Effectiveness of Clipping for Definitive Colonic Diverticular Bleeding in Preventing Early Recurrent Bleeding

Objective Clipping is a common technique for managing colonic diverticular bleeding (CDB), despite the lack of published evidence regarding its effectiveness. We aimed to evaluate the effectiveness of clipping for CDB in preventing early recurrent bleeding. Methods This dual-center retrospective study included 93 patients who underwent emergency hospitalization for bloody stool, diagnosed with definitive CDB, and treated with clipping or conservative treatment. The primary outcome was early recurrent bleeding. A logistic regression analysis was performed to assess the association between the occurrence of early recurrent bleeding and clipping with adjustment for propensity scores. Secondary outcomes included death, transfusion, length of hospitalization, need for transcatheter arterial embolization or surgery, and adverse events. Results The patient characteristics were similar between the clipping (n=85) and conservative treatment (n=8) groups. The rate of early recurrent bleeding was significantly lower in the clipping group than in the conservative treatment group [23.5% (20 cases) vs. 75% (6 cases), p=0.005]. In the propensity score-adjusted logistic regression analysis, the odds ratio for early recurrent bleeding in the clipping group was 0.094 (95% confidence interval, 0.008-0.633, p=0.026). Secondary outcomes were not significantly different between the two groups. Stigmata of recent hemorrhage (SRH) at the time of recurrent bleeding was identified in 79.2% of patients (19/24). In the clipping group, recurrent bleeding was observed in 62.5% of cases (10/16) from the same diverticulum. However, early recurrent bleeding tended to be less likely with direct clipping (p=0.072). Conclusion Clipping for definite CDB was more effective in preventing early recurrent bleeding than conservative treatment.     

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very‐low‐density lipoprotein (VLDL) and low‐density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration‐to‐dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (r_s  = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (r_s  = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high‐density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (r_s  = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein‐binding and decreased metabolism of amiodarone.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Lipoproteins can carry not only serum lipids but also certain lipophilic compounds such as amiodarone. Changes in the lipoprotein‐binding of amiodarone may lead to highly variable pharmacokinetics and poor concentration–effect relationships of the drug.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the association between serum amiodarone concentration and serum lipid levels in patients with arrhythmia, as well as the lipoprotein‐binding and metabolism of amiodarone in the hyperlipidemic state.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Serum amiodarone concentration is increased in patients with hypertriglyceridemia and it is positively correlated with serum triglyceride levels. These results are attributable to an increase in the circulating lipoprotein‐bound form of amiodarone and decreased metabolism of the drug in the hypertriglyceridemic state.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Changes in the lipoprotein‐binding of amiodarone can help explain differences in the pharmacokinetics and pharmacodynamics of amiodarone related to normotriglyceridemic and hypertriglyceridemic states.     

Prediction of human pharmacokinetics for low‐clearance compounds using pharmacokinetic data from chimeric mice with humanized livers

Development of low‐clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CL_int) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro–in vivo extrapolation is widely used to predict human CL, its application has been limited for low‐CL_int compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB‐mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low‐CL_int compounds with no significant turnover in a human hepatocyte assay was investigated using PXB‐mouse methods, such as single‐species allometric scaling (PXB‐SSS) approach and a novel physiologically based scaling (PXB‐PBS) approach that assumes that the CL_int per hepatocyte is equal between humans and PXB‐mice. The percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 89% and 100%, respectively, for both PXB‐SSS and PXB‐PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB‐mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB‐mice are useful tools for predicting the human CL of low‐CL_int compounds that are slowly metabolized.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

It is important to identify low‐clearance (CL) compounds that are slowly metabolized during the drug discovery process, but the ability of in vitro–in vivo extrapolation to predict human CL decreases as the value of intrinsic CL (CL_int) decreases. Although chimeric mice with humanized livers (PXB‐mice) have been reported to be useful for predicting human CL, their applicability to low‐CL_int compounds with no significant turnover in human hepatocyte assays has not been clarified.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study examined the predictive accuracy of PXB‐mouse methods for low‐CL_int compounds.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In addition to the previously reported single‐species allometric scaling approach, we proposed a novel physiologically based scaling approach. Both methods displayed much greater predictive accuracy for low‐CL_int compounds than conventional multispecies allometric scaling approaches.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The findings should improve the accuracy of human pharmacokinetic prediction and enable efficient and safe first‐in‐human studies.     

IgA Vasculitis in an Oldest-old Patient Successfully Treated with Glucocorticoid

A 94-year-old man was diagnosed with immunoglobulin A vasculitis (IgAV), and losartan was initiated. His renal function rapidly deteriorated over a month; therefore, methylprednisolone was administered intravenously for three days followed by oral prednisolone. Renal function improvement and both proteinuria and hematuria remission were observed within six months. Prednisolone tapering was completed at eight months. In this case, we monitored the patient carefully and started glucocorticoids as soon as the patient''s renal function deteriorated. We were thus able to treat the patient with a relatively small dose of glucocorticoids in a short treatment period without any adverse events due to glucocorticoids.     

Temporal trends of subsequent breast cancer among women with ovarian cancer: a population-based study

Archives of Gynecology and Obstetrics - To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers. This is a retrospective study examining the...     

Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380‐4062 bp for gBRCA1, and between 3249‐5681 bp and 6645‐7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.     

Enteral metallic stenting by balloon enteroscopy for obstruction of surgically reconstructed intestine

We present three cases of self-expandable metallic stent (SEMS) placement using a balloon enteroscope (BE) and its overtube (OT) for malignant obstruction of surgically reconstructed intestine. A BE is effective for the insertion of an endoscope into the deep bowel. However, SEMS placement is impossible through the working channel, because the working channel of BE is too small and too long for the stent device. Therefore, we used a technique in which the BE is inserted as far as the stenotic area; thereafter, the BE is removed, leaving only the OT, and then the stent is placed by inserting the stent device through the OT. In the present three cases, a modification of this technique resulted in the successful placement of the SEMS for obstruction of surgically reconstructed intestine, and the procedures were performed without serious complications. We consider that the present procedure is extremely effective as a palliative treatment for distal bowel stenosis, such as in the surgically reconstructed intestine.