Population pharmacokinetics and exposure-clinical outcome relationship of remdesivir major metabolite GS-441524 in patients with moderate and severe COVID-19.

Although remdesivir, a prodrug of nucleoside analog (GS-441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID-19) treatment, its pharmacokinetics (PKs) in patients with COVID-19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS-441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure-clinical outcome relationship. The serum concentrations of remdesivir and GS-441524 (102 points in 39 patients) were measured using liquid chromatography-tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2-5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42-85), 1.74 m2 (1.36-2.03), and 68 mL/min/1.73 m2 (33-113), respectively. A compartment model with first-order elimination combined with remdesivir and GS-441524 was used for nonlinear mixed-effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS-441524 was eliminated relatively slowly (half-time = 17.1 h). The estimated apparent clearance (CL) and distribution volume of GS-441524 were 11.0 L/h (intersubject variability [ISV]% = 43.0%) and 271 L (ISV% = 58.1%), respectively. The CL of GS-441524 was significantly related to the eGFR (CL × [eGFR/68]0.745 ). The post hoc area under the curve of GS-441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS-441524 accumulation depended on eGFR in patients with COVID-19. However, no relevance of exposure-clinical outcome was not suggestive of the dose adjustment of remdesivir.

Population Pharmacokinetics of Nivolumab in Japanese Patients with Nonsmall Cell Lung Cancer.

BACKGROUND: Nivolumab is an antiprogrammed death-1 (PD-1) antibody used for immuno-oncological therapy of various cancers, including nonsmall cell lung cancer (NSCLC). This study aimed to characterize the real-world population pharmacokinetics (PK) of nivolumab in patients with NSCLC. METHODS: PK samples were collected by opportunistic sampling of Japanese patients with NSCLC treated with nivolumab monotherapy. Population PK analysis was performed using a two-compartment model in Nonlinear Mixed Effect Model. Patient-specific factors such as body weight, age, sex, serum albumin, estimated glomerular filtration rate, performance status, programmed cell death receptor ligand 1 expression in tumors, and treatment periods were evaluated as potential covariates for clearance. RESULTS: A total of 223 serum samples collected from 34 patients were available for analysis. The median (min-max) age and weight were 69 years (38-83 years) and 62.7 kg (36.8-80.5 kg), respectively. The mean (95% confidence interval) clearance estimate was 0.0064 L/h (0.0058-0.0070 L/h). The inclusion of the ALB level, estimated glomerular filtration rate, and treatment period significantly improved the model fit. CONCLUSIONS: A real-world nivolumab population PK model was developed using an opportunistic sampling strategy in Japanese patients with NSCLC. Further studies are warranted to characterize the exposure-response relationship and determine the optimal dosing regimens for these patients.

Association between 25-hydroxyvitamin D levels and COVID-19 severity.

BACKGROUND AND AIMS: Despite reports on the impact of vitamin D status on coronavirus disease 2019 (COVID-19) severity, the association between low vitamin D status and severe COVID-19 remains unclear. Moreover, researchers have not determined the aforementioned association in Japanese patients. This study aimed to investigate the association between 25-hydroxyvitamin D [25(OH)D] levels and COVID-19 severity in Japanese patients. METHODS: This retrospective observational study included 117 consecutive patients with COVID-19 admitted to the Kobe City Medical Center General Hospital between October 01, 2020, and January 31, 2021. We measured the serum 25(OH)D levels using blood specimens collected within 5 days of hospital admission using liquid chromatography-tandem mass spectrometry. RESULTS: There were 21 (17.9%), 73 (62.4%), 19 (16.2%) and 4 (3.4%) patients with severe deficiency (<10 ng/mL), deficiency (10-<20 ng/mL), insufficiency (20-<30 ng/mL), and sufficiency (≥30 ng/mL) of vitamin D, respectively. In univariate logistic regression analyses, lower serum 25(OH)D levels [odds ratio (OR) 1.18 per 1 ng/mL decrease, 95% confidence interval (CI) 1.04-1.33, p = 0.007] were significantly associated with invasive mechanical ventilation (IMV) or death. In a multivariate logistic regression analysis, low serum 25(OH)D levels [OR 1.22 per 1 ng/mL decrease, 95% CI 1.06-1.40, p = 0.005] were significantly associated with IMV or death. The cut-off value of serum 25(OH)D levels was 10.4 ng/mL, calculated by the receiver operating characteristic curve to detect the requirement for IMV or death. CONCLUSIONS: To the best of our knowledge, this is the first study to assess the association between vitamin D status and COVID-19 severity in Japanese patients. Low serum 25(OH)D level was detected as an independent risk factor for severe COVID-19 among Japanese patients.

Population pharmacokinetics of favipiravir in patients with COVID-19.

The antiretroviral drug favipiravir (FPV) inhibits RNA-dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID-19). However, its pharmacokinetics in patients with COVID-19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography-tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27-89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11-2.2 m2 ), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one-compartment model with first-order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID-19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID-19, but dose-dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.

Plasma concentration of amitriptyline and metabolites after resuscitation from cardiopulmonary arrest following an overdose: A case report.

It may need to pay attention to the sustention of moderate cardiotoxicity and delayed elevation of plasma 10-hydroxynortriptyline level in severe amitriptyline overdose case.

Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID-19.

Since December 2019, a novel coronavirus (severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID-19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID-19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high-performance liquid chromatography in patients with severe COVID-19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty-nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8-12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half-maximal effective concentration (9.7 µg/mL) against SARS-CoV-2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID-19.

Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex.

Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Aß) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Aß in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the α-C terminal fragment (α-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the α-secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in α-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP-1 facilitates the GluR1 membrane insertion through CREB activation and increases α-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Aß oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking.

[Familial type III hyperlipoproteinemia].

Familial type III hyperlipoproteinemia(HLP) is characterized by increased plasma triglyceride(TG) and plasma remnant lipoproteins(chyromicron remnants and VLDL remnants i.e. IDL). Remnants predispose affected subjects to premature or accelerated atherosclerosis. Clinical features of type III HLP with apo E2/2 genotype are examined in 26 Japanese patients. Mean levels of plasma TG, total cholesterol, LDL cholesterol and remnant cholesterol(RLP-C) were 374, 256, 74 and 49 mg/dL, respectively. High plasma RLP-C levels above 30 mg/dL and high plasma RLP-C/plasma TG ratio above 0.1 are very useful for diagnosis of type III HLP. Fifty-four point two percent of the patients had diabetes mellitus and 66.2 % of the patients had metabolic syndrome. Diabetes and obesity contribute to the occurrence of type III HLP with apo E2/2 genotype in Japan. Coronary heart disease(CHD) occurred in 41.7% of the patients. Type III HLP is strongly associated with atherosclerosis in Japan.

Apolipoprotein B-48 to triglyceride ratio is a novel and useful marker for detection of type III hyperlipidemia after antihyperlipidemic intervention.

AIM: Remnant lipoproteins are atherogenic and are accumulated in patients with type III hyperlipidemia (HL). Although type III HL is diagnosed by phenotyping apolipoprotein (apo) E, this procedure is time-consuming and inconvenient for routine clinical use. Clinical indices for screening type III HL in untreated HL patients have been proposed; however, in clinical settings, HL patients are promptly treated with lipid-lowering agents without diagnosing the underlying cause. We investigated whether existing clinical indices for screening type III HL as well as the apo B-48/triglyceride (TG) ratio, which was suggested to be related to the accumulation of small chylomicron (CM) remnants, are useful after the initiation of lipid-lowering therapies. METHODS: In 25 normolipidemic subjects and 191 treated HL patients (type I, n =6; IIa, 62; IIb, 66; III, 12; IV, 22; and V, 23) from Osaka University Hospital and related hospitals, fasting low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TG, and apolipoproteins were measured and clinical indices were evaluated statistically. RESULTS: Apo B-48 levels were significantly higher in patients with type I, III, and V HL, and TG levels were significantly higher in patients with type I and V HL. The apo B-48/TG ratio was significantly higher only in patients with type III HL compared with other types of HL (p<0.001), and was statistically significant among the other clinical indices (AUC-ROC value, 0.895; cut-off value, 0.110). CONCLUSION: The apo B-48/TG ratio is a novel and useful marker for detecting type III HL even after the initiation of lipid-lowering interventions.

Background to discuss guidelines for control of plasma HDL-cholesterol in Japan.

A decrease in high density lipoprotein-cholesterol (HDL-C) is a strong risk factor for atherosclerotic disorders in Japan, probably more important than an increase in low density lipoprotein-cholesterol (LDL-C). While there are rational grounds for the argument that elevation of HDL-C leads to decreased risk, there has as yet been no direct evidence of such an effect. If elevation of HDL-C decreases the risk, this effect is expected throughout the normal range of HDL-C or perhaps even higher than that. Simulation based on epidemiological data indicated that it may eventually reduce the incidence of ischemic heart disease by 60-70% in Japan. In the risk management guideline, "low" HDL-C is presently defined as 40 mg/dL or below. While there is no evidence that strongly urges a change in this definition, the results of epidemiological studies support "The higher the HDL-C level, the lower the risk,"even in the "normal range". Elevation of the HDL-C level may reduce the risk, probably at least up to 70 mg/dL; however, there are no supportive data for this effect still being obtained over 80 mg/dL. Patients with homozygous CETP deficiency should be followed-up while controlling other risk factors, so as not to dismiss the possibility of a risk increase with an extremely elevated HDL-C level.

Management of type IIb dyslipidemia.

Although the Japan Atherosclerosis Society guideline for the diagnosis and prevention of atherosclerosis cardiovascular diseases for the Japanese population provides targets for low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol to prevent cardiovascular disease in patients with dyslipidemia, there is no guideline specifically targeting the treatment of type IIb dyslipidemia, which is one of the most common types of dyslipidemia, along with type IIa and type IV dyslipidemia. Type IIb dyslipidemia is important because it sometimes accompanies atherogenic lipid profiles, such as small, dense LDL, remnants, low HDL cholesterolemia. It is also associated with type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease (CKD), and most patients with familial combined hyperlipidemia (FCHL) show this phenotype; therefore, it is assumed that patients with type IIb dyslipidemia have a high risk for cardiovascular disease. Thus, the management of type IIb dyslipidemia is very important for the prevention of cardiovascular disease, so we have attempted to provide a guideline for the management of type IIb dyslipidemia.

Diagnosis and management of type I and type V hyperlipoproteinemia.

Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by a decisive abnormality of the lipoprotein lipase (LPL)- apolipoprotein C-II system, whereas the cause of type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. Since the relationship of hypertriglyceridemia with atherosclerosis is not as clear as that of hypercholesterolemia, and since type I and V hyperlipoproteinemia are relatively rare, few guidelines for their diagnosis and treatment have been established; however, type I and V hyperlipoproteinemia are clinically important as underlying disorders of acute pancreatitis, and appropriate management is necessary to prevent or treat such complications. Against such a background, here we propose guidelines primarily concerning the diagnosis and management of type I and V hyperlipoproteinemia in Japanese.

Lipids behavior and adverse effects for oral antidiabetic agents in patients with Type 2 diabetes treated with sulfonylureas alone based on systematic review.

The secondary and adverse effects when biguanides, alpha-glycosidase inhibitor or thiazolidine derivative was used with sulphonylurea agent (SU) as compared with those with SU alone in Type 2 diabetes patients by using Systematic Review. Two-agent concurrent treatment groups, taken from studies in which subjects were assigned to a group given only a sulfonylurea agent and a group given a sulfonylurea agent with the other glycemic control agent (combination of a sulfonylurea agent and a biguanide agent (I), combination of a sulfonylurea agent and an alpha-glucosidase inhibitor (II), and combination of a sulfonylurea agent and thiazolidinedione (III)), were studied in a randomized controlled trial. The secondary efficacy outcome measures were total cholesterol (TC), triglyceride (TG), HDL-C, LDL-C, and change in body weight. The incidence of hypoglycemia, feeling of fullness, diarrhea, liver dysfunction, and edema was investigated as a safety outcome measure, and the clinical significance of concurrent treatment with a sulfonylurea agent in addition to the other glycemic control agent was investigated. With respect to (II), an antidiabetic effect was showed. As for (III), it had the disadvantage of increased body weight. Furthermore, increase of HDL-C levels, in particular, was observed. The improving effect of (III) on serum lipids may be clinically effective for considering the pathologic condition of diabetes, which is often complicated by hyperlipidemia.

A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.

Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive inherited disorder, characterized by marked hypertriglyceridemia, eruptive xanthoma, hepatosplenomegaly, recurrent attacks of pancreatitis, and markedly low or absent LPL activity in postheparin plasma. A majority of LPL deficient patients have been reported to have point mutations in the LPL gene; however, we find a complex deletion-insertion mutation by Alu elements, mobile retrotransposons, in a patient with LPL deficiency. This patient suffered from acute pancreatitis, showed chylomicronemia and lacked detectable LPL activity or mass in her postheparin plasma. Southern blot analysis and long-range PCR of the patient's DNA demonstrated a 2.2-kb deletion encompassing exon 2. Sequence analysis revealed (1) a 2.3-kb deletion between an AT-rich region adjacent to an Alu element in intron 1 and another Alu element in intron 2; (2) an insertion of approximately 150bp 5'-truncated Alu sequence with a poly (A) tail at the deletion point. The inserted sequence belongs to Alu Yb9, the youngest subfamily of Alu elements. The deletion occurred at the consensus cleavage site (3'-A|TTTT-5') without target site duplication. These findings indicated that Alu retrotransposition caused the complex deletion-insertion. The patient was homozygous for this complex mutation, which eliminates exon 2 and leads to LPL deficiency. To our knowledge, the patient is the first case with LPL deficiency due to a complex deletion-insertion mediated by Alu repetitive elements.

Plasma lipid levels and nutritional intake in childhood- and adolescence-onset young type 1 diabetic patients in Japan.

In recent years, the diet of the young Japanese has changed to westernized diet with high fat content. Childhood-onset type 1 diabetic patients have had good diet training since onset of the disease, but adolescence-onset type 1 diabetic patients have already established westernized diet habit at onset of the disease, which may not be easily improved. We hypothesized that a difference of the age at onset of the disease may affect nutritional status and plasma lipid levels in Japanese type 1 diabetic patients. Plasma lipid levels and nutritional intake were compared between childhood- and adolescence-onset young type 1 diabetic patients. Our research involved 9 childhood-onset type 1 diabetic patients (childhood group), 11 adolescence-onset type 1 diabetic patients (adolescent group), and 24 age-matched non-diabetic control subjects. There were no significant differences in age and body mass index (BMI), daily energy intake among the childhood group, the adolescent group, and the non-diabetic control group. There was no significant difference in HbA1c level between the childhood group and the adolescent group. The adolescent group had significantly higher plasma levels of total cholesterol, triglyceride, and low-density lipoprotein (LDL)-cholesterol than the childhood group (p<0.01, <0.05, and <0.001, respectively) or the control group (p<0.001, <0.001, and <00.001, respectively). The adolescent group had significantly lower plasma level of high-density lipoprotein (HDL)-cholesterol than the childhood group (p<0.05). The adolescent group had significantly higher percentage energy intake from fat (31.7%, p<0.001), higher saturated fatty acids intake (19.0g/day, p<0.01), and higher cholesterol intake (428mg/day, p<0.05), and significantly lower polyunsaturated fatty acids intake (13.4g/day, p<0.05) and lower fiber intake (9.5g/day, p<0.01) than the childhood group. It is concluded that young Japanese type 1 diabetic patients with onset of adolescence have lipid abnormalities, which may be mainly caused by westernized dietary habits.

Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients.

OBJECTIVE: The aim of this study was to investigate the effect of apolipoprotein (apo)E4 allele on plasma LDL cholesterol response to calorie-restricted diet therapy in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Twenty-four diabetic patients with the apoE3/3 genotype and 11 diabetic patients with the apoE4/3 genotype were recruited. Participants were hospitalized for calorie-restricted diet therapy (25.0 kcal. kg body wt(-1). day(-1)) for 14 days. Body weight, fasting plasma glucose (FPG) levels, and plasma lipid levels on hospital days 1 and 14 were compared between the two apoE genotype groups. RESULTS: There were no significant differences in baseline FPG levels, HbA(1c) levels, BMI, and plasma levels of total cholesterol, triglyceride, and HDL cholesterol between the two apoE genotype groups, but baseline plasma levels of LDL cholesterol were significantly higher in the apoE4/3 group than in the apoE3/3 group. Body weight decreased slightly and FPG levels decreased significantly after diet therapy in both apoE genotype groups. In the apoE3/3 group, only plasma levels of triglyceride decreased significantly after diet therapy, whereas in the apoE4/3 group, plasma levels of triglyceride, total cholesterol, and LDL cholesterol decreased significantly after diet therapy. The decrease (percentage of change) in total cholesterol (-16.3 vs. -6.6%) and LDL cholesterol (-15.6 vs. -0.7%) after diet therapy was significantly greater in the apoE4/3 group than in the apoE3/3 group. CONCLUSIONS: Calorie-restricted diet therapy is more effective in reducing plasma LDL cholesterol in type 2 diabetic patients with the apoE4 allele.

Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells.

To look for new candidates for agents to use in maintenance therapy for myeloma patients, the growth inhibitory effects of a 3-hydroxy-3-mehtylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), simvastatin, was analyzed using human myeloma cell lines. Several investigations have indicated growth reduction in certain lineages of cancer cells including one report on myeloma, and inhibitory effects of statins on GTPases and involving MAP-kinases. Most (12 out of 13) myeloma lines examined showed growth inhibition when cultured with various concentrations (1-30 microM) of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Furthermore, myeloma cells treated with simvastatin clearly showed inactivation of various MAP-kinase pathways such as ERK1/2, MEK1/2, JNK, and p38. Based on these findings, statins may be suitable for clinical usage in maintenance therapy for myeloma patients.

IL-6 is a key factor in growth inhibition of human myeloma cells induced by pravastatin, an HMG-CoA reductase inhibitor.

Although recent developments in initial chemotherapeutic regimens and stem cell transplantation have achieved improvements of initial remission for myeloma patients, relapse and recurrence are still major problems. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been developed for treating hyperlipidemia. Recently, there have been several reports concerning the effects of statins on cancer cells including liver, colon, leukemia, malignant B, stomach, and breast cells. In this study, the in vitro effects of pravastatin on human myeloma cells and the factors closely related to its growth inhibitory effects were examined. Although concentrations were higher than those used clinically, 4 out of 10 myeloma lines showed growth inhibition by pravastatin. The study of factors related to the inhibition indicated IL-6 is important. Indeed, rhIL-6 abolished pravastatin-induced growth inhibition in KMS-21BM cells which did not express IL-6. Statins may be useful in maintenance therapy for myeloma after the screening of IL-6 status.

Rescue of beta-cell exhaustion by diazoxide after the development of diabetes mellitus in rats with streptozotocin-induced diabetes.

In this study, we attempted to demonstrate the possibility of rescuing beta-cell exhaustion by chronic intervention with an ATP-sensitive K(+) channel opener, diazoxide, which reduces the stress of insulin secretion, using rats with streptozotocin-induced diabetes. Three groups of male Wistar rats: (i) controls (n = 7), (ii) streptozotocin (30 mg/kg i.v.)-induced diabetic rats (n = 10), and (iii) streptozotocin-induced diabetic rats treated with diazoxide 30 mg/kg for 6 weeks (n = 10), were studied. Intraperitoneal 2-g glucose tolerance testing was performed every 2 weeks, and pancreatic tissue was examined after 6 weeks of treatment with diazoxide. The insulin concentration in diabetic rats treated with diazoxide was significantly higher than in diabetic rats without diazoxide (6.6 +/- 1.6 vs. 2.4 +/- 1.0 ng/ml, P < 0.05). The islet size and its cell number were reduced in diabetic rats compared to those in normal control rats. In normal control rats, 88% of pancreatic islet cells were insulin-positive, while 50% or less were positive in diabetic rats. However, islet size and its cell size appeared to be well preserved by diazoxide treatment. The average mass of islets in diazoxide-treated rats was significantly larger than that in untreated control animals. In addition, the degree of immunostaining for insulin was obviously higher in rats treated with diazoxide than in rats without diazoxide. Pancreatic proinsulin mRNA was restored in rats treated with diazoxide. The present study demonstrated that diazoxide protected from further damage the pancreatic beta-cells both functionally and morphologically in streptozotocin-induced diabetic rats by suppression of excessive insulin secretion. Our results strongly suggest the possibility that chronic intervention with an ATP-sensitive K(+) channel opener prevents the progress of deranged beta-cell function even after the development of diabetes mellitus.