Comprehensive analysis of responses from ChatGPT to consumer inquiries regarding over-the-counter medications.

Background: The use of generative artificial intelligence (AI) applications such as ChatGPT is becoming increasingly popular. In Japan, consumers can purchase most over-the-counter (OTC) drugs without having to consult a pharmacist, so they may ask generative AI applications which OTC drugs they should purchase. This study aimed to systematically evaluate responses from ChatGPT to consumer inquiries about various OTC drugs. Methods: We selected 22 popular OTC drugs and 12 typical consumer characteristics, including physical and disease conditions and concomitant medications. We input a total of 264 questions (i. e., all combinations of drugs and characteristics) to ChatGPT in Japanese, asking whether it is safe for consumers with each characteristic to take these OTC drugs. We used the generic name for 10 of the 22 drugs and the brand name for the remaining 12. Responses were evaluated based on the following three criteria: 1) coherence between the question and response, 2) scientific correctness, and 3) appropriateness of the instructed actions. When we received a response that satisfied all three criteria, we input the exact same question on a different day to assess reproducibility. Results: The proportions of ChatGPT's answers that satisfied criteria 1, 2, and 3 were 79.5%, 54.5%, and 49.6%, respectively. However, the proportion of responses that satisfied all three criteria was only 20.8% (55/264); 61.8% (34/55) of these responses were reproduced when the same question was input again on a different day. Compared with questions using generic names, those using brand names resulted in lower coherence and scientific correctness. Among the 12 characteristics, the appropriateness of the instructed actions tended to be lower in responses to questions about driving and concomitant medications. Conclusions: Our study revealed that ChatGPT was less accurate in its responses and less consistent in its instructed actions compared with the package inserts. Our findings suggest that Japanese consumers should not consult ChatGPT regarding OTC medications, especially when using brand names.

Effect of renin-angiotensin system inhibitors on pemetrexed plus platinum-induced hematological toxicities: a multicenter retrospective study using three propensity score analyses.

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20-2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19-2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11-1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

Review of clinical studies on the nocebo effect.

Objective: To review clinical studies on the nocebo effect. PubMed was searched for relevant clinical studies as well as studies on the relationship between the nocebo effect and genes. Data sources: A total of 35 clinical studies on the nocebo effect and one study on its relationship with genes were selected for review. All were conducted outside Japan. Results and conclusion: An increasing number of clinical studies on the nocebo effect are being published. The 36 studies selected for review were grouped into the following five categories: (1) studies of how differences in participant characteristics such as personality affect susceptibility to the nocebo effect, (2) studies of how differences in provision of information about side effects affect susceptibility to the nocebo effect, (3) studies of how nocebo conditioning affects susceptibility to the nocebo effect, (4) studies of nocebo response mechanisms, and (5) studies of the nocebo effect and genetic polymorphisms. The first four categories comprised 5, 19, 8, and 3 studies, respectively, and the fifth comprised 1 study. Most of the studies investigated how differences in the provision of information affect susceptibility to the nocebo effect. Few studies investigated individual differences in the nocebo effect (differences between responders and non-responders) or mechanisms of the nocebo effect.

Relationship between medication adherence and glycemic control in Japanese patients with type 2 diabetes.

A cross-sectional survey of 358 patients was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Univariate and multivariate regression analyses of glycosylated hemoglobin (HbA1c) were performed in addition to assessing demographic and disease characteristics and MMAS-8. In conclusion, medication adherence as measured by the MMAS-8 score independently contributes to altering the HbA1c level in the range of 1.12 %. The number of medications prescribed and insulin use are also related to HbA1c.

Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis.

In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6±1.3 µg/ml in patients with methotrexate and 1.0±0.5 µg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production.

Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment.

Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT*3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT*3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.

Case report: dose adjustment of warfarin using genetic information and plasma concentration monitoring.

WHAT IS KNOWN AND OBJECTIVE: Carbamazepine is known to interact with warfarin. We report on a case of this interaction and on its management using the patient's genetic information. CASE SUMMARY: The case concerns a 74-year-old Japanese woman with a mood disorder and a central retinal vein occlusion. She was on therapy that included carbamazepine and had started to take warfarin. However, the patient's prothrombin time expressed as the international normalized ratio (PT-INR) was 1·40 despite taking a dose three times higher than the average. The patient's S-warfarin concentration was 0·15 µg/mL and R-warfarin was 0·52 µg/mL. Her cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1), genotypes were *1/*1 and -1639GA, respectively. The VKORC1 genotype indicated that she would require an even higher dose. We proposed a further increase in dose and the patient's PT-INR rose to 1·99. WHAT IS NEW AND CONCLUSION: The patient required a high warfarin dose because of the VKORC1 genotype, and induction of CYP2C9 by carbamazepine. We improved the patient's pharmacotherapy based on her genetic information.

Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole antifungal agents.

WHAT IS KNOWN AND OBJECTIVE: Both itraconazole (ITCZ) and voriconazole (VCZ) are potent inhibitors of cytochrome P450 (CYP) 3A, and their effects have been reported to be equal. However, ITCZ is metabolized by CYP3A, whereas VCZ is mainly metabolized by CYP2C9 and CYP2C19 and only partially by CYP3A. We experienced the case of a patient who showed a 5-fold increase in trough levels of tacrolimus (FK) level after switching from ITCZ to VCZ. Our objective is to discuss the mechanism of the increase drug-drug interaction in terms of serum concentration of the azole drugs and patient pharmacogenomics. CASE SUMMARY: A 53-year-old woman was treated with FK (1 mg/day) for lupus nephritis. Because fungal infection was suspected, she received ITCZ (100 mg/day). When ITCZ was replaced with VCZ (400 mg/day), the blood concentration of FK increased markedly from 6·1 to 34·2 ng/mL. During coadministration with FK, the levels of ITCZ and VCZ were 135·5 ng/mL and 5·5 µg/mL, respectively, with the VCZ level around 3-fold higher than the previously reported level (1·4-1·8 µg/mL). Her CYP genotypes were CYP2C19*1/*2, CYP3A4*1/*1 and CYP3A5*3/*3. WHAT IS NEW AND CONCLUSION: The patient was a CYP2C19 intermediate metabolizer (IM) and deficient in CYP3A5. The increase in plasma VCZ level appears to have been at least in part, associated with the CYP2C19 IM phenotype. One possible explanation for the marked increase in blood FK concentration was increased inhibition of CYP3A because of the impaired metabolism and subsequent increased plasma concentration of VCZ. This case shows that the severity of drug interactions may be influenced by metabolic gene polymorphism.

CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects.

WHAT IS KNOWN AND OBJECTIVE: Polymorphisms in the gene encoding CYP4F2 may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitamin K. To determine the genetic factors that cause large inter-patient variability in warfarin efficacy, we investigated the relationship between serum warfarin concentration and CYP4F2 V433M (1347C>T, rs2108622) polymorphism in Japanese subjects. METHODS: Gene variations in VKORC1, CYP2C9 and CYP4F2 were analysed in 126 Japanese patients treated with warfarin. The daily dosage of warfarin, concentration of S- and R-warfarin in plasma, and prothrombin time international normalized ratio (PT-INR) was used as the pharmacokinetic and pharmacodynamic indices. RESULTS AND DISCUSSION: The maintenance dose of warfarin was larger in the CYP4F2 1347 CT genotype group (3·59±1·80 mg/day, P=0·027) than in the CYP4F2 CC genotype group (2·88±1·00 mg/day). CYP4F2 1347C>T polymorphism significantly affected serum R-warfarin concentration when the VKORC1-1639 genotypes are AG and GG. WHAT IS NEW AND CONCLUSION: Although a significant inter-patient difference in warfarin maintenance dose was observed between the CYP4F2 CC and CT genotypes, serum S-warfarin concentration was not significantly different between them. An effect of CYP4F2 V433M polymorphism on warfarin maintenance dose was observed but was relatively small when compared to the effects of CYP2C9 and VKOR polymorphism.

Influence of CYP2C9 and vitamin k oxide reductase complex (VKORC)1 polymorphisms on time to determine the warfarin maintenance dose.

Polymorphisms in cytochrome P450 (CYP) 2C9 and the vitamin K oxide reductase complex subunit 1 (VKORC1) greatly affect the maintenance dose of warfarin. To prevent adverse events, immediate dose adjustment is required. The purpose of this study was to investigate the influence of these polymorphisms on the time taken to determine the warfarin maintenance dose for individual patients, and to assess the advantages of genotype-based dosing on initial anticoagulant therapy. We analyzed the genotypes of CYP2C9 and VKORC1 from 72 patients. The number of days taken to determine the maintenance dose was compared with the genotypes. The time taken to determine the maintenance dose of warfarin in group A (CYP2C9*1/*1, VKORC1 -1639AA), B (*1/*1, - 1639GA), C (*1/*3, - 1639AA), and D (*1/*3, - 1639GA) patients was 19 +/- 19, 28 +/- 28, 27 +/- 20 and 7 days, respectively. We analyzed the relationship between the initial dose of warfarin and the number of days required to determine the maintenance dose based on the VKORC1 genotypes. Patients with the VKORC1 - 1639AA genotype and who were initially treated with more than 3mg warfarin, required approximately 2 weeks for the maintenance dose to be determined. Patients with the VKORC1 - 1639GA genotype and the same initial warfarin dosage required approximately a month; however, patients initially treated with 5 mg of warfarin only required 9.5 +/- 5.3 days. We found a tendency that the time taken to determine the warfarin maintenance dose depends on the genotypes. Genotype-based dosing may improve initial anticoagulant therapy.

Pharmacokinetic individualization of high-dose methotrexate chemotherapy for the treatment of localized osteosarcoma.

Individualization of high-dose methotrexate (MTX) dosing is important to achieve therapeutic levels (700-1,000 microM) for osteosarcoma. Therefore we developed a pharmacokinetically (PK) individualized dosage regimen to maintain MTX concentrations of 700 microM (1 h bolus followed by 5 h maintenance infusion) and evaluated its safety and efficacy. Loading and maintenance doses were calculated by the PK parameters based on 2-compartment model analysis. Thirty-two courses of chemotherapy were performed in 9 patients with osteosarcoma. The maximum concentrations during maintenance infusion in 31 courses (97%) were above 700 microM. Only 1 patient developed severe hepatotoxicity as adverse effect. Total body clearance of MTX decreased in 4 patients when weekly MTX chemotherapy was performed for 3 consecutive weeks. Although the clearance was changed, the average MTX concentrations were maintained at about 700 microM by the PK individualization. The 5-year survival rate was 77.8% (7 of 9 patients), and all of them have survived for more than 9 years. This PK individualization is safe and useful for tailoring high-dose MTX therapy to achieve therapeutic levels.

Demonstration of either endogenous recurrence or exogenous reinfection by restriction endonuclease cleavage analysis of herpes simplex virus from patients with recrudescent genital herpes.

By using restriction endonuclease (RE) cleavage analysis, either endogenous recurrence or exogenous reinfection of herpes simplex virus (HSV) was clarified in 45 male and 20 female subjects with recrudescent genital herpes. All of the plural (two to ten) isolates from 63 (205 isolates) out of 65 subjects (97%) were HSV-2. Two isolates from only one of 65 subjects (1.5%) were HSV-1, and they showed the same RE profile. In addition, an HSV-1 and five HSV-2 isolates were obtained from the remaining one female patient (1.5%), indicating that an exogenous HSV-1 strain has been reinfected during HSV-2 recrudescences. HSV-2 isolates were furthermore classified into genotypes of HSV-2 using 16 different RE markers with five REs. Two hundred and ten HSV-2 isolates from 64 subjects were classified into 27 distinct genotypes, in which some predominant genotypes and seven new genotypes were found. Plural HSV-2 isolates obtained from 63 out of 64 subjects, including one subject from whom an HSV-1 and five HSV-2 strains were isolated, were classified into the same genotypes, indicating that they may be regarded as recrudescent genital herpes by the reactivation of the same endogenous strain. However, the RE profiles of two HSV-2 strains from the remaining one subject were different. Thus, it was finally found that only two out of 65 subjects (3%) were reinfected with exogenous strains. These results lead to the conclusion that almost all recrudescent genital herpes are due to the reactivation of an initially infected HSV-2 strain, and are occasionally due to reinfection with distinct HSV strains of either the same or a different type.

Genomic comparison of herpes simplex virus type 1 isolates from Japan, Sweden and Kenya.

One-hundred and seventy-two epidemiologically unrelated herpes simplex virus type 1 (HSV-1) strains isolated in Japan (104 strains) and Sweden (68 strains) were compared by analysis of their genome structures using four restriction endonucleases, BamHI, KpnI, SalI and HindIII. In addition, 32 Kenyan HSV-1 isolates previously compared to Japanese isolates were included for further comparison with the Swedish isolates. Remarkable and statistically significant differences were found between the HSV-1 isolates from the three countries. One-hundred and thirty cleavage sites were examined, and it was shown that isolates from two of the three countries were statistically distinguishable at 27 of these loci. Pairwise comparison between isolates from Japan and Sweden, Kenya and Sweden, and Japan and Kenya revealed variation in 18, 16 and 23 sites, respectively. By considering gains and losses of 19 sites, the total of 204 strains could be classified into 92 distinct cleavage patterns. Isolates from the three countries could be distinguished from each other by the pattern, except for one Swedish and two Kenyan isolates which shared a pattern. Twenty-one fragments that were present or absent only in individual isolates from one or other of the three countries could be detected. These results show that HSV-1 strains from geographically separate countries or anthropologically different races have distinct distributions of endonuclease recognition sites.

Genome variations in herpes simplex virus type 2 strains isolated in Japan and Sweden.

One-hundred and twenty-three epidemiologically unrelated strains of herpes simplex virus type 2 (HSV-2) isolated in Japan and Sweden (68 Japanese and 55 Swedish isolates) were compared by analysis of their genomes using five restriction endonucleases: BamHI, KpnI, EcoRI, HindIII and Bg/II. Seven of the 93 restriction sites examined showed statistically significant variation between isolates from the two countries. However, HSV-2 isolates were less variable than the HSV-1 isolates previously analysed from the same countries. Using 12 restriction sites as markers, the HSV-2 isolates were classified into 41 cleavage patterns; 17 were specific for Japanese isolates and 15 were specific for Swedish isolates. Correlation coefficients between some sets of 12 markers were significant, but significant correlations between Japanese and Swedish isolates were distinct for each country. Both Japanese and Swedish isolates were assigned to three major patterns with no significant difference in incidence. In contrast, in two other major patterns, differences in incidence between the isolates were statistically significant. These results suggest that HSV-2 populations in geographically separated countries have distinct cleavage site distributions.

Subtypes of herpes simplex virus type 1 in Japan: classification by restriction endonucleases and analysis of distribution.

An attempt was made to classify herpes simplex virus type 1 (HSV-1) isolates into subtypes on the basis of the combination of the gain or loss of specific cleavage sites of HSV-1 genomes with each of three restriction endonucleases (Bam HI, Kpn I, and Sal I). According to the criteria we used for the determination of HSV-1 subtypes, 93 strains of HSV-1 that were isolated in three areas of Japan (Sapporo, Tottori, and Kagawa) were tentatively classified into eight subtypes: subtypes A-H. The bulk of the strains (84 of 93) fell into three subtypes: A, C, and H. There were highly significant differences (P less than .01) in the proportion of subtypes A and H that were isolated in Sapporo as compared with those isolated in Tottori and in Kagawa, which are geographically far from Sapporo. No significant differences, however, were found in subtypes isolated in Tottori as compared with those isolated in Kagawa, which are geographically close to each other. These data suggest that there might be a correlation between the genome structure of HSV-1 and the areas of their isolation in Japan.

Restriction endonuclease cleavage analysis of herpes simplex virus isolates obtained from three pairs of siblings.

Cleavage of herpes simplex virus type 1-infected cell DNA with restriction endonucleases showed that profiles of paired isolates obtained from three groups of siblings were essentially identical. This finding is different from that for profiles of other paired isolates that are epidemiologically unrelated. One set of paired isolates of the three had completely identical profiles. However, two other sets of paired isolates yielded minor heterogeneity in fragments derived from the regions spanning the unique repeat junction and repeated regions of the herpes simplex virus type 1 genome. This suggests that the regions of the herpes simplex virus genome are variable during viral DNA replication. This finding also supports the hypothesis that the same variants tend to be transmitted and thereafter perpetuate within a family cluster.