Risk Factor for Rash in Patients Receiving Cytarabine and Idarubicin Induction Therapy for Acute Myeloid Leukemia.

Background/Aim: Rash is a common adverse event (AE) observed during cytarabine and idarubicin induction therapy in patients with acute myeloid leukemia (AML). Previous studies have highlighted the challenge in predicting the onset and duration of rash. This study aimed to determine the factors that affect the onset of rash in patients receiving induction therapy for AML. Patients and Methods: This retrospective study involved 97 patients with AML who received induction chemotherapy with cytarabine and idarubicin at the Department of Hematology, Kyushu University Hospital between January 2008 and June 2022. The factors associated with rash were identified through a multivariate stepwise logistic regression analysis. Subsequently, the patient's characteristics were compared between those with risk factors and those without risk factors using a matched pair analysis. Results: Pre-existing leukopenia [odds ratio (OR)=3.294; 95% confidence interval (CI)=1.272-8.531] and good performance status (PS=0) (OR=2.717; 95%CI=1.087-6.792) were significant risk factors for rash development. Conversely, the matched pair analysis indicated that patients with pre-existing leukopenia, excluding those with a PS score of 0, exhibited a significantly (p=0.015) higher incidence of rash than those without it. Conclusion: Both multivariate logistic regression analysis and matched pair analysis identified pre-existing leukopenia as a primary risk factor for rash development associated with cytarabine and idarubicin chemotherapy.

Cholecystokinin receptor type A are involved in the circadian rhythm of the mouse retina.

The retina is the only organ projecting external light to the suprachiasmatic nucleus. Cholecystokinin receptor type A (Cckar/Cckar) is one of the essential factors for light reception in retinal cells. As there was a lack of literature on the matter, we aimed to elucidate the cause of the time-dependent phase change in clock gene expression. We found that Cckar mRNA expression in retinal cells exhibited diurnal variations. The rhythm of expression of the clock gene Per1/Per2 in retinal cells was altered in Cckar -/- mice. The light sensitivity of retinal cells was evaluated in wild-type mice, which showed c-Fos was activated in the ganglion cell layer more than in the inner granular layer. This increase in the number of c-Fos-positive cells was suppressed by lorglumide, a Cckar antagonist. Treatment of rat retina primary cells with lorglumide suppressed Per2 transcription, which was altered in a time-dependent manner relative to the Per2 expression. Light irradiation studies in Cckar -/- mice did not exhibit an increase in Period expression in the suprachiasmatic nucleus. These results indicate that Cckar is among the factors that regulate the cycle of clock genes on the retina. Cckar knockout attenuates the light responsiveness of suprachiasmatic nucleus and reduces the expression amplitude of Period genes in the retina. Thus, Cckar may contribute to entrainment of the light environment and maintenance of the expression cycle of Period gene, which is one of the core clock genes.

Medical Economic Effect of Pharmaceutical Interventions by Board-Certified Pharmacists in Palliative Pharmacy for Patients with Cancer Using Medical Narcotics in Japan: A Multicenter, Retrospective Study.

BACKGROUND: The Japanese Society for Pharmaceutical Palliative Care and Sciences specializes in pharmacology in the field of palliative medicine. More than 700 board-certified pharmacists in palliative pharmacy (BCPPP) are actively involved in palliative pharmacotherapy at various hospitals and pharmacies. The purpose of this study was to determine the economic effect of pharmaceutical interventions by BCPPPs. METHODS: This multicenter retrospective study included 27 medical centers and analyzed the medical economic effect of interventions by BCPPPs (17 pharmacists) and non-BCPPPs (24 pharmacists) on patients using medical narcotics for cancer pain in September 2021. RESULTS: The percentage of patients who received a pharmaceutical intervention and whose drug costs were reduced by pharmacist intervention was significantly higher in the BCPPP group than in the non-BCPPP group. Although there was no significant difference between the two groups in drug cost reduction per patient per month (BCPPP group: $0.89 [-$64.91 to $106.76] vs. non-BCPPP group $0.00 [-$1,828.95 to $25.82]; P = 0.730), the medical economic benefit of pharmacist intervention in avoiding or reducing adverse drug reactions was higher in the BCPPP group ($103.18 [$0.00 to $628.03]) than in the non-BCPPP group ($0.00 [$0.00 to $628.03]) (P = 0.070). The total medical economic benefit-the sum of these-was significantly higher in the BCPPP group ($88.82 [-$14.62 to $705.37]) than in the non-BCPPP group ($0.66 [-$1,200.93 to $269.61]) (P = 0.006). CONCLUSION: Pharmacological intervention for patients with cancer using medical narcotics may have a greater medical economic benefit when managed by BCPPPs than by non-certified pharmacists in Japan.

Improvement of Medication Guidance Sheet for Total Body Irradiation/Cyclophosphamide Followed by Allogeneic Hematopoietic Stem Cell Transplantation Based on Real Monitoring Data.

BACKGROUND/AIM: Adverse events (AEs) must be managed during cancer therapy. We had previously developed a medication guidance sheet (MGS) to monitor AEs after conditioning therapy with allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether this sheet can accurately predict the type, onset, and duration of AEs in clinical practice. In this study, we evaluated the clinical utility of the original MGS in patients receiving total body irradiation (TBI) and cyclophosphamide (CY). PATIENTS AND METHODS: Fifty-eight patients who underwent TBI/CY were included. The types, onsets, and durations of AEs observed during real monitoring were compared with those listed in the original MGS. RESULTS: A total of 361 subjective AE symptoms were observed, all of which were predictive, as listed in the MGS. However, the durations of several AEs were longer than expected. Thus, the prediction accuracy for all AEs was 67.0%. The accuracy rate was the lowest for anorexia (6.7%), followed by diarrhea (42.6%), and nausea/vomiting (55.6%). Acute graft versus host disease (GVHD) most likely caused the prolongation of AEs. Subsequently, the original MGS was revised to account for the possible occurrence of acute GVHD. CONCLUSION: When monitoring AEs in patients receiving a TBI/CY conditioning regimen for HSCT, the involvement of acute GVHD-associated AEs should be considered. In this respect, the present modified MGS is particularly useful for rapid and accurate monitoring of AEs.

Development of Real-world Data-based Medication Instruction Sheet for Acute Myeloid Leukemia Patients Receiving High-dose Cytarabine Consolidation Therapy.

BACKGROUND/AIM: For quick and accurate monitoring of potential adverse events (AEs) during concurrent chemotherapy, we had previously developed innovative medication instruction sheets (MIS) for a variety of chemotherapy regimens. However, it is still unclear whether these sheets correctly predict the type and time course of the onset and recovery of AEs. Therefore, we monitored AEs in patients with acute myeloid leukemia (AML) receiving high-dose cytarabine (HD-AraC) using the original MIS. PATIENTS AND METHODS: Patients who received HD-AraC following remission induction chemotherapy were included in this study. Data obtained from AE monitoring were evaluated, and the original MIS was modified as appropriate. RESULTS: Among 41 patients, a total of 203 AEs (139 non-hematological and 64 hematological) were observed after chemotherapy. By contrast, all but one patient (97.6%) experienced 102 AEs (43 non-hematological and 59 hematological) before chemotherapy. The AEs that appeared after chemotherapy were all predicted items described in the original MIS; however, their onset and duration were not consistent with the predicted data, in which the prediction accuracy was 69.1% for non-hematological AEs and 1.6% for hematological events. Based on these monitoring data, the original MIS was revised, which led to an increase in the prediction accuracy to 94.2% for nonhematological events and 100% for hematological events. CONCLUSION: Preexisting AEs should be considered when preparing MIS for consolidation therapy with HD-AraC. The modified MIS based on AE monitoring exhibited a sufficiently high prediction accuracy.

Ameliorating effects of cystine and theanine in a cancer cachexia mouse model.

Cachexia is a common cancer complication and is associated with weight loss and anorexia. In this study, we investigated the ameliorating effects of cystine and theanine on cancer cachexia using a mouse model. In mice carrying the colon cancer cell line C-26, there was a suppression of body weight increase and reduction in both internal fat and lower limb muscles. Repeated cystine and theanine administration significantly prevented weight loss, internal fat loss, lower limb muscle loss, and serum IL-6 increase in the cachexia model. These results suggested that cystine and theanine may be effective in ameliorating cancer cachexia.

Medical Opioid Disposal in Fukuoka and Kumamoto Cities.

Medical expenses are increasing year by year in Japan. However, the quantity of disposed medical opioids is not well known. In this study, we assessed disposed medical opioids in community pharmacies of Fukuoka city and in all of medical organizations of Kumamoto cities for 3 and 2 years, respectively. We collected official opioid disposal reports in Kumamoto city and Fukuoka City Pharmaceutical Association (FCPA) disposal information sheet in Fukuoka city. The total amount of disposed opioids was worth 7.1 million Yen from 2017 to 2019 in Fukuoka city, and 8.9 million Yen in for 2 years (2018 and 2019) in Kumamoto city. In Fukuoka city, the most disposed opioid was 20 mg Oxycontin®, worth approximately 940000 Yen. In Kumamoto city we assessed data in different organizations. The most disposed opioid was 5 mg Oxinorm® at a cost of 600000 Yen at the medical institutions over the 2-year study period. The most disposed opioid was 40 mg Oxycontin®, at a cost of 640000 Yen in community pharmacies. Two hundred micrograms E-fen® buccal tablet was the most disposed of opioid, was amounting to 960000 Yen in wholesalers. On the whole in Kumamoto city, non-dispensing was the most common reason of disposal. These results indicate that the amount of disposed opioids is huge. Small package simulation studies suggest that smaller package units of MS-Contin®, Anpec® suppository, and Abstral® sublingual tablet may be able to reduce the amount of disposed opioids.

Usefulness of a Medication Instruction Sheet for Patients Receiving Cytarabine and Idarubicin Induction Therapy for Acute Myeloid Leukemia.

BACKGROUND/AIM: To monitor adverse events rapidly and accurately during combination chemotherapy, we established an innovative medication instruction sheet (MIS) including cytarabine and idarubicin induction therapy. However, it is unclear whether this MIS allows for the accurate prediction of adverse events and their onset timing in a clinically significant manner. We therefore evaluated the clinical usefulness of our MIS for monitoring adverse events. PATIENTS AND METHODS: Patients who received cytarabine and idarubicin induction therapy for acute myeloid leukemia (AML) at the Department of Hematology, Kyushu University Hospital between January 2013 and February 2022 were included. The real-world clinical data were compared to the MIS to determine the accuracy of the MIS for predicting the onset and duration of adverse events in patients with AML during induction chemotherapy. RESULTS: Thirty-nine patients with AML were included in this study. Overall, 294 adverse events were noted, all of which were predicted items in the MIS. Among the 192 non-hematological adverse events, 131 (68.2%) occurred during a similar period as that listed in the MIS, whereas among the 102 hematological adverse events, 98 (96.1%) appeared earlier than expected. For the non-hematological events, the onset and duration of elevated aspartate aminotransferase levels and nausea/vomiting coincided well with those listed in the MIS, whereas the predictive accuracy for rashes was the lowest. CONCLUSION: Hematological toxicity was not predicted because of the bone marrow failure associated with AML. Our MIS was useful for rapidly monitoring non-hematological adverse events in patients with AML receiving cytarabine and idarubicin induction therapy.

Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08−0.56), p < 0.01, doxazosin 0.41 (0.10−1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38−0.76), p < 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.

Analysis of the thinking process of pharmacists in response to changes in the dispensing environment using the eye-tracking method.

BACKGROUND: Pharmacists must understand the mechanisms by which dispensing errors occur and take appropriate preventive measures. In this study, the gaze movements of pharmacists were analyzed using an eye-tracking method, to elucidate the thinking process of pharmacists when identifying target drugs and avoiding dispensing errors. METHODS: We prepared verification slides and projected them on a large screen. Each slide comprised a drug rack area and a prescription area; the former consisted of a grid-like layout with 55 drugs and the latter displayed dispensing information (drug name, drug usage, location number, and total amount). Twelve pharmacists participated in the study, and three single-type drugs and six double-type drugs were used as target drugs. We analyzed the pharmacists' method of identifying the target drugs, the mechanisms by which errors occurred, and the usefulness of drug photographs using the error-induction (-) /photo (+), error-induction (+) / (+), and error-induction (+) /photo (-) models. RESULTS: Visual invasion by non-target drugs was found to have an effect on the subsequent occurrence of dispensing errors. In addition, when using error-induction models, the rate of dispensing error was 2.8 and 11.1% for the photo (+) and photo (-) models, respectively. Furthermore, based on the analysis of eight pharmacists who dispensed drugs without errors, it was clear that additional confirmation of "drug name" was required to accurately identify the target drug in the photo (+) model; additionally, that of "location number" was required to pinpoint directly the position of target drug in the photo (-) model. CONCLUSIONS: By analyzing the gaze movements of pharmacists using the eye-tracking method, we clarified pharmacists' thinking process which was required to avoid dispensing errors in a complicated environment and proved the usefulness of drug photographs in terms of both reducing the complexity of the dispensing process and the risk of dispensing errors. Effective measures to prevent dispensing errors include ensuring non-adjacent placement of double-type drugs and utilization of their image information.

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5−20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32−0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

Evaluation of Medication Instruction Sheets for Patients Undergoing R-CHOP Therapy in Non-Hodgkin's Lymphoma.

BACKGROUND/AIM: High-dose chemotherapy is frequently administered to patients with hematologic malignancies, thereby causing severe adverse drug reactions (ADRs) at a relatively high frequency. To precisely monitor ADRs, we developed a medication instruction sheet (MIS) for patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination therapy for non-Hodgkin's lymphoma (NHL). Herein, we evaluated the usefulness of the MIS for managing ADRs in patients who received R-CHOP therapy. PATIENTS AND METHODS: We included patients aged ≥20 years who received R-CHOP therapy as first-line treatment for NHL at the Department of Hematology, Kyushu University Hospital, between August 2014 and December 2018. Medical professionals evaluated the possible occurrence of ADRs according to the present MIS and ADRs were graded according to the Common Toxicity Criteria, version 4.0 (National Cancer Institute, Bethesda, MD, USA). Finally, the accuracy of the MIS in predicting the occurrence of ADRs of different grades and during definite periods was evaluated. RESULTS: Seventy-five patients with NHL were included in the present study. Overall, 359 ADR events were monitored, which were predicted ADR items listed in the MIS. Among these, 254 (71%) events occurred during the same period as those listed in the MIS. The onset timing of any grade of an infusion reaction and peripheral neuropathy precisely matched those listed in the MIS. However, the accuracy of the MIS was reduced in patients with thrombocytopenia (42%). CONCLUSION: The present MIS could be useful for monitoring ADRs in patients with cancer undergoing R-CHOP therapy.

Time to Onset of Bendamustine-associated Skin Damage Using the Spontaneous Reporting System.

BACKGROUND/AIM: Bendamustine-associated skin damage occurs frequently in Japan and can have a profound impact on health-related quality of life. To our knowledge, there are no reports on the timing of skin damage caused by bendamustine. This study assessed trends in and the time to onset of skin damage caused by bendamustine using the Japanese Adverse Drug Reaction Reporting Database (JADER). PATIENTS AND METHODS: Data related to skin damage with more than five reported cases from April 2004 to March 2021 were extracted from JADER, and the relative risk of adverse events was estimated using the reporting odds ratio and 95% confidence interval. The data were analyzed for time to onset of skin damage. RESULTS: JADER included a total of 2,450 reports of adverse drug reactions from bendamustine. Of these, 170 skin ailments of 10 types were reported to be associated with bendamustine. Significant associations for skin damage were found for rash, herpes zoster, and infusion-related reactions. The reporting odds ratios (with 95% confidence interval) for rash, herpes zoster, and infusion-related reaction were 1.63 (1.19-2.21), 3.25 (2.20-4.78), and 7.25 (4.84-10.85), respectively. The median onset (interquartile range) of rash, herpes zoster, and infusion-related reactions caused by bendamustine were 13 (10-28), 60 (28-107), and 6 (1-28) days, respectively. CONCLUSION: A comprehensive study using a pharmacovigilance approach enabled us to identify that a rash or infusion-related reaction may be expected within 2 weeks of treatment with bendamustine and that the onset of herpes zoster occurs at a median of 2 months after treatment with bendamustine.

Mechanisms and Safety of Antidepressant-Like Effect of Nutmeg in Mice.

Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This study evaluates the mechanisms underlying this antidepressant-like effect and safety of nutmeg n-hexane extract (NNE) in mice. Tail suspension and open field tests showed that NNE (10 mg/kg, per OS (p.o.)) significantly decreased the immobility time of mice without effecting their spontaneous locomotor activity. The reduction of immobility time of mice elicited by NNE was significantly inhibited by ketanserin (5-hydroxytryptamine (5-HT)2A/2C receptor antagonist), ondansetron (5-HT3 receptor antagonist), and yohimbine (α2 receptor antagonist). WAY100635 (5-HT1A receptor antagonist) tended to inhibit the effect of NNE but without significance. Testing according to the Organisation for Economic Co-operation and Development Guidelines, no mice died due to administrated NNE (2000 mg/kg, p.o.), and behavioral and weight changes were not seen in the acute toxicity test. In the Ames test, no increase in the number of revertant colonies for each bacterial strain test strains TA98 and TA100 by nutmeg powder was observed either with or without metabolic activity by S9 mix. These results suggest that NNE shows an antidepressant-like effect involving various serotonergic and noradrenergic nervous systems and maybe a highly safe natural preparation.

Usefulness of Medication Guidance Sheets for Patients With Non-Hodgkin's Lymphoma Receiving ESHAP±R Therapy.

BACKGROUND/AIM: The occurrence of chemotherapy-related serious adverse events (AEs) is associated with a poor prognosis of hematopoietic malignancies. We have developed a medication guidance sheet (MGS) for monitoring AEs occurring when combining chemotherapy with etoposide, methylprednisolone, cisplatin, cytarabine, and rituximab (ESHAP±R). In this study, the usefulness of MGS was investigated in non-Hodgkin's lymphoma patients. PATIENTS AND METHODS: The MGS was used to monitor AEs in 48 adult patients receiving ESHAP±R. The prediction accuracy of the MGS was estimated before and after modification based on practical data. RESULTS: A total of 246 AEs developed, all of which were predicted by the MGS. Among them, 149 events (61%) occurred during the same period as those predicted by the MGS. After modification of MGS for the onset and duration of AEs, the accuracy increased to 84%. CONCLUSION: The accuracy of the original MGS for ESHAP±R was insufficient but greatly improved after the AEs duration modification.

Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data.

BACKGROUND: Drug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. METHODS: Herein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA's database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague-Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. RESULTS: Simvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. CONCLUSION AND RELEVANCE: Thus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS).

PURPOSE: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. METHODS: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. RESULTS: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. CONCLUSIONS: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory PIPN effects. This review summarizes the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Thus, enhancing translational research to translate pre-clinical research into clinical research is important.

Ibudilast suppresses oxaliplatin-induced mechanical allodynia and neurodegeneration in rats.

Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01-10 µM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome.

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65-0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.