Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice.

Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

Effects of the combined administration of risedronate and menatetrenone on bone loss induced by tacrolimus in rats.

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.

[Selection of Chemotherapy Regimen on the Basis of Monitoring NLR and Soluble PD-L1 during CRC Chemotherapy].

AIM: It is known that the neutrophil-to-lymphocyte ratio(NLR)is associated with outcomes in patients with cancer. In this study, changes in the NLR and soluble programmed death-1 ligand-1(sPD-L1)levels were assessed in patients with metastatic colorectal cancer treated with chemotherapy. METHODOLOGY: Ten patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to April 2017 at the Niitsu Medical Center Hospital. The NLR was calculated based on complete blood counts obtained prior to the administration of chemotherapy. Serum sPD-L1 levels were measured by enzyme-linked immunosorbent assay. NLR and sPD-L1 level changes from baseline were compared with tumor response and tumor markers. RESULTS: A relationship was found between sPD-L1 levels and NLR after the treatment of metastatic colorectal cancer(r=0.241, p=0.0459). Decreased sPD-L1 levels were associated with reduced NLR and tumor marker levels. Increased sPD-L1 levels were not related to elevated tumor marker levels. CONCLUSION: Changes in the NLR and sPD-L1 levels during chemotherapy may have a uniquely predictive value in patients with CRC treated with chemotherapy.

Effects of the calcineurin inhibitors cyclosporine and tacrolimus on bone metabolism in rats.

Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats.

Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a long-term administration of gabapentin should be regularly monitored for changes in bone mass.

[The Changes in the Neutrophil-to-Lymphocyte Ratio Can Predict the Timing of Chemotherapeutic Regimen Alteration in Patients with Metastatic Colorectal Cancer].

AIM: In order to determine if the changes in the neutrophil-to-lymphocyte ratio(NLR)can predict the timingof regimen alteration, the outcome of chemotherapy for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Thirty patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to December 2015 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to administration of chemotherapy and at the time of the best response. We defined the period with an NLR≤2.5 as the total interval of an NLR≤2.5. The role of the NLR in overall survival was determined by univariate and multivariate Cox regression models. RESULTS: The median overall survival was 27 months in patients with an NLR≤2.5(n=22)and 11 months in those with an NLR>2.5 (n=8)at the best response(p<0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The patients who survived for more than 3 years were introduced to a second-line treatment prior to achievingan NLR>2.5. The period with an NLR≤2.5(p=0.001)and prechemotherapy CA19-9(p<0.0001)were independent, significant predictors of better survival in multivariate analysis. CONCLUSION: The introduction of a new chemotherapeutic regimen prior to achievingan NLR>2.5 predicted better survival in patients with mCRC.

Effects of the antiepileptic drugs topiramate and lamotrigine on bone metabolism in rats.

Long-term treatment with antiepileptic drugs (AED) is associated with an elevated risk of bone fracture due to decreased bone mineral density (BMD). Phenytoin has been shown to affect bone metabolism adversely, whereas newly developed AEDs have not been studied. This study evaluated the effects of topiramate and lamotrigine on bone metabolism in rats. Five-week-old male Sprague-Dawley rats were treated orally with phenytoin (20 mg/kg), topiramate (5 or 20 mg/kg), or lamotrigine (2 or 10 mg/kg) daily for 12 weeks. Phenytoin reduced bone strength, measured by maximum load to failure of the femoral mid-diaphysis, along with reduced femur total BMD. Serum tartrate-resistant acid phosphatase-5b levels significantly increased after phenytoin treatment, while serum osteocalcin levels decreased after topiramate 20 mg/kg treatment. Furthermore, osteoblast surface and bone mineralizing surface were significantly lowered by topiramate. Lamotrigine treatment did not affect bone strength, BMD, or bone turnover. We demonstrated that phenytoin treatment significantly increased bone resorption and lowered BMD and bone strength. Since lamotrigine did not affect bone metabolism, it can be concluded that lamotrigine is safety medicine for bone health. Topiramate was associated with decreased bone formation, which may affect bone strength and BMD with chronic use. Thus, patients taking topiramate should be monitored for changes in BMD to avoid risk of fracture.

Effect of the antidiabetic agent pioglitazone on bone metabolism in rats.

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonists used as therapy for type 2 diabetes. However, clinical studies reported that the therapeutic modulation of PPARγ activity using TZDs may induce negative effects on bone metabolism. This study aimed to evaluate the effect of the TZD pioglitazone on bone metabolism in rats. Male Wistar rats were treated orally with pioglitazone 5 or 20 mg/kg daily for 24 weeks. Bone strength was evaluated using a 3-point bending method, and bone histomorphometry was analyzed. Bone mineral density (BMD) was measured using quantitative computed tomography, and serum biochemical markers were examined. Pioglitazone caused a decrease in cortical and trabecular BMD of whole femur. A reduction in bone strength properties of the femoral mid-diaphysis was observed in the 20 mg/kg pioglitazone treated group. Bone histomorphometric analysis revealed that osteoblast surface and mineralizing surface were decreased, whereas osteoclast surface and number were increased after treatment with 20 mg/kg pioglitazone. Altogether, this study demonstrated that pioglitazone may repress bone formation and facilitate bone resorption. The resulting imbalance of bone metabolism leads to a reduction in BMD with a subsequent increase in bone fragility.

[Change of Blood Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients with Metastatic Colorectal Cancer].

AIM: The impact of neutrophil-to-lymphocyte ratio(NLR)changes on the outcome of chemotherapy for metastatic colorectalcancer (mCRC)was analyzed retrospectively. METHODOLOGY: Twenty seven patients with unresectable mCRC were administered chemotherapy from January 2005 to December 2014 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to the administration of chemotherapy and at the best response. We defined the period with NLR≤2.5 as the totalintervalof NLR≤2.5. The impact of NLR on overallsurvivalwas determined using univariate and multivariate Cox regression models. RESULTS: The median overall survival was 26 months in patients with an NLR≤5(n= 22), and 11 months in those with an NLR>5(n=5)before chemotherapy(p=0.03). The median overall survival was 31 months in patients with an NLR≤2.5(n=19), and 11 months in those with an NLR>2.5(n=8)at the best response(p< 0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The period with an NLR≤2.5 was the only independent, statistically significant predictor of better survival in multivariate analysis(p=0.001). CONCLUSION: The change of NLR may be a dynamic predictor of better survivalin patients with mCRC.

[Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer].

AIM: The effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Twenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B). RESULTS: The objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death. CONCLUSION: Pharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.

[Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report].

A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit.

Distribution of vitamin K2 in subchondral bone in osteoarthritic knee joints.

PURPOSE: Vitamin K may have multiple effects on articular cartilage and subchondral bone that could modulate the pathogenesis of osteoarthritis (OA). The purpose of this study was to evaluate the distribution of vitamin K2 in harvested bones obtained during total knee arthroplasty in knee OA patients. METHODS: High-performance liquid chromatography was used to measure vitamin K2 in harvested bones obtained during 58 TKA procedures. Vitamin K2 levels were analysed in the medial (FM) and lateral (FL) femoral condyles and in the medial (TM) and lateral (TL) tibial condyles. RESULTS: There was significantly more vitamin K2 in the lateral femoral and tibial condyles than in the corresponding medial condyles (FL vs. FM, p < 0.0001; TL vs. TM, p < 0.0001). There was significantly more vitamin K2 in the FL than in the TL (p = 0.003), and in the FM, vitamin K2 levels were higher than those of the TM, although this was not significant (n.s.). There were no significant differences in vitamin K2 levels in men versus women nor was there a significant correlation with age. CONCLUSIONS: This study suggested that vitamin K2 might affect bone turnover since medial condyles showing advanced OA had lower vitamin K2 levels, while lateral condyles showing less advanced OA contained more vitamin K2. Gender and age were not correlated with vitamin K2 localization. All cases had Grade IV OA, and this study suggested that OA grade might be important in controlling the vitamin K2 levels in human bones.

[Effect of pylorus-preserving pancreaticoduodenectomy on serum levels of 5-fluorouracil during S-1 treatment for pancreaticobiliary malignancy].

AIMS: The aim of this study was to evaluate the effect of surgical procedures on the serum levels of 5-fluorouracil (5-FU) in patients undergoing S-1 treatment for pancreaticobiliary malignancy. METHODOLOGY: From January 2003 through December 2008, 27 chemotherapy-naive patients who underwent a surgical procedure for pancreaticobiliary malignancy received S-1 chemotherapy for unresectable or recurrent disease. The primary site of disease was: the extra hepatic bile duct (n=10); gallbladder (n=8); pancreas (n=6); or ampulla of Vater (n=3). The surgical procedure was: pylorus-preserving pancreaticoduodenectomy (PPPD) (n=6); combined major hepatic and bile duct resection (n=6); bilioenteric anastomosis (n=4); or exploratory laparotomy (n=11). S-1 (80-120 mg/day) was administered orally twice daily for 28 days, followed by 14 days without therapy. Subsequently, the serum levels of 5-FU were measured using the HPLC-UV method. RESULTS: The median number of cycles administered per patient was 6 (range, 2-13). Although grade 3 watery eye developed in one patient, neither grade 4 toxicities nor treatment-related deaths were observed. The overall response rate was 19%, the median overall survival time was 9 months, and the 1-year cumulative survival rate was 11%. The maximum levels of 5-FU in the sera of individual patients differed significantly according to the surgical procedure (Kruskal-Wallis test; p=0. 0049); the patients who underwent PPPD had the highest 5-FU levels, as compared with the other patients (Mann-Whitney test; p= 0.003). CONCLUSIONS: The type of operative procedure appears to influence the serum levels of 5-FU in S-1-treated surgical patients with pancreaticobiliary malignancy. Given the possibility of elevated levels of 5-FU in the sera of patients who are treated with S-1 after PPPD, adverse events must be monitored carefully in this cohort.

[Pharmacokinetic monitoring of 5-fluorouracil may improve the clinical benefit with an individualized regimen-a case report].

Serum levels of 5-fluorouracil(5-FU)were measured in a patient receiving pharmacokinetic modulation chemotherapy( PMC), with 5-FU, as well as a combination of oxaliplatin and infusional 5-FU plus leucovorin(FOLFOX). A 77- year-old man presented with unresectable multiple hepatic metastases after abdominoperineal resection of rectal / carcinoma, and was successfully treated by PMC. The patient initially received infusional 5-FU at 750 mg/m(2) once a week, and showed a partial response. Serum 5-FU levels were higher at night, and the peak concentration of 5-FU was / 398 ng/mL. After 13 months of PMC, second-line chemotherapy with FOLFOX was initiated because new liver metastases had appeared. After 4 cycles of FOLFOX4, progression was observed, and the concentration profile of 5-FU / was measured. The area under the concentration vs. time curve(AUC ngxh/mL)was smaller with FOLFOX4 than with PMC, so the FOLFOX6 regimen was tried instead. The AUC increased and disease progression was suppressed. This case shows that individual adjustment of the dose and regimen based on pharmacokinetic monitoring can increase the clinical benefit of fluorouracil.

[Team-based medical care can improve tailor made chemotherapy for colorectal cancer].

We report that team-based medical care has an important role in tailor made chemotherapy for colorectal cancer. We organized a chemotherapy support team to facilitate the early detection of toxicity and to get hold of therapeutic needs in individual patients. We also measured the circadian variation of 5-fluorouracil plasma concentrations to permit tailor dosed chemotherapy. To date, the chemotherapy support team has managed the performance of pharmacokinetic modulating chemotherapy in 30 patients with unresectable or recurrent colorectal cancer. The median survival time was 19 months after the first-line chemotherapy and 14 months after the second-line treatment. Our results suggest that team-based medical care is practically useful for tailor made chemotherapy in patients with colorectal cancer.