. The relationship between actual dietary preparation status and ADR and emetic complications was analyzed.ResultsA total of 127,200 cases were enrolled, including 49,676 cases in the fasting group (57 years ± 13, 56.79% men) and 77,524 cases in the non-fasting group (60 years ± 13, 54.55% men). No statistical difference was found in the overall incidence of ADR (0.211% vs. 0.254%, p = 0.126) or emetic complications (0.030% vs. 0.046%, p = 0.158) between the two groups, and no aspiration pneumonia or death occurred. For patients with an ICM-ADR history, the ADR incidence in non-fasting group was significantly lower than fasting group (2.424% vs. 12.371%, p = 0.002). For patients with hypertension, injection dose ≥ 100 mL, injection rate ≥ 5 mL/s, and Iopromide 370 usage, non-fasting was associated with higher ADR incidence (p < 0.05). 36.67% of the patients experienced unnecessary excessive fasting in practice. Excessive fasting (≥ 10 h) and more water ingestion (≥ 500 mL) within 1 h prior to CECT were associated with higher ADR incidence (p < 0.05).ConclusionUnrestricted food ingestion would not increase the overall risk of ADR and emetic complications. For some special patient subgroups, non-fasting, excessive fasting, and more water ingestion were associated with higher ADR incidence.

A comprehensive analysis of the efficacy and safety of COVID-19 vaccines

The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21–75 cases per million doses; myocarditis/pericarditis, 2–3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.

Assessment of Patient’s Response about Adverse Drug Reactions Receiving AC (Adriamycin, Cyclophosphamide) Therapy: A Survey Research

Background: Adverse drug reactions (ADRs) are most common among cancer patients receiving treatment. AC therapy which is a combination protocol of Adriamycin (doxorubicin) and Cyclophosphamide are the common therapies used for breast cancer treatment due to their effectiveness and cost of therapy breast cancer. AC combination is administered every 3 weeks, and 4 cycles are given.&#x0D; Objectives: To assess various ADRs reported by patients on AC combination therapy and their severity to ensure safe and effective treatment.&#x0D; Design: Prospective observational.&#x0D; Setting: Cancer hospital Jamshoro Pakistan.&#x0D; Patients and Methods: A hospital based observational study included 160 female patients suffering from breast cancer and receiving AC combination for treatment by purposive sampling method from June 2015- January 2018 at cancer hospital Jamshoro Pakistan. ADRs reported were compared against international standard references of drug literature such as British National Formulary (BNF) 2017 and ADR severity assessment scale (Modified Hartwig and Siegel scale).&#x0D; Main Outcome Measures: Frequency and severity of ADRs.&#x0D; Results: The common ADRs reported were, nausea and vomiting, acidity, fatigue, hair fall as common non-hematologic and leukopenia among hematologic ADRs. Those patients reported high severity ADRs according to severity scale persist for longer duration and required antidote for management with medical intervention.&#x0D; Conclusion: The present study shows that a patient’s response towards AC therapy is critical and therefore each patient must be monitored and those at high risk of developing ADRs from this therapy must be provided additional care.

[Retrospective analysis and discussion on 74 cases of adverse reactions of traditional Chinese medicine injection].

As a modern dosage form drug with rapid effect, traditional Chinese medicine (TCM) injection has been more and more used in clinical practice. Meanwhile the safety of TCM injection has attracted more and more attention. The retrospective analysis on 74 cases of adverse reaction of TCM injections collected from 2007 to 2016 in the Third Affiliated Hospital of Beijing University of Chinese Medicine showed that the proportion of men and women with adverse reactions was 0.54:1; the average age was 62.5 years old; 21 kinds of TCM injections were involved. Among them, the most reported were blood-regulating agents. The top four kinds of TCM injections with highest adverse drug reactions (ADRs) were Tanreqing injection, Danhong Injection, Shuxuening Injection and Xuesaitong for injection. The top three clinical manifestations of adverse reactions were lesions of skin and its appendages, damage of circulatory system and damage of nervous system. The potential causes of the adverse reactions of TCM injections were analyzed, and it was believed that individual difference, medicine, pharmaceutical excipients, solvent and TCM syndrome differentiation may be the main five causes for the adverse reactions of TCM injections. In order to reduce the adverse reactions of TCM injections, it is suggested that the clinical pharmacists should participate in the application management of TCM injections in the hospital; the production enterprises shall strengthen the whole life cycle management of the drugs; and at the same time, the drug control and administration authorities should improve the drug management methods constantly and encourage the development of TCM injections to the high quality level.

Intensive monitoring of adverse drug reactions to antipsychotic medications in the inpatient psychiatry department of a secondary care hospital of UAE

Background: Antipsychotics are a class of medications used primarily for the treatment of psychotic disorders. However, these medications are associated with potential adverse drug reactions (ADRs). Aim: To monitor the incidence and nature of ADRs in the psychiatric inpatient department of a secondary care hospital of Ras Al Khaimah, UAE. Materials and Methods: This was an observational, prospective, noninterventional study, conducted in the psychiatric inpatient setting of a secondary care hospital. Psychiatric inpatients of all age groups and both the gender, diagnosed with any psychotic disorder, and hospitalized in the psychiatry ward and managed with at least one antipsychotic medication were included in the study. The causality, severity, and preventability of ADRs were assessed using different assessment scales. Results: Out of 170 patients, 38 patients reported at least one ADR with an incidence rate of 22.3%. The most common ADRs were weight gain 15 (29.4%) due to olanzapine, followed by pseudo‑parkinsonism 11 (21.6%) due to parenteral haloperidol. Schizophrenia (18, 35.3%), followed by bipolar I disorder (10, 19.6%) was the most common condition associated with ADRs. Female gender and duration of hospital stay were found to be significant (P < 0.05) predictors of occurrence of ADRs. Conclusion: A high incidence of ADRs was observed in the inpatients of psychiatry department, especially of mild nature and probably preventable types. The study highlights the importance of intensive monitoring by pharmacists to identify high ADR risk psychiatric inpatients. To reduce the ADR risk, specific and frequent monitoring for antipsychotics is recommended such as weight and extrapyramidal symptoms.

Glycaemic adverse drug reactions from anti-neoplastics used in treating pancreatic cancer.

Pancreatic carcinoma is the most lethal cancer, with a 5-year survival rate of <5%. Hyperglycemia is one of the severe adverse drug reactions (ADRs) in cancer treatment. The aim was to analyze the blood glucose-related ADR of antineoplastics in treating pancreatic cancer. Antineoplastic drugs were selected from Martindale-The Complete Drug Reference (36th edition). ADR data were extracted from VigiBase, the WHO Uppsala Monitoring Centre, and the WHO's specialist center for drug safety. Nineteen antineoplastic drugs were selected; VigiBase provided their ADR records including total 235,625 records and 27 heading ADR items, 1348 records of glucose metabolism disorders (GMDs), and 807 records of hyperglycemia. Based on the emphasized nine antineoplastic drugs with high hyperglycemic ADR incidence, we found: fluorouracil, sorafenib and pemetrexed with high ADR record of metabolism and nutrition disorders; fludarabine and flutamide with high ADR of GMD ratio. All the hyperglycemia ratios of the 9 antineoplastics were more than 50.0%, except pemetrexed and sorafenib. Thoroughly, doxorubicin carried high absolute records and ratios in hyperglycemic conditions. Pancreatic carcinoma is an aggressive malignancy typically associated with severe hyperglycemia. Furthermore, hyperglycemia is one of the severe ADRs from antineoplastics, which must be paid special attention to when treating in pancreatic carcinoma, especially doxorubicin, fluorouracil, and gemcitabine. Such real-time monitoring or pretreatment gene test can be suggested.

Effect of endurance for adverse drug reactions on the preference for aggressive treatments in cancer patients.

Cancer patients receiving chemotherapy will sometimes conceal their discomfort, but an excessive endurance for adverse drug reactions (ADRs) can lead to a poorer prognosis. The aim of this study was to clarify the association between ADR endurance and a preference of cancer patients for aggressive treatments. A cross-sectional study was undertaken of inpatients under 75 years of age receiving injectable systemic chemotherapy or oral chronic medications at hospitals in Japan. Subjects were asked to respond to a validated questionnaire to assess the extent of their ADR endurance and whether they would choose a novel, more aggressive therapy if their life expectancy was estimated at 2 years. Study participants were separated into the chemotherapy group (n = 36) and the non-chemotherapy group (n = 78). In the chemotherapy group, patients who had moderate ADR endurance scores were more likely to choose the new therapy (0-33, 34-67, and 68-100 points: 0.0, 54.5, and 27.3 %; χ (2) test, p = 0.15). Additionally, every patient on long-term chemotherapy (≥3 years) had high ADR endurance scores but did not choose the new, riskier treatment. In the non-chemotherapy group, the proportion of those choosing the new therapy was linearly associated with higher ADR endurance scores (25.9, 38.2, and 64.7 %; p = 0.04). Cancer patients may prefer aggressive therapies, even when self-estimations of ADR endurance are not very high, especially if they have been receiving chemotherapy for a short period of time. These patients should be observed with great caution.

587P - Post-Marketing Survey of Panitumumab in Japanese Patients with Unresectable Colorectal Cancer: Interim Report of 3,005 Patients

ABSTRACT Background Panitumumab (P-mab) was approved in April 2010 in Japan for treatment of unresectable, advanced or recurrent colorectal cancer with wild-type KRAS, both in monotherapy and in combination with chemotherapy for all lines of treatment. Objectives To investigate the status of post-marketing use and adverse drug reactions (ADRs) of P-mab in Japan, and to assess the safety and efficacy of P-mab in Japanese patients. Methods All-case surveillance (all patients were registered before starting P-mab therapy by the central registration method) was conducted since the product launch. All the patients were examined for eligibility requirements such as KRAS genotype, patient performance status and combination regimen and registered for this study before starting P-mab therapy. Results Between June 2010 until November 2010, 3,091 patients were enrolled. Background information of the 3,005 patients that were collected by October 2011 was as follows: male/female: 1,912/1,093, mean age: 65.0 years (range 18–90), colorectal cancer: 3,005, KRAS genotype wild/ mutant/ not determinable: 2,925/3/77, first line/ second line/third line or later treatment: 312/542/2,150, PS 0-1/2/3/4:2,743/236/22/4 and P-mab monotherapy/combination with chemotherapy: 1,232/1,766. Combination regimens: FOLFOX/ FOLFIRI/ other anticancer agents were 563/1,004/456. Overall incidence of ADRs was 83.7%, Grade 3 or higher ADRs were 24.7%. Incidence of ADRs of special interest for this surveillance: skin disorder / interstitial lung disease/ infusion reaction/ electrolyte abnormality/ cardiac disorder were 77.8%/ 1.3%/ 1.5%/ 18.3%/ 0.2%. The median survival time of patients with P-mab monotherapy as third line treatment was 10.3 months. Conclusion P-mab was administered to patients who met the eligibility requirements and the appropriate use was confirmed. The safety profile of P-mab in the post-marketing use was similar to that previously reported in the clinical trials. The risk/benefit balance for use of P-mab in patients with unresectable colorectal cancer remains favorable. Disclosure K. Sugihara: Membership on advisory board: Takeda, Merck Serono,Chugai Sponsored research and honoraria: Takeda, Taiho, Chugai, Yakult, Bristol-Myers Squibb, Merck Serono, Daiichi-sankyo. Sponsored research: Kyowa Hakko Kirin No other conflict of interest. N. Boku: Membership on advisory board and honoraria: Takeda No other conflict of interest. A. Gemma: Membership on advisory board and honoraria: Takeda No other conflict of interest. N. Yamazaki: Membership on advisory board and honoraria: Takeda, Bristol-Myers Squibb, Merck Serono No other conflict of interest. K. Muro: Membership on advisory board: Takeda Honoraria: Takeda, Yakult, Chugai, Taiho, Bristol-Myers Squibb, Daiichi-sankyo, Merck Serono No other conflict of interest. T. Hamaguchi: Membership on advisory board: Takeda Honoraria: Takeda, Daiichi-sankyo No other conflict of interest. T. Yoshino: Sponsored research: Bayer, Taiho, Daiichi-sankyo,Quintiles Membership on advisory board: Takeda Honoraria: Chugai, Takeda, Bristol-Myers Squibb, Yakult, Merck Serono No other conflict of interest. H. Ueno: Emproyee of Takeda Pharmaceutical Co., Ltd. who sponsored this survey No other conflict of interest. A. Ohtsu: Membership on advisory board,consultant: Takeda, Daiichi-sankyo, Novartis Pharma, Chugai, Taiho Honoraria: Takeda, Daiichi-sankyo, Taiho, GlaxoSmithKline, Pfizer, Yakult, Bristol-Myers Squibb, Merck Serono No other conflict of interest.

Post-marketing Safety Evaluation of S-1 in Patients with Inoperable or Recurrent Breast Cancer: Especially in Patients Treated with S-1 + Trastuzumab

ObjectiveThe purpose of this study was to assess the safety of S-1 in Japanese in inoperable or recurrent breast cancer patients.MethodsA prospective post-marketing surveillance was performed at 313 sites in Japan in patients with inoperable or recurrent breast cancer treated with S-1. We examined 1361 patients between January 2006 and December 2007 with regard to the incidence of adverse drug reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.ResultsAt least one adverse drug reaction was encountered by 858 patients, with an overall incidence of 63.0% (858/1361). The incidence of Grade 3 or higher adverse drug reactions in a descending order was 14.7% (200/1361). In this study, the most common combination drug was trastuzumab. The overall incidence of adverse drug reactions was 63.5% (431/679 patients) in patients treated with S-1 alone, and 55.9% (66/118 patients) in patients treated with S-1 + trastuzumab.ConclusionsMonotherapy with S-1 or combination therapy with S-1 + trastuzumab was well tolerated for inoperable or recurrent breast cancer patients.

Toward the integration of personalized and systems medicine: challenges, opportunities and approaches.

Personalized MedicineVol. 8, No. 1 EditorialFree AccessToward the integration of personalized and systems medicine: challenges, opportunities and approachesQing YanQing YanPharmTao, PO Box 5672, Santa Clara, CA 95056, USA. Search for more papers by this authorEmail the corresponding author at qyan@pharmtao.comPublished Online:22 Dec 2010https://doi.org/10.2217/pme.10.77AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: biomarkersgenotypesnetworkspathwayspersonalized medicinepharmacogenomicsphenotypessystems biologytranslational bioinformaticswellnessChallenges & new concepts in biomedicineIn this era of change, biomedicine is heading toward a revolutionary new path. This path is a transformation from reductionism toward a holistic paradigm, from ‘one-size-fits-all’ therapeutics towards personalized medicine. Such changes are necessary to meet the challenges in healthcare and the pharmaceutical industry, for example, the high costs in healthcare, low efficacy of drugs and increased incidents of adverse drug reactions (ADRs). ADRs are one of the leading causes of death and illness in the USA [1]. Although the research and development costs in the pharmaceutical industry are soaring, high-profile drug withdrawals are elevating, while the US FDA’s approval for new drugs is decreasing [2]. At the same time, the gap between biomedical science and clinical practice has made it hard to translate scientific advancements into improved healthcare.These challenges and difficulties are calling for the development of new strategies, new concepts, or even a new kind of medicine to meet these goals: ▪ Providing individualized optimal therapy with high efficacy and low ADRs;▪ Treatment of the whole system with a focus on prevention of disease;▪ Promotion of the mind–body health and wellness in the physical, mental, social and environmental dimensions [3].Such ‘new medicine’ will come from the integration of personalized and systems medicine. Ideally, the new medicine will bring the right prevention methods or therapeutics to the right person or patient with the right dosages at the right time.Personalized medicine: from disease-centered to human-centered medicinePersonalized medicine deals with individual diversities and the complexity of the human body. Current healthcare models are disease-oriented and focus on pathogens and environmental or external factors [4]. Personalized medicine would enable the change from such disease-centered medicine to human-centered medicine. Pharmacogenomics arose in response to such recognition. Pharmacogenomics studies genetic variations among individuals to predict disease susceptibility and responses to therapeutic agents [5,6]. The investigation of genetic diversity may enable the identification of optimal drug targets for certain patient populations, and empower physicians to make the right decisions. By focusing on patients’ genetic or biomarker profiles, pharmacogenomics represents the evolution from treating the disease itself to treating the malfunction of an individual person, the ‘root’ of the disease [7]. With such practices, patients can be regrouped and drugs can be recategorized. For instance, similar diseases may require different treatments, while different diseases may be treated with the same or similar approaches.Because of the diversity of patients’ biological backgrounds, the same disease may be caused by genetic variation in different people, who will respond differently to the same drug. For example, polymorphisms in the ABCB1 gene contribute to cancer risk and different therapeutic responses [8]. Patients with certain genotypes, such as 1236C/C, showed poorer survival than patients with other genotypes. Such situations require individualized treatments for the same disease (cancer) to ensure the best possible results. On the other hand, patients with the same or similar biomarker profiles but with different diseases, may be grouped together to accept the same or similar therapeutics. For example, inflammation is a multiscale process associated with many diseases from cardiovascular disease to cancer [9]. The same genetic factors involved in inflammation, such as peroxisome proliferator activated receptor g (PPARg), can serve as potent drug targets for different diseases, including diabetes, allergic diseases and respiratory virus infections [10,11].Such an approach of regrouping of patients and recategorization of drugs based on patients’ biomarker profiles (but not diseases) would have many benefits. It may help reduce the adverse events and improve the therapeutic efficacy when the drugs can match the patients seamlessly. In addition, the application range of existing drugs may be broadened to more diseases, and drug combination therapies can be used, which would actually save money for the healthcare industry. More importantly, this approach would bring hope for the transformation from disease treatment to prevention. The biomarker profiling of patients may allow for the prediction of disease predispositions and prognosis. Such a type of prediction would enable the prevention of the diseases and block the disease development path for early-stage cures. This is how pharmacogenomics will contribute to preventive medicine and help solve the problems of high costs, low efficacy and high ADRs in healthcare.Integration with systems medicine: understanding multidimensional interactionsWhile pharmacogenomics helps elucidate the association between patient genetic diversity and phenotypic responses, such studies should not be limited to single biomarker genes or SNPs [12]. This is because genes interact with each other, as well as with other molecules such as drugs and the environment. Using computational methods, systems biology may help us simulate large networks of interacting components, identify associations and patterns, and create predictive models [13]. Systems medicine, the practice of systems biology, needs to be integrated into the drug-development processes to solve the key issues in pharmacogenomics. These key issues include the structure–function relationships at various levels, the genes–drugs–environment interactions and the association of genotypes to disease and drug-response phenotypes [13].These key issues are correlated with each other at the molecular, cellular, tissue/organ, system and environmental levels. Specifically, altered genetic structures may cause malfunctions at the molecular level and affect the downstream pathways and interactions among different components at the cellular level [13]. These alterations may lead to tissue or organ disorders that are manifested as disease phenotypes and symptoms of the whole body. Furthermore, altered genetic structures and functions may affect the gene–drug interactions and drug-response phenotypes. On the other hand, interactions among systems, drugs and the environment at higher levels may have an impact on genetic structures and functions at the molecular level, which would, in turn, change downstream pathways and phenotypes, forming a feedback loop. The understanding of such an interwoven network may be the ultimate key to accurately identifying drug targets and to preventing adverse reactions.Among these issues, the genotype–phenotype correlation connects the information at different dimensions from the molecular level to the whole organism. This correlation represents the core value of systems biology, demonstrating that the behavior of a whole system does not merely come from its separated building blocks, but through the complex interrelationships and interactions between them [12]. A good example of this is inflammation, one of the best models for applying the translational systems biology framework [9,14]. For instance, complex NF-kB and p38 signaling pathways are involved in various phenotypes of inflammation, cancer and microbial infections [14]. The exploration of systemic interactions and feedbacks rather than single molecules is needed to understand the inflammatory processes and relevant disease phenotypes.Systems medicine would also contribute to the understanding of the mind–body relationships for achieving the ultimate goal of wellness in the physiological and mental dimensions. Emerging multidisciplinary areas such as psychoneuroimmunology (PNI) may benefit greatly from systems biology approaches. PNI studies the correlations and interactions among the psychological processes, the nervous system, the immune system and the endocrine system [15]. For example, the cytokine network plays a central role in PNI [16,17]. The brain cytokines, including IL-1β and IL-6, are involved in food intake, fever, sickness and anxiety-like behaviors [18,19]. Systems biology approaches can help construct computational models of such highly intercorrelated and multivariate networks in mind–body connections [17].Tools for the practice: biomarkers, technologies & translational bioinformaticsAn important component in the accurate practice of personalized and systems medicine is systemic biomarker identification, which is crucial for quantified diagnosis and prognosis, treatment selection and the profiling and grouping of patients. Biomarkers are objectively measured indicators of biologic states such as diseases and drug responses [12]. They can be analyzed in various functional pathways at different systems levels, including genetic markers at the molecular level, and imaging and physiological indicators at the system level [12]. Multiple biomarkers need to be combined in a comprehensive profile that summarizes the diagnostic and drug-response patterns which can then be used to identify patient subgroups and establish predictive models. For example, predictive and prognostic biomarkers for different subsets of patients have been used for outcome prediction and assessment in diseases including cancer, cardiovascular diseases, respiratory diseases and neurological diseases [12].Advanced technologies and tools are crucial for such comprehensive biomarker identifications. High-throughput technologies enable the measurement and cataloging of genes, proteins, interactions and behaviors in various conditions [12]. For instance, protein microarrays have been used extensively for pathways and pharmacoproteomics studies [20]. These methods allow genome-wide association studies to identify biomarkers for diagnosis and outcome assessments [14]. For example, genome-wide association studies have identified distinct cancer susceptibility loci among different ethnic groups [21].One of the most significant obstacles in current medical practice is the translation of scientific discoveries into better therapeutic outcomes. A critical factor in this process is the accessibility and analysis of integrated data within and across functional domains [12]. Translational bioinformatics is a powerful method to bridge this gap from the biomedical side to the informatics side [12]. On the biomedical side, translational bioinformatics would enable the simulation of networks of interacting components, the identification of patterns and patient subgroups from biomarker profiles and the establishment of predictive models. For example, a bioinformatics tool was used to correlate biomarkers including HER2 and estrogen receptor with survival outcomes in breast cancer patients [22]. The tool identified two distinct subpopulations of tumors with different levels of expressers. Moreover, on the informatics side, methods based on data integration, data mining and knowledge representation can promote data sharing across domains and provide decision support for both researchers and clinicians [12]. For example, the integration of information from multiple layers of biological regulation from multiple genome-wide data sources has been found to improve the prediction of cancer outcome [23].Conclusion & future perspectiveAlthough biomedicine is facing many obstacles and difficulties, appropriate solutions can transform the challenges into opportunities. The integration of personalized and systems medicine offers the prospect of the development of a better medicine that provides optimal therapies with high efficacy and low ADRs. This new medicine would be human-centric with the focus on prevention and the promotion of holistic health in the physical, mental and environmental dimensions. Specifically, the application of pharmacogenomics and systems biology will bring new concepts and methods into medicine, such as the regrouping of patients and recategorization of drugs based on pattern identifications and systemic biomarker profiles. These approaches would enable the construction of predictive models for the understanding of structure–function relationships, genotype–phenotype associations and interactions and networks at the molecular, cellular, system and environmental levels [13]. These practices would also improve our understanding of the mind–body relationships toward achieving the ultimate goal of personalized wellness. Tools such as high-throughput technologies and translational bioinformatics would serve as the technologies to bring us to this bright future.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Ross CJ, Carleton B, Warn DG et al.: Genotypic approaches to therapy in children: a national active surveillance network (GATC) to study the pharmacogenomics of severe adverse drug reactions in children. Ann. NY Acad. Sci.1110,177–192 (2007).Crossref, Medline, CAS, Google Scholar2 Caskey CT: The drug development crisis: efficiency and safety. Annu. Rev. Med.58,1–16 (2007).Crossref, Medline, CAS, Google Scholar3 Hawks SR, Smith T, Thomas HG et al.: The forgotten dimensions in health education research. Health Educ. Res.23(2),319–324 (2008).Crossref, Medline, Google Scholar4 Ray O: The revolutionary health science of psychoendoneuroimmunology: a new paradigm for understanding health and treating illness. Ann. NY Acad. 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Genome Med.1,39 (2009).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByNetworks and Dynamic Models in Systems Medicine: OverviewTranslational bioinformatics: An introductionHow clinical biobanks can support precision medicine: from standardized preprocessing to treatment guidance14 November 2019 | Expert Review of Precision Medicine and Drug Development, Vol. 4, No. 6Precision Medicine14 December 2018Translational and Disease BioinformaticsIntroductionSystems and Dynamical MedicineApplying Translational Bioinformatics for Biomarker DiscoveryFrom Psychoneuroimmunology to Personalized, Systems, and Dynamical Medicine4 October 2016Stress and Inflammation: Translational Implications in Mind–Body Medicine4 October 2016The Inflammatory Networks and Dynamical Patterns in Psychoneuroimmunology4 October 2016Biobanks in the era of personalized medicine: objectives, challenges, and innovation22 February 2016 | EPMA Journal, Vol. 7, No. 1Diverse array-designed modes of combination therapies in Fangjiomics13 April 2015 | Acta Pharmacologica Sinica, Vol. 36, No. 6A Review on Korean Medicine and Personalized Medicine: Syndrome-based Personalized Medicine on the Basis of Syndrome Differentiation and Treatment30 September 2014 | Journal of Korean Medicine, Vol. 35, No. 3Personalizing health care: feasibility and future implications13 August 2013 | BMC Medicine, Vol. 11, No. 1Rise and Demise of Bioinformatics? Promise and Progress26 April 2012 | PLoS Computational Biology, Vol. 8, No. 4The Role of Psychoneuroimmunology in Personalized and Systems Medicine24 July 2012Translational Implications of Inflammatory Biomarkers and Cytokine Networks in Psychoneuroimmunology24 July 2012Translation of psychoneuroimmunology into personalized medicine: a systems biology perspectiveQing Yan3 November 2011 | Personalized Medicine, Vol. 8, No. 6Toward knowing the whole human: next-generation sequencing for personalized medicineIan Toma, Georges St Laurent & Timothy A McCaffrey26 July 2011 | Personalized Medicine, Vol. 8, No. 4 Vol. 8, No. 1 Follow us on social media for the latest updates Metrics History Published online 22 December 2010 Published in print January 2011 Information© Future Medicine LtdKeywordsbiomarkersgenotypesnetworkspathwayspersonalized medicinepharmacogenomicsphenotypessystems biologytranslational bioinformaticswellnessFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

再発多発性骨髄腫に対するボルテゾミブ療法における副作用発現頻度と発現時期の調査

Bortezomib was approved in 2006 for use in patients with multiple myeloma.Although a high frequency of adverse drug reactions (ADRs) was reported in some clinical studies on bortezomib,little information is available on the time of occurrence of the ADRs.Therefore,we investigated the ADRs in 15 patients with relapsed multiple myeloma who received bortezomib alone or combined with dexamethasone,for 2 cycles.The ADRs with high frequencies were constipation (80.0%),leucopenia (73.3%),anemia (73.3%),fatigue (73.3%),peripheral neuropathy (66.7%) and thrombocytopenia (66.7%).The number of leukocytes decreased to the minimum on the 9th day and had recovered on the 14th day.The number of platelets decreased to the minimum on the 13th day,and had recovered on the 19th day.Gastrointestinal adverse reactions including constipation,diarrhea,nausea and vomiting were observed from the 5th day.Based on these results,we prepared a patient education sheet showing the times of occurrence of high frequency ADRs in the therapy schedule visually.This sheet should be useful in gaining the understanding of patients and their families regarding bortezomib therapy as well as enhancing its safety.

Genome-wide association studies: powerful tools for improving drug safety and efficacy

most closely implicated in disease pathology for the individual patient. Such clinical applications may still be many years away, as even in cases where new therapeutics will be developed based on newly discovered risk alleles and their corresponding protein targets, it typically takes at least one decade for a new drug to reach the market. The question then arises, what types of GWAS will be more likely to lead to clinical applications in the foreseeable future? GWAS are still costly, due to the need for large (typically over 1000) patient cohorts and to the fact that recruitment costs are not decreasing (even though genotyping costs continue to fall). A relatively less explored area in GWAS, and one where we feel that clinical applications may arrive much sooner compared with information regarding carrying disease risk alleles, is the study of pharmacogenetics – the genetic contribution to drug response. More specifically, GWAS could be harnessed for improving drug response – both safety and efficacy – for many current medicines. Drugs are often not safe enough: according to a 2006 report by the Centers for Disease Control (CDC) adverse drug reactions (ADRs) account for nearly 7% of all hospital admissions in the USA, with even higher frequencies seen in small children and the elderly [4,5]. Similarly, high ADR rates were observed in the UK [6]. While much knowledge has accumulated over the last two decades regarding genetic factors implicated in ADRs, mostly affected by polymorphic alleles of genes coding for drug-metabolizing enzymes (DME) and drug transporters, applying this knowledge in the clinic suffers from several barriers, which include a lack of reliable data on the genetics of drug response [7,8]. GWAS, thanks to their statistical power and lack of presumptions, offer the potential for bridging this knowledge gap through their capacity to scan the entire human genome in very large patient cohorts [9]. We live in an exciting era for genetics! This is a direct consequence of the availability of powerful and affordable genotyping technologies, along with the development of robust computational methods for analyzing large genetic datasets from patient cohorts. Technology has improved to the point where assessment of 1,000,000 SNPs across the human genome is a ‘normal’ task. The present issue of Pharmacogenomics includes a focus on genome-wide association studies (GWAS). The last 3 years have seen an unprecedented number of publications reporting on new GWAS, most of them concerning the discovery of new disease risk alleles [1–3]. Hundreds of recently published GWAS have opened new insights on genetic risk factors for a wide variety of complex human diseases, from diabetes and asthma to multiple sclerosis and several types of cancer. It remains to be seen to what extent this wealth of novel information on disease risk alleles will go toward improving healthcare.

A prospective, observational cohort study to elicit adverse effects of antiretroviral agents in a remote resource-restricted tribal population of Chhattisgarh

Objective:To assess the adverse effects of antiretroviral therapy (HAART) and its adherence in HIV-infected patients, in remote and tribal area with restricted resources.Materials and Methods:This was a prospective, observational study carried out at Department of Medicine, Government Medical College, Jagdalpur. A set of questions were asked and adverse drug reactions (ADRs) were recorded for every patient.Results:79 HIV positive patients were analyzed. Among them, 68 (86%) had at least one ADR. The mean ADR per patient was 1.64 (±1.09). The most common ADR in our study was peripheral neuropathy (20.83%), followed by skin rashes (15.83%). Twenty-one patients (26.58%) had severe (grade-3 and grade-4) ADRs. Female patients had more ADRs (45.71%) than males (11.36%); severe ADRs had a statistically significant positive correlation with sex and CD4 cell count of the patients.Conclusion:In spite of high ADRs, HAART is the only answer to HIV/AIDS; thus, management requires a highly precise balance between benefits of durable HIV suppression and the risks of drug toxicity to achieve the therapeutic goals, with conventional drugs or with newer less toxic agents.