Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

Metallothionein (MT) 1 and 2 are ubiquitously expressed cysteine-rich, low molecular weight proteins. MT expression is upregulated in skeletal muscle during aging. MTs also play role in multiple types of skeletal muscle atrophy. Meanwhile, it has been reported that MT1 and MT2 gene deficiency increases myogenesis in MT knockout (MTKO) mice. However, little is known about the effect of MTs on muscle formation and atrophy. In this study, we investigated the effect of MT1 and MT2 gene knock-out using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CRISPR-Cas9) system in an in vitro skeletal muscle differentiation model (C2C12 cell line). MT deficiency promoted myogenic differentiation and myotube formation in C2C12 cells. Muscle-specific transcription factors MyoD and myogenin were found to be upregulated at the late stage of myotube differentiation in MTKO cells. Furthermore, the fast-twitch myosin heavy chain (MyHC) protein expression was similar in MTKO and mock-transfected myotubes, but slow-MyHC expression was higher in MTKO cells than in mock cells. The MT gene deletion did not affect the number of fast MyHC-positive myotubes but increased the number of slow MyHC-positive myotubes. Treatment with the antioxidant N-acetylcysteine (NAC) inhibited the increase in the number of slow MyHC-positive myotubes as well as slow-MyHC expression in MTKO cells. In contrast, NAC treatment did not alter the number of fast MyHC-positive myotubes or the expression of fast-MyHC in MTKO cells. These results suggest that the antioxidant effects of MTs may be involved in slow-twitch myofiber formation in skeletal muscle.

A shift towards obtaining emergency contraceptives without a prescription have been discussed in Japan. In response to this social background, we aimed at investigating the background of sexual intercourse, emergency contraceptive use, and knowledge of sexual and reproductive health education among women of reproductive age in Japan. In this study, we conducted a national wide cross-sectional questionnaire survey using a total of 4 web-based domains (background, sexual history, emergency contraceptives, and sexual and reproduction-related knowledge) composed of 50 questions. We obtained responses from a total of 4,631 participants of varying age groups (18–25, 26–35, and 36–45 years old) and 47 prefectures (84 to 118 from each prefecture). Among participant responses, 69.7% are sexually active, of which 49.0% had experiences of sexual intercourse with an unknown person. The responses from a total of 737 participants who have sexual intercourse, know of emergency contraceptives, and have experienced a situation that necessitated the use of emergency contraceptives, were analyzed. Of these participants, 46.4% (342/737) took emergency contraceptives, while 43.6% (321/737) participants did not take emergency contraceptives. Participants who have the knowledge for obtaining emergency contraceptives through the correct means were 52.6% (2438/4631). This study showed that approximately half of participants may not have correct knowledge of emergency contraceptives. In addition, approximately half of sexually active participants are facing unintended pregnancies due to a lack of sexual and reproductive awareness. Hence, comprehensive sex education is necessary to achieve social and regulatory changes centered on emergency contraceptives.

Recently, microneedling as a cosmetic product has attracted attention as one way to improve skin barrier function and moisturizing function to reduce wrinkle formation. However, some cases of erythema and edema have been reported as side effects. In order to develop safer microneedle cosmetics, we investigated whether microneedles can improve skin barrier function and moisturizing function even when applied in a non-invasive manner that does not penetrate the stratum corneum. We established the condition of non-penetrating microneedle application on reconstructed human full-thickness skin models and examined the effect on the skin models when microneedles were applied under this condition. Microneedle application increased the gene expression of serine palmitoyltransferase long chain base subunit (SPTLC) 3, filaggrin, and transglutaminase 1. The amount of ceramide produced by SPTLC was also increased by microneedle application. Gene expression of filaggrin-degrading enzymes and the amount of free amino acids, a product of filaggrin degradation, were also increased by microneedling. These results suggest that non-invasive microneedle application can improve skin barrier function and moisturizing function by increasing the amount of ceramide and natural moisturizing factors.

Ca_v3.2 channels belong to the T-type calcium channel (T-channel) family, i.e., low voltage-activated calcium channels, and are abundantly expressed in the nociceptors, playing a principal role in the development of pathological pain. The channel activity of Ca_v3.2 is suppressed by zinc under physiological conditions. We thus tested whether dietary zinc deficiency would cause Ca_v3.2-dependent nociceptive hypersensitivity in mice. In the mice fed with zinc deficient diet for 2 weeks, plasma zinc levels declined by more than half, and mechanical allodynia developed. The dietary zinc deficiency-induced allodynia was restored by T-channel inhibitors or by Ca_v3.2 gene silencing. These data demonstrate that zinc deficiency induces Ca_v3.2-dependent nociceptive hypersensitivity in mice, thereby suggesting that pain experienced by patients with diseases accompanied by zinc deficiency (e.g., chronic kidney disease) might involve the increased Ca_v3.2 activity.

Bortezomib, an anticancer drug for multiple myeloma and mantle cell lymphoma, causes severe adverse events and leads to peripheral neuropathy. The associated neuropathy limits the use of bortezomib and could lead to discontinuation of the treatment; therefore, effective intervention is crucial. In the present study, we statistically searched for a drug that could alleviate bortezomib-induced peripheral neuropathy using adverse event self-reports. We observed that specific inhibitors of the mechanistic target of rapamycin (mTOR) lowered the incidence of bortezomib-induced peripheral neuropathy. These findings were experimentally validated in mice, which exhibited long-lasting mechanical hypersensitivity after repeated bortezomib treatment. This effect was inhibited for hours after a systemic injection with rapamycin or everolimus in a dose-dependent manner. Bortezomib-induced allodynia was accompanied by the activation of spinal astrocytes, and intrathecal injection of mTOR inhibitors or an inhibitor of ribosomal protein S6 kinase 1, a downstream target of mTOR, exhibited considerable analgesic effects in a dose-dependent manner. These results suggest that mTOR inhibitors, which are readily available to patients prescribed bortezomib, are one of the most effective therapeutics for bortezomib-induced peripheral neuropathy.

Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist–urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26–0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47–9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.

Since small extracellular vesicle (sEVs) are involved in cell-to-cell communication via transfer of certain bioactive molecules and have the capability to overcome biological barriers against drug transport, their use as a drug delivery system (DDS) has been demonstrated in treatment of a diverse range of diseases. However, some issues in drug encapsulation have been pointed out, including low encapsulation efficiency and poor reproducibility. It was previously reported that liposomes containing phosphatidylserine (PS) can fuse together in the presence of calcium ion, which allows for drug encapsulation into the resultant liposomes (i.e., calcium fusion method). On the other hand, PS is reportedly present in lipid membrane of sEVs as a distinct lipid composition. We therefore hypothesized that PS-mediated membrane fusion of sEVs with PS-liposomes encapsulating therapeutic agents via the calcium fusion method can be applied to convenient drug encapsulation into sEVs. Membrane fusion of PS-liposomes and sEVs derived from murine melanoma B16F1 cells (B16-sEVs) was firstly confirmed. The obtained nanoparticles, termed chimeric nanoparticles (CM-NP), showed comparable cellular uptake to B16-sEVs into B16F1 cells. Moreover, CM-NP encapsulating an anticancer drug doxorubicin (DOX) (CM-NP-DOX) could be prepared by membrane fusion of PS-liposomes encapsulating DOX (PS-Lipo-DOX) and B16-sEVs. CM-NP-DOX exhibited a superior anticancer effect on B16F1 cells in vitro compared with PS-Lipo-DOX. These findings suggest that the calcium fusion method could be applied for membrane fusion of sEVs and PS-liposomes, and that this approach would likely be useful for efficient drug encapsulation into sEVs, as well as increasing liposome functionality.

The anticancer drug oxaliplatin is associated with peripheral neuropathy as a side effect accompanied by mechanical and cold allodynia. Although the superficial layer of the spinal cord dorsal horn is known to receive information primarily from peripheral pain nerves, to our knowledge, no in vivo electrophysiological analyses have been conducted to determine whether oxaliplatin administration increases the excitability of superficial layer neurons. Therefore, in vivo extracellular recordings were performed to measure action potentials in the deep and superficial layers of the spinal cord dorsal horn in rats treated with a single dose (6 mg/kg) of oxaliplatin. Action potentials were produced by mechanical stimulation with von Frey filaments to the hindlimb receptive fields. The results revealed that the firing frequency of action potentials increased relative to the intensity of mechanical stimulation, and that both deep and superficial layer neurons in the spinal cord dorsal horn increased significantly in oxaliplatin-treated compared with vehicle-treated rats, especially in the superficial layer. Several superficial layer neurons showed spontaneous firing that was not seen in vehicle-treated rats. In addition, a clear increase was seen in the firing frequency of neurons in the superficial layer of oxaliplatin-treated rats in response to a cold stimulus (here, the addition of acetone to the hindlimb receptive field). This study suggests that the superficial spinal cord dorsal horn strongly reflects the pain pathophysiology in peripheral neuropathy induced by oxaliplatin administration, and that the superficial layer neurons are useful for in vivo electrophysiological analysis using this pathological model.

Tramadol is metabolized by CYP2D6 to an active metabolite, which in turn acts as an analgesic. This study aimed to investigate the impact of CYP2D6 genotype on the analgesic effect of tramadol in clinical practice. A retrospective cohort study was performed in patients treated with tramadol for postoperative pain after arthroscopic surgery for rotator cuff injury during April 2017–March 2019. The impact of CYP2D6 genotypes on the analgesic effects was assessed by the numeric rating scale (NRS) pain scoring and analyzed by the Mann–Whitney U test. Stepwise multiple linear regression analysis was performed to identify predictive factors for the area under the time-NRS curve (NRS-AUC), which was calculated using the linear trapezoidal method. Among the 85 enrolled Japanese patients, the number of phenotypes with CYP2D6 normal metabolizer (NM) and intermediate metabolizer (IM) was n = 69 (81.1%) and n = 16 (18.9%), respectively. The NRS and NRS-AUC in the IM group were significantly higher than those in the NM group until Day 7 (p < 0.05). The multiple linear regression analysis indicated that the CYP2D6 polymorphism was a prediction factor of the high NRS-AUC levels in Days 0–7 (β = 9.52, 95% CI 1.30–17.7). In IM patients, the analgesic effect of tramadol was significantly reduced one week after orthopedic surgery in clinical practice. Therefore, dose escalation of tramadol or the use of alternative analgesic medications can be recommended for IM patients.

Transient receptor potential (TRP) channels play a significant role in taste perception. TRP ankyrin 1 (TRPA1) is present in the afferent sensory neurons and is activated by food-derived ingredients, such as Japanese horseradish, cinnamon, and garlic. The present study aimed to investigate the expression of TRPA1 in taste buds, and determine its functional roles in taste perception using TRPA1-deficient mice. In circumvallate papillae, TRPA1 immunoreactivity colocalised with P2X2 receptor-positive taste nerves but not with type II or III taste cell markers. Behavioural studies showed that TRPA1 deficiency significantly reduced sensitivity to sweet and umami tastes, but not to salty, bitter, and sour tastes, compared to that in wild-type animals. Furthermore, administration of the TRPA1 antagonist HC030031 significantly decreased taste preference to sucrose solution compared to that in the vehicle-treated group in the two-bottle preference tests. TRPA1 deficiency did not affect the structure of circumvallate papillae or the expression of type II or III taste cell and taste nerve markers. Adenosine 5′-O-(3-thio)triphosphate evoked inward currents did not differ between P2X2- and P2X2/TRPA1-expressing human embryonic kidney 293T cells. TRPA1-deficient mice had significantly decreased c-fos expression in the nucleus of the solitary tract in the brain stem following sucrose stimulation than wild-type mice. Taken together, the current study suggested that TRPA1 in the taste nerve contributes to the sense of sweet taste in mice.

Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with allergens. The optimal treatment for ACD is to avoid contact with allergens. However, in some cases, avoiding exposure is not possible when the allergens are unknown. Therefore, establishing treatment methods other than allergen avoidance is important. We previously reported that the continuous administration of methionine, an essential amino acid, in a mouse model of atopic dermatitis alleviated its symptoms. In the present study, we investigated the effect of methionine on a mouse model of ACD caused by 1-fluoro-2,4-dinitrobenzene (DNFB). Differences in the effect of methionine were observed in DNFB-induced ACD model mice based on the mouse strain used. This difference was attributed to the suppression of hepatic dimethylglycine (DMG) production, which is associated with the suppression of hepatic betaine-homocysteine methyltransferase (Bhmt) expression by ACD. Although we did not reveal the mechanism underlying DMG suppression, our study suggests the presence of interactions between the liver and skin in dermatitis, such as the regulation of hepatic metabolic enzyme expression in dermatitis and the alleviation of dermatitis symptoms by the hepatic metabolism status of DMG.

Anticancer drugs exhibit many side effects, including skin pigmentation, which often lowers patient QOL. However, the mechanism of pigmentation caused by anticancer drugs remains unknown. The purpose of this study was to elucidate the mechanism of anticancer drug-induced skin pigmentation using 5-fluorouracil (5-FU), a widely used anticancer drug. Specific pathogen-free, 9-week-old Hos:HRM-2 male mice were intraperitoneally administered 5-FU daily for 8 weeks. Skin pigmentation was observed at the end of the study. Mice treated with 5-FU were also administered inhibitors of cAMP, α-melanocyte-stimulating hormone (α-MSH), and adrenocorticotropic hormone (ACTH) for analysis. Administration of oxidative stress, nuclear factor-kappa B (NF-κB), cAMP, and ACTH inhibitors reduced pigmentation in 5-FU-treated mice. These results indicate that the oxidative stress/NF-κB/ACTH/cAMP/tyrosinase pathway plays an important role in pigmentation in 5-FU-treated mice.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the only enzyme that converts inactive glucocorticoids to active forms and plays an important role in the regulation of glucocorticoid action in target tissues. JTT-654 is a selective 11β-HSD1 inhibitor and we investigated its pharmacological properties in cortisone-treated rats and non-obese type 2 diabetic Goto-Kakizaki (GK) rats because Asians, including Japanese, are more likely to have non-obese type 2 diabetics. Systemic cortisone treatment increased fasting plasma glucose and insulin levels and impaired insulin action on glucose disposal rate and hepatic glucose production assessed by hyperinsulinemic-euglycemic clamp, but all these effects were attenuated by JTT-654 administration. Cortisone treatment also reduced basal and insulin-stimulated glucose oxidation in adipose tissue, increased plasma glucose levels after administration of the pyruvate, the substrate of gluconeogenesis, and increased liver glycogen content. Administration of JTT-654 also inhibited all of these effects. Cortisone treatment decreased basal and insulin-stimulated 2-deoxy-D-[1-³H]-glucose uptake in 3T3-L1 adipocytes and increased the release of free fatty acids and glycerol, a gluconeogenic substrate, from 3T3-L1 adipocytes, and JTT-654 significantly attenuated these effects. In GK rats, JTT-654 treatment significantly reduced fasting plasma glucose and insulin levels, enhanced insulin-stimulated glucose oxidation in adipose tissue, and suppressed hepatic gluconeogenesis as assessed by pyruvate administration. These results demonstrated that glucocorticoid was involved in the pathology of diabetes in GK rats, as in cortisone-treated rats, and that JTT-654 ameliorated the diabetic conditions. Our results suggest that JTT-654 ameliorates insulin resistance and non-obese type 2 diabetes by inhibiting adipose tissue and liver 11β-HSD1.

Extravasations are common manifestations of iatrogenic injuries associated with intravenous therapy. Cytotoxic agents are already subject to a relatively well-defined management strategy in healthcare institutions and classified into three groups according to the extent of damage from extravasation: vesicants, irritants, and non-tissue-damaging agents. Therefore, careful monitoring and initial treatment according to the severity of the skin injury decreases the incidence of extravasation injury. In contrast, high osmolarity, acidic or alkaline, and/or vasoconstrictive activity have all been suggested as possible causes of tissue injury due to the extravasation of noncytotoxic agents. However, the severity of the injuries has not been classified. Therefore, due to a lack of awareness, case reports of severe extravasation injury caused by noncytotoxic agents are increasing. In this paper, we review case reports and animal experiments and classify the severity of extravasation injury by noncytotoxic agents into three categories. Parallel to cytotoxic agents, the classification provides appropriate warning of possible injury severity, helping medical personnel better understand the severity of tissue damage and prevent injury severity during extravasation.

Early life stress has a significant impact on development of the central nervous system (CNS), with lasting rather than transient consequences; therefore, it is important to alleviate these effects. In recent years, functional communication between the CNS and gut microbiota through the so-called brain-gut-microbiota axis has been examined, and it is likely that prebiotics contribute to development of the CNS through the gut microbiota. In this study, we performed behavioral, neurohistological, and fecal microbiota analyses in early-weaned mice to examine the effects of 2′-fucosyllactose (2′-FL), a human milk oligosaccharide, on anxiety induced by early life stress. Mice weaned at 17 d old (17-d mice) showed anxiety-like behaviors, such as decreased time in the open arms in the elevated plus maze test, compared to mice weaned at 24 d old (24-d mice). The number of cells that were positive for the neuronal activity marker c-Fos in the amygdala was also higher in 17-d mice. The behavioral and neural abnormalities caused by early weaning were alleviated by post-weaning ingestion of 2′-FL. The composition of the fecal microbiota differed among control diet-fed 24-d and 17-d mice, and 2′-FL diet-fed 17-d mice. These findings indicate that human milk oligosaccharides 2′-FL alleviate early stress-induced anxiety, amygdala hyperactivity, and gut microbiota changes.

Endogenous hydrogen polysulfides are radical scavengers, and the resulting thiyl radical may catalyze isomerization of the cis-double bond to a trans-double bond. This study examined whether oxidized linoleate species with trans/trans-conjugated diene moieties were generated in the 15-lipoxygenase/linoleate/hydrogen polysulfide system at a lower oxygen content. When 40 µL of 0.1 M phosphate buffer (pH 7.4) containing 1.0 mM linoleate, 1.0 µM soybean 15-lipoxygenase, and 100 µM sodium trisulfide was placed in a 0.6 mL polypropylene microtube for 1 h at 25 °C, the proportion of (E/E)-oxo-octadecadienoic acids (OxoODEs) content to the total OxoODEs content was estimated to be more than 80% (mol/mol). OxoODEs are generated through the pseudoperoxidase reaction of ferrous 15-lipoxygenase with hydroperoxy octadecadienoic acids (HpODEs), which are produced by the lipoxygenase reaction of ferric 15-lipoxygenase. The content of OxoODEs was positively correlated with the content of 9-HpODEs, indicating that 9-HpODEs production is involved in converting ferric 15-lipoxygenase to ferrous 15-lipoxygenase. Furthermore, when 40 µL of 0.1 M phosphate buffer (pH 7.4) containing 1.0 mM linoleate, 1.0 µM soybean 15-lipoxygenase, 100 µM sodium trisulfide, and nitroxyl radical (carbon-centered radical-trapping agent, 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-N-oxyl (CmΔP)) was incubated in a 0.6 mL polypropylene microtube at room temperature, CmΔP-(E/Z)-ODEs were isomerized to CmΔP-(E/E)-ODEs in a time-dependent manner and this isomerization was inhibited by a radical scavenger, Trolox. The results indicate that thiyl radicals derived from hydrogen polysulfides isomerize trans/cis conjugated diene moiety to the trans/trans moiety.

In the present study, we have obtained a temperature-sensitive replication mutant in the Escherichia (E.) coli–lactic acid bacterium (LAB) shuttle vector pLES003-b carrying erythromycin-resistance gene by error-prone PCR technique. Among 858 clones obtained in the construction of the random mutation libraries of pLES003-b in the ori and repA regions, three clones could grow normally at 28 °C but not at 42 °C. One of the clones was designated as pLES003-b TS1. The sequencing analysis of pLES003-b TS1 revealed that the plasmid has four substitution mutations (376G > A, 435A > T, 914C > A, and 1996T > A) and one insertional mutation (1806_1807insA). Among those mutations, substitution mutation 914C > A, which leads to a CGC-to-AGC codon change at position 44 of the RepA protein (arginine-to-serine substitution mutation: R44S in RepA), was predicted to be a cause of temperature sensitivity. Therefore, the C-to-A substitution was introduced into the repA gene in pLES003-b using a site-directed mutagenesis method, and the resultant plasmid was electroporated into a Lactobacillus (L.) plantarum cell. The resultant transformant cannot grow at 42 °C in the presence of erythromycin, which is used as a selective marker, indicating that the R44S point mutation in the RepA protein may be crucial for temperature sensitivity. Furthermore, we have developed a new plasmid as an efficient genetic engineering tool for random insertional mutagenesis in LABs using a combination of transposon Tn10 and the temperature-sensitive replication system in pLES003-b. The resultant plasmid vector, which was designated pLES-Tn10-TS1, would be useful for genetic analysis of the functional molecule in lactic acid bacterial strains.

The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug–drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 d) was significantly different (p = 0.043) from that in the US (4253 d), though it was not significantly different from that in the EU (4655 d). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.