Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

A Multicenter Retrospective Observational Study Analyzing the Effect of Polypharmacy on Oxycodone Tolerability.

Polypharmacy is becoming increasingly troublesome in the treatment of cancer. The aim of this study was to explore the effects of concomitant polypharmacy comprising drugs that inhibit CYP3A4 and/or CYP2D6 on the oxycodone tolerability in patients with cancer. We conducted a multicenter retrospective study encompassing 20 hospitals. The data used for the study were obtained during the first 2 wk of oxycodone administration. The incidence of oxycodone discontinuation or dose reductions due to side effects and oxycodone-induced nausea and vomiting (OINV) were compared between patients not treated with either inhibitor and those treated with concomitant CYP3A4 or CYP2D6 inhibitors. The incidence of oxycodone discontinuation or dose reductions in patients treated with ≥3 concomitant CYP2D6 inhibitors (18.2%) tended to be higher than that in patients without this treatment (8.2%; p = 0.09). Moreover, the incidence of OINV in patients treated with 2 concomitant CYP3A4 inhibitors (29.8%) was significantly higher than that in patients without this treatment (15.5%; p = 0.049). Multivariate analysis showed that more than two concomitant CYP3A4 inhibitors and no concomitant use of naldemedine were independent risk factors for OINV. Concomitant polypharmacy involving CYP3A4 inhibitors increases the risk of OINV. Therefore, medications concomitantly used with oxycodone should be optimized.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

New-onset type 1 diabetes and Graves' disease after antiretroviral therapy in a patient with human immunodeficiency virus infection.

Patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy can develop autoimmune diseases, referred to as immune-inflammatory reconstitution syndrome. Nevertheless, only a few reports on the onset of type 1 diabetes as immune-inflammatory reconstitution syndrome are available. A 40-year-old Japanese man with HIV infection was initiated with antiretroviral therapy at the age of 29 years. He developed Graves' disease at 35 years and diabetes, with a hemoglobin A1c of 6.5%, and maintained insulin secretion at 38 years. His antiglutamic acid decarboxylase antibody level was >2,000 U/mL, and he was diagnosed with slowly progressive type 1 diabetes. At the age of 40 years, he was admitted to our hospital with diabetic ketosis. We retrospectively assayed his stored plasma samples for thyroid-stimulating hormone receptor antibody and antiglutamic acid decarboxylase antibody, which showed positive conversion after initiating antiretroviral therapy, suggesting that Graves' disease and type 1 diabetes developed as a probable result of immune-inflammatory reconstitution syndrome.

Clinical significance of tumor markers in patients with type 2 diabetes: a retrospective observational study.

Aim: To cross-sectionally and longitudinally investigate the association between tumor markers (Cancer embryonic antigen (CEA) Carbohydrate antigen 19-9 (CA19-9)) and malignancies in type 2 diabetes patients without evidence of malignancy. Materials and Methods: The study included 707 patients admitted for the treatment of diabetes from 1 August 2010 to 1 September 2018. Serum CEA and CA19-9 levels were measured for screening of malignancies at admission. Abdominal ultrasonography, computed tomography, and endoscopy were performed for close examination. The percentage of patients diagnosed with malignancy was calculated, and among those without malignancy, the incidence of malignancies was examined after discharge. Results: A total of 26 patients (3.7%) were newly diagnosed with malignancy during hospitalization. The optimal cut-off value of CEA and CA19-9 by receiver operating characteristic analysis was 5.0 ng/mL and 75 U/mL, and their positive predictive values (PPV) were 8.7% and 22.5%, respectively. The addition of CA19-9 to age, smoking status, body mass index, and glycated hemoglobin significantly improved classification performance for malignancy using net reclassification improvement (0.682, 95% CI 0.256-1.107) and integrated discrimination improvement (0.150, 95% CI 0.007-0.294). Among 681 patients without malignancies during hospitalization, 30 patients (4.4%) developed malignancies during an average follow-up of 3.9 years. CA19-9 (hazard ratio: 1.005, 95% CI: 1.003-1.008) was associated with the development of malignancies. Conclusions: PPV of serum CEA and CA19-9 for detecting malignancy was high in type 2 diabetes patients with poor glycemic control. Measuring CA19-9 was found to be valuable to cross-sectionally and longitudinally detect malignancies. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00594-x.

Analysis of drug adverse events in elderly patients based on the Japanese Adverse Drug Event Report Database.

WHAT IS KNOWN AND OBJECTIVE: Compared with the general adult population, pharmacokinetics and changes in drug responsiveness occur to a greater extent in the elderly. Interactions may occur between drugs used in combination to treat various diseases and may cause adverse events (AEs). We conducted a cross-sectional risk assessment of AEs in elderly patients based on information gathered from Japanese medical practices with the goal of obtaining information that will contribute to optimizing pharmacotherapy. METHODS: The Japanese Adverse Drug Event Report database was used to determine the incidence of AEs in elderly patients (aged 80 years or older) compared with patients aged less than 80 years old by evaluating the reporting odds ratio using the data obtained from reports. RESULTS AND DISCUSSION: Hypnotics and anxiolytics, as well as anticoagulants and theophylline, were identified as groups of drugs that warrant special attention in the elderly. Hypnotics and anxiolytics, especially those that are short-acting, tend to cause delirium and geriatric syndromes including falls and fractures. With respect to anticoagulants, no increase in the risk of bleeding was evident and the dose was believed to be properly adjusted; however, there was an increased risk of anemia. Theophylline toxicity tended to occur more frequently in the elderly, suggesting the need for drug monitoring. WHAT IS NEW AND CONCLUSION: Based on these cross-sectional studies, the evaluation of the risk of AEs for drugs commonly used in the elderly based on near real-world information was achieved.

Effect of manuka honey on human immunodeficiency virus type 1 reverse transcriptase activity.

Manuka honey (MkH), derived from New Zealand manuka tree (Leptospermum scoparium), is considered a therapeutic agent owing to its antibacterial, antioxidant, antifungal, antiviral, anti-inflammatory, and wound healing activities. In this study, the inhibitory effect of five honey types, including MkH, on HIV-1 RT activity was evaluated, using an RT assay colorimetric kit, according to the manufacturer's instructions with slight modifications. MkH exerted the strongest inhibitory effect in a dose-dependent manner, with a half maximal inhibitory concentration (IC50) of approximately 14.8 mg/mL. Moreover, among the MkH constituents, methylglyoxal (MGO) and 2-methoxybenzoic acid (2-MBA) were determined to possess anti-HIV-1 RT activity. MGO and 2-MBA in MkH were identified by High Performance Liquid Chromatography (HPLC) and Liquid Chromatograph - Mass Spectrometry (LC-MS/MS). The findings suggest that the inhibitory effect of MkH on the HIV-1 RT activity is mediated by multiple constituents with different physical and chemical properties.

Non-COVID-19 Patients with Life-threatening Diseases Who Visited a Fever Clinic: A Single-center, Observational Study in Tokyo, Japan.

Objective In fever clinics screening coronavirus disease (COVID-19), there could be patients with life-threatening diseases that physicians should not overlook. We exploratorily investigated the final diagnosis among non-COVID-19 hospitalized patients who visited the fever clinic. Methods This was a retrospective, observational, and single-centered study conducted in the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. We conducted a retrospective chart review of patients who visited the fever clinic in the NCGM from 11 March 2020 to 24 April 2020. Patients Patients who met the following clinical criteria visited the fever clinic in the NCGM: (1) body temperature >37.5°C, (2) any symptoms consistent with COVID-19 or (3) referral from local healthcare facilities. In the fever clinic, all patients who met the above criteria had severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test with nasopharyngeal swab specimens. Patients with severe symptoms or an unstable condition were sent to an outpatient clinic for infectious diseases for further evaluation and treatment. Results Among 1,470 patients who visited the fever clinic, 84 patients were hospitalized, and 45 of them were diagnosed as having COVID-19. Among the remaining 39 non-COVID-19 patients, there were nine patients with life-threatening diseases. The life-threatening diseases included acute heart failure, septic shock, pneumocystis pneumonia, peritonsillar abscess, and necrotizing fasciitis. Conclusion Physicians should evaluate each patient carefully while considering other life-threatening conditions even in such a COVID-19 pandemic era.

Evaluation of Tumor Tissue Fixation Effects of Formulation Modified Mohs Pastes in Mice and Their Water-Absorbing Properties.

Mohs paste (MP) is a hospital preparation containing zinc hydrochloride and zinc oxide starch. It is a topical medication used to fixate tissues for the removal of inoperable skin tumors and the management of hemorrhage and exudates, and to prevent foul odor resulting from secondary infections. However, it has problems, such as changes in hardness and viscoelasticity with time and liquefaction by exudate. It has been reported that the modified MP with D-sorbitol (S-MP) and the modified MP using the cellulose instead of starch (C-MP) have excellent physicochemical stability and better handling than original MP (O-MP). In this study, the effect of prescription improvement of MP on the pharmacological effect was examined with reference to water absorbing property, and its tumor tissue invasion fixation depth as an indicator. In the S-MP and C-MP, the amounts of water absorption did not differ significantly from those in the O-MP. The hardness of S-MP was decreased and liquefied like O-MP after absorbing water. In contrast, C-MP retained its form even after water absorption. The subcutaneous tumors in mice treated with modified MP formulations were measured for invasion fixation depth at 6 and 24 h after application. And the tissue status was observed using computed tomography. In all MPs, invasion fixation depth increased depending on application time. S-MP and O-MP depths did not differ significantly. The invasion depths of the C-MP significantly increased compared with those in the O-MP. These results suggest that C-MP had a high tissue fixation rate.

[Clinical Application of Basic Research on Mohs' Paste to Meet Medical Needs].

　Mohs' paste (MP), which is widely used in medical services as a specific hospital preparation, has been considered to have demerits, such as increased hardness after preparation and marked adhesiveness. However, factors associated with variations in its physical properties have not yet been clarified. Therefore, we conducted studies to clarify the physicochemical phenomena influencing such variations, and also examined prescription drug designs of MP preparations that are difficult to use clinically due to the above-mentioned demerits, with a view to improving their usability. Furthermore, with cooperation from the director of the Department of Palliative Care and Maintenance Therapy and certified wound ostomy and continence (WOC) nurses of Yokohama Minami Kyousai Hospital, we clinically applied an improved form of MP I. We also examined the effects of an improved MP II (designed as a stable formulation) in mice. This is an example of the clinical application of basic research to design a new clinical formulation in order to meet medical needs.

Preparation and Evaluation of Modified Mohs Paste without Starch.

Mohs paste is an external preparation containing zinc hydrochloride and zinc oxide starch as the main ingredient, and it is used for the palliative treatment of patients with surgically untreatable malignant tumors. However, it has problems, such as changes in hardness and viscoelasticity with time and liquefaction by exudate. To overcome these problems, we modified the formulation of Mohs paste by excluding starch, which is the cause of physical changes, and investigated the base. In the modified Mohs paste using the macrogol ointment for the base, no marked change with time was noted in the hardness, malleability, or elongation property, and the water-absorbing properties were equivalent to those of Mohs paste immediately after preparation. The hardness did not decrease even after absorbing water. The drug release rate increased 1.5 times with the modified Mohs paste. Based on these findings, the risk of liquefaction-associated damage of the surrounding skin decreased on using the modified Mohs paste, and preparing in advance became possible. These results suggest that the modified Mohs paste using the macrogol ointment for the base exhibits an equivalent effect for control of exudate and a high effect for tissue fixation.

Nurturing Pharmacists Who Contribute to Clinical Practice through Galenical-pharmaceutical Studies.

In clinical environments, difficulty in the uniform preparation of Mohs paste has been noted, due to variations in its physical properties, and despite preparations being based on the same prescriptions. Therefore, studies have been conducted to clarify the physicochemical phenomena influencing such variations, and then to develop a prescription design that will improve the usability of this product through the use of additives with sufficient safety, thereby addressing the above-mentioned demerit. An improved form of Mohs paste, not containing the starch that is responsible for the variations in physical properties, was developed in consideration of appropriate bases, and its pharmacological mechanisms were examined, with a focus on its hemostatic effects. Furthermore, clinical training regarding reliably consistent Mohs paste preparation was provided in medical institutions performing collaborative drug therapy management (CDTM).

Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9.

1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4'-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the K(m) and CL(int) values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K(m) or S50, Vmax and CL(int) or CLmax values for the 4'-glucuronidation of liver and intestinal microsomes between humans and monkeys. 3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4'-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.