Impact of Cachexia and Opioid Analgesic Cotreatment on Pregabalin Pharmacokinetics and Central Nervous System Symptoms in Cancer Patients.

BACKGROUND: Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment. METHODS: Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography. RESULTS: The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, ß = 0.31) and opioid analgesic cotreatment (ß = 0.24) were also identified in addition to eGFR (ß = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data. CONCLUSIONS: In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.

A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain.

BACKGROUND: Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS: After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-µm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS: The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS: This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan.

Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in 'bottle (closed)', 'bottle (in use)', and 'laminated' storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies.

Clinicopathological and molecular features of colorectal serrated neoplasias with different mucosal crypt patterns.

OBJECTIVES: Endoscopic examination shows that serrated neoplasias (SNs), such as serrated adenomas and sessile serrated adenomas, exhibit different mucosal crypt patterns. However, it remains unclear whether advanced serrated polyps with different mucosal crypt patterns have different clinicopathological or molecular features. METHODS: We classified the mucosal crypt patterns of 86 SNs into three types (hyperplastic, adenomatous, and mixed pattern) and evaluated their clinicopathological and molecular features. RESULTS: We found significant differences in the proliferative activity status between SNs with mixed/adenomatous patterns and those with the hyperplastic patterns. SNs with the hyperplastic pattern were frequently located in the proximal colon and had a macroscopically superficial appearance, whereas SNs with the adenomatous pattern were often located in the distal colon and had a protruding appearance. Furthermore, a significant difference was observed in the frequency of the CpG island methylator phenotype (CIMP), involving the methylation of two or more CIMP-related genes (MINT1, MINT2, MINT31, p16, and MLH1), between SNs with the hyperplastic pattern and those with the mixed/adenomatous patterns (18/32 (56%) vs. 8/28 (29%) or 7/26 (27%); P=0.0309 or P=0.0249, respectively). Moreover, the prevalence of KRAS mutations was significantly higher in SNs with the adenomatous pattern than in those with the hyperplastic pattern (7/26 (27%) vs. 1/32 (3%); P=0.0173). In comparison with other patterns, the mixed pattern was detected more frequently in mixed serrated polyps (MSPs), which contain separate histological components. Some MSPs exhibited concordant molecular alterations among the different histological components. CONCLUSIONS: The clinicopathological and molecular features of SNs correlated strongly with their mucosal crypt patterns, which were observed using chromoendoscopy.

Stability of Hydrocortisone in Oral Powder Form Compounded for Pediatric Patients in Japan.

Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.

Stability of clonidine hydrochloride in an oral powder form compounded for pediatric patients in Japan.

BACKGROUND: Clonidine hydrochloride is used to treat sedative agent withdrawals, malignant hypertension, and anesthesia complications. Clonidine is also prescribed off-label to pediatric patients at a dose of 1 µg/kg. The commercially available enteral form of clonidine, Catapres® tablets, is often compounded into a powder form by pharmacists to achieve dosage adjustments for administration to pediatric patients. However, the stability and quality of compounded clonidine powder have not been verified. The objectives of this study were to formulate a 0.2 mg/g oral clonidine hydrochloride powder and assess the stability and physical properties of this compounded product in storage. METHODS: A 0.2 mg/g clonidine powder was prepared by adding lactose monohydrate to crushed and filtrated clonidine tablets. The powder was stored in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. The stability of clonidine at 25 °C ± 2 °C and 60% ± 5% relative humidity was examined over a 120-d period in "bottle (closed)," "bottle (in use)," and "laminated paper" storage conditions. Drug dissolution and powder X-ray diffraction analysis were conducted to assess physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify clonidine and its degradation product, 2,6-dichloroaniline (2,6-DCA). RESULTS: Clonidine content was maintained between 90.0 and 110.0% of the initial contents in all packaging and storage conditions. After 120 d of storage, 2,6-DCA was not detected, and no crystallographic and dissolution changes were observed. CONCLUSIONS: Compounded clonidine powder stability was maintained for 120 d at 25 °C ± 2 °C and 60% ± 5% relative humidity. This information may contribute to the management of clonidine compounded powder in community and hospital pharmacies in Japan.

The influence of feeding on gastric acid suppression in Helicobacter pylori-positive patients treated with a proton pump inhibitor or an H2-receptor antagonist after bleeding from a gastric ulcer.

BACKGROUND: This study investigated the influence of feeding on gastric acid suppression in Helicobacter pylori-positive patients treated with intravenous infusions of proton pump inhibitors (PPIs) or with H2-receptor antagonists (H2-RAs) after bleeding from a gastric ulcer. METHODS: Forty-nine H. pylori-positive patients with bleeding gastric ulcers (44 men and 5 women) were divided into four groups: one group received an H2-RA while fasting, one group received an H2-RA while eating regularly, one group received a PPI while fasting, and one group received a PPI while eating regularly. Intragastric pH was monitored during fasting and nonfasting to calculate the pH 3 and pH 4 holding times and the mean pH. RESULTS: During a 24-h fast, the pH 3 and pH 4 holding times and the mean pH were significantly higher in patients administered omeprazole (PPI; 93.2 +/- 9.2%, 90.6 +/- 11.1%, and 6.9 +/- 0.6, respectively) than in those administered ranitidine (H2-RA; 61.0 +/- 27.5%, 55.8 +/- 29.1%, and 4.8 +/- 1.3, respectively; P<0.001 for all). Results were similar during feeding (PPI meal, 98.9 +/- 2.6%, 98.3 +/- 3.7%, and 6.9 +/- 0.3; H2-RA meal, 59.8 +/- 17.6%, 49.7 +/- 18.0%, and 4.3 +/- 0.7, respectively; P<0.001 for all). In addition, the pH 3 and pH 4 holding times and the mean pH in the H2-RA meal group were not significantly lower than those in the H2-RA group (P=0.999, P=0.865, and P=0.687, respectively). The values in the PPI and PPI meal groups were similar (P=0.872, P=0.777, and P>0.999, respectively). CONCLUSIONS: Gastric acid suppression during the administration of an H2-RA or a PPI soon after the cessation of gastric bleeding was scarcely affected by feeding. It may well be that H. pylori-positive patients with bleeding gastric ulcer can resume a regular diet and return to work soon after bleeding ceases.

Primary micropapillary carcinoma of the colon: a case report and literature review.

We report a case of micropapillary carcinoma (MPC) of the transverse colon. A 56-year-old woman was admitted to our hospital with hematochezia. A lower gastrointestinal examination revealed an irregular ulcerative tumor of approximately 60 mm diameter with marginal elevation in the transverse colon. Abdominal computed tomography showed multiple swollen lymph nodes. A histological examination of the resected specimen revealed that cancer cells had invaded the subserosa. Microscopically, small papillary cells proliferated with lacuna spaces and the cribriform glandular configuration was observed. Immunohistochemically, the basal surface of the neoplastic cell clusters was diffusely positive for MUC1. No primary tumor was observed except for the colon. Therefore, this tumor was diagnosed as a primary MPC of the colon. Since a colorectal MPC was first reported in 2005, seven case reports and three pathological reviews have been presented in the English literature. MPC has an aggressive behavior with a high incidence of lymphovascular invasion and nodal metastases. We should take intensive chemotherapy for colorectal MPC into account, even if surgical resection is curative.

Right colon cancer presenting as hemorrhagic shock.

A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock. An abdominal computed tomography scan revealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extravasation of blood from the gastroduodenal artery (GDA) into the colon. Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon. Therefore, right hemicolectomy combined with pylorus-preserving pancreaticoduodenectomy was performed. Histologically, the tumor was classified as a moderately differentiated adenocarcinoma. Moreover, cancer cells were mainly located in the colon but had also invaded the duodenum and pancreas and involved the GDA. Immunohistochemically, the tumor cells were positive for cytokeratin (CK)20 and carcinoembryonic antigen (CEA) but not for CK7 and carbohydrate antigen (CA)19-9. The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site. Although En bloc resection of the tumor with pancreaticoduodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival, patients undergoing these procedures should be carefully monitored, particularly when the tumor involves the main artery.

Evaluation of endoscopic ultrasonography in colorectal villous lesions.

BACKGROUND AND AIMS: The choice of therapeutic procedure for colorectal neoplasias depends largely on the depth of tumor invasion. This study examined the value of endoscopic ultrasonography (EUS) in determining whether local resection is applicable for colorectal villous lesions. MATERIALS AND METHODS: We performed EUS on 125 colorectal neoplasias classified into two categories, villous ( n=35) and nonvillous lesions ( n=90), according to their colonoscopic morphological features. We compared the EUS and clinicopathological findings for each lesion. RESULTS: The overall accuracy of EUS-based evaluation of tumor invasion depth was 60% in villous lesions and 91% in nonvillous lesions. In villous lesions 37% were overstaged and 3% understaged, and in of nonvillous lesions 6% were overstaged and 3% understaged. In differentiating mucosal neoplasias (M)/submucosal cancers with slight invasion (SM-s) from non-M/SM-s, the values in villous and nonvillous lesions were, respectively: sensitivity 60% and 86%, specificity 100% and 99%, and accuracy 66% and 96%. Large (>/=20 mm wide, >/=5 mm high) or rectal villous lesions were more likely than nonvillous lesions to be misjudged with regard to the differentiation between M/SM-s and non-M/SM-s. CONCLUSION: It is difficult to determine the depth of invasion in villous lesions, especially large or rectal lesions, using only EUS. EUS-based evaluation alone cannot determine the appropriate treatment for colorectal villous lesions.

Primary small cell carcinoma of the stomach.

We report on an 80-year-old man with primary gastric small cell carcinoma (SmCC). He was admitted to hospital with hematemesis. An upper gastrointestinal examination revealed an irregularly ulcerated tumor, 60 mm in diameter, on the lesser curvature of the stomach body extending to the cardia. An endoscopic biopsy revealed a solid proliferation of intermediate-sized tumor cells with hyperchromatic nuclei and scanty cytoplasm. Immunohistochemically, the neoplastic cells were positive for neuron-specific enolase and chromogranin A, but negative for carcinoembryonic antigen. No tumor was detected on examination of the chest. Therefore, primary gastric SmCC was diagnosed preoperatively. To date, only 38 cases of primary gastric SmCC, including our case, have been reported. By using endoscopic biopsy, approximately two-thirds of cases have been diagnosed incorrectly. In the reported cases of gastric SmCC, the endoscopic findings frequently indicated a submucosal tumor. Gastric SmCC is clinically aggressive and has an extremely poor prognosis, even when discovered at an early stage. Most patients with gastric SmCC die within 1 year of diagnosis. Although a standard treatment for gastric SmCC has not been established, intensive chemotherapy should be considered to promote long-term survival. We believe that careful examination, including immunohistochemical investigation, is necessary for determining the therapeutic strategy whenever gastric SmCC is suspected during endoscopy.