Investigation of pharmacokinetics of crushed imidafenacin 0.1-mg tablet after single oral administration in healthy men

The crushing of tablets and opening of capsules should not be performed without proper care, as these actions may adversely affect the pharmaceutical release mechanisms. However, various clinical circumstances occasionally necessitate these actions. The long-term stability of the commercial formulation of imidafenacin was confirmed after crushing of tablets. For the safe administration of crushed imidafenacin tablets, we examined the pharmacokinetics of crushed imidafenacin 0. 1-mg tablet after single oral administration in healthy men. Plasma concentrations were measured in 6 male volunteers (age, 33.3 ± 10.6 years) orally administered crushed imidafenacin under fasting conditions. Imidafenacin was rapidly absorbed and plasma concentrations peaked (Cmax) at 414 ± 108 pg/ml after 1.5 h (Tmax ; median), after which the drug was rapidly eliminated with a half-life (t1/2) of 2.8 ± 0. 3 h. Area under the plasma concentration-time curve (AUC0-10) was 1,680 ± 334 pg?h/ml. There were no significant differences in Cmax, Tmax and t1/2 between the crushed and tablet medications. Thus, crushing has almost no influence on the pharmacokinetics of imidafenacin. Consequently, this study was made available as information for patients requiring crushed anticholinergic agents.     

Intracranial chondroma arising from the skull base: two case reports featuring the image findings for differential diagnosis

We reported two cases of intracranial skull base chondroma and discussed the differential diagnosis and the treatment strategies. The first case was a 39-year-old male who presented with left exophtalmos, visual loss and oculomotor disturbance. MRI showed a huge tumor occupying the bilateral cavernous sinus. Partial removal of the tumor was performed through the left orbitozygomatic subtemporal approach. The second case was a 54-year-old male who presented with left hemiparesis. MRI showed a brain stem infarction with a huge tumor located at the right middle fossa. Partial removal was performed through the right orbitozygomatic subtemporal approach. In these two cases, the histopathological diagnosis of the tumors was benign chondroma and the size of residual tumors have not changed for one year without any additional therapy. Although preoperative definite diagnosis for skull base chondromas is difficult, strategies for diagnosis and treatment without any complication are essential. In our cases, chondromas showed low uptake in PET images, which might be useful for differentiation between chondromas and chordomas. The current popular surgical approach for parasellar tumors is transcranial such as the orbitozygomatic subtemporal approach. In surgical removal of skull base chondromas, it is advisable to try to confirm the diagnosis preoperatively with characteristic image findings and to consider the best approach in each case to decompress the involved nerves without any complications.     

Acute lymphocytic leukemia recurring in the spinal epidural space

A 27-year-old man presented with a very rare spinal epidural mass associated with recurrence of acute lymphocytic leukemia (ALL) manifesting as acute progressive neurological deficits. The patient presented with shoulder pain and ambulatory difficulties 3 years after remission of ALL treated by bone marrow transplantation. Magnetic resonance imaging revealed an epidural mass extending from C-7 to T-3, which compressed the cord and extended to the intervertebral foramen along the roots. After decompression surgery, the symptoms dramatically improved. Histological examination showed clusters of immature lymphocytes consistent with recurrence of leukemia, so chemotherapy and radiation therapy were carried out. At 1 year after the operation, no local mass expansion or systemic progression of leukemia had occurred. Leukemic mass must be considered in the differential diagnosis of spinal epidural mass, even in patients with ALL.     

Hepatectomy-Related Hypophosphatemia: A Novel Phosphaturic Factor in the Liver-Kidney Axis

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na⁺-dependent phosphate (Pi) uptake decreased by 50%–60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na⁺-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.Inorganic phosphate (Pi) absorption in the renal proximal tubules and small intestine is important for Pi homeostasis.¹ The Na⁺-dependent Pi (Na/Pi) transport system includes type IIa and type IIc Na/Pi transporters, which are localized in the apical membrane of the proximal tubular cells, and type IIb Na/Pi transporters, which are localized in the apical membrane of the intestinal epithelial cells.^1,2 Pi (re)absorption is regulated by the dietary Pi content, parathyroid hormone (PTH), and the active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)₂D₃].³ Other phosphaturic hormones, termed phosphatonins, also control renal Pi handling.⁴ The discovery that fibroblast growth factor (FGF) 23, the first identified phosphatonin,⁵ originated from osteocytes established the concept of the bone-kidney axis.^6,7The incidence of liver transplantation has steadily increased and the incidence of partial hepatectomy (PH) has also consequently increased.⁸ Hypophosphatemia frequently occurs after liver resection.^9–11 Acute hypophosphatemia causes septicemia and is associated with a poor prognosis.^11,12 Acute hypophosphatemia is of considerable clinical relevance because many hepatectomized patients develop marked hypophosphatemia and, thus, large doses of Pi replacement are required to maintain metabolic homeostasis.¹³ Urinary Pi excretion is markedly increased in many patients. After hepatectomy, hypophosphatemia is associated with hyperphosphaturia.¹³For many years, the increased metabolic demand of the regenerating liver was considered the underlying pathologic mechanism of hypophosphatemia. The magnitude of Pi uptake by the recovering liver, however, cannot explain the severity of the resulting hypophosphatemia.¹¹ Hepatectomy-induced hypophosphatemia is associated with an increased renal fractional excretion index for Pi unrelated to intact FGF23, FGF7, or secreted frizzled-related protein 4 as a phosphaturic factor,¹⁴ indicating that other factors have a role in the pathogenesis of hypophosphatemia.Nicotinamide (NAM) inhibits intestinal and renal Na/Pi transport activity in normal rats.^15–17 Administration of NAM to rats produces a specific dose-dependent inhibition of Na/Pi transport across the renal brush-border membrane (BBM) and an increase in urinary Pi excretion.^16,17 NAM suppresses hyperphosphatemia in hemodialysis patients.¹⁸ Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the first rate-limiting step in converting NAM to NAD,^19,20 which is essential for cellular metabolism, energy production, and DNA repair.^20–22 Nampt exists in two known forms: intracellular Nampt (iNampt) and secreted extracellular Nampt (eNampt).²³ eNampt also generates an intermediate product, nicotinamide mononucleotide (NMN).²³Our findings indicate that the acceleration of NAM metabolism through Nampt function in the kidney is involved in the hepatectomy-induced hypophosphatemia in rodent models. This study also suggests that NAM metabolism through the liver-kidney axis is important in Pi homeostasis.     

Outcome of sentinel lymph node biopsy in breast cancer using dye alone: a single center review with a median follow-up of 5 years

Purpose

Various techniques are used for sentinel lymph node biopsy (SLNB) in breast cancer. While subareolar injection with dye alone is a relatively easy method, few studies have reported the outcome with a follow-up period. This study presents our results of SLNB using dye alone.

Methods

Between November 2002 and December 2010, 701 patients with breast cancer underwent SLNB using subareolar injection of indocyanine green or indigo carmine. Sentinel lymph node (SLN)-negative patients were followed without axillary lymph node dissection (ALND).

Results

SLNs were detected in 654 of 701 patients (93.3 %), and the rate increased to 98.1 % over the course of the study. The mean number of SLNs removed was 1.5. There was no significant difference in the detection rate between two dyes. No adverse events resulted from the injection of dyes. Of the 654 patients, 136 (20.8 %) had SLN metastasis. Five hundred patients were followed without ALND. Thirty-six patients experienced disease relapse during a median follow-up of 60 months. Thirteen patients (2.6 %) had regional lymph node relapse, and eight of them could undergo salvage lymph node dissection. The 5-year disease-free and overall survival rates were 92.4 and 96.1 %, respectively.

Conclusion

SLNB using subareolar injection with dye alone was safe and feasible even after a long follow-up.     

Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.     

Current status of countermeasures for infectious diseases and resistant microbes in the field of urology

A worldwide increase in antimicrobial‐resistant microbes due to the improper use of antimicrobial agents, along with a lack of progress in developing new antimicrobials, is becoming a societal problem. Although carbapenem‐resistant Enterobacteriaceae, which are resistant to carbapenem antimicrobials, first appeared in 1993, treatment options remain limited. Mechanisms behind antimicrobial resistance involve changes to microbial outer membranes, drug efflux pump abnormalities, β‐lactamase production and the creation of biofilms around cell bodies. Genetic information related to these forms of antimicrobial resistance exists on chromosomes and plasmids, and when located on the latter can easily be transmitted to other strains, no matter the species, which creates a risk of antimicrobial resistance spreading exceptionally rapidly. To prevent the spread of antimicrobial resistance, the World Health Organization in 2015 published an action plan on antimicrobial resistance, based on which World Health Organization member countries have laid out specific policies and targets. Urinary tract infections are a type of healthcare‐associated infection, and the sexually transmitted disease pathogen, Neisseria gonorrhoeae, has been included in a list of microbes that pose a risk to human health published by the US Centers for Disease Control and Prevention. Urologists face numerous problems when attempting to use antimicrobials properly, which is one method of dealing with antimicrobial resistance. Therefore, this article describes the current state of resistant microbes associated with urinary tract infections and countermeasures for antimicrobial resistance, including new antimicrobials.     

Unilateral cerebral polymicrogyria with ipsilateral cerebral hemiatrophy

We evaluated six children in whom MR imaging showed unilateral cerebral polymicrogyria associated with ipsilateral cerebral atrophy and ipsilateral brain stem atrophy. The aim of this study was to clarify whether this disorder based on neuroimaging constitutes a new homogeneous clinical entity. The subjects were six children whose ages at the time of MR imaging ranged from 8 months to 11 years. Their clinical and MR features were analyzed. All of the children were born between 38 and 42 weeks gestation, without any significant perinatal events. Spastic hemiplegia and epilepsy were observed in all of the patients, and mental retardation was observed in four. The MR findings included unilateral cerebral polymicrogyria associated with ipsilateral cerebral hemiatrophy and ipsilateral brain stem atrophy in all patients. The ipsilateral sylvian fissure was hypoplastic in four patients. These patients showed relatively homogeneous clinical and neuroimaging features. Although the additional clinical features varied according to the site and the extent affected by the polymicrogyria, this disorder could constitute a new relatively homogeneous clinical entity.     

Whole plantar nerve conduction study with disposable strip electrodes

Introduction: A new method to evaluate whole plantar nerve conduction with disposable strip electrodes (DSEs) is described. Methods: Whole plantar compound nerve action potentials (CNAPs) were recorded at the ankle. DSEs were attached to the sole for simultaneous stimulation of medial and lateral plantar nerves. We also conducted medial plantar nerve conduction studies using an established method and compared the findings. Results: Whole plantar CNAPs were recorded bilaterally from 32 healthy volunteers. Mean baseline to peak amplitude for CNAPs was 26.9 ± 11.8 μV, and mean maximum conduction velocity was 65.8 ± 8.3 m/s. The mean amplitude of CNAPs obtained by our method was 58.2% higher than that of CNAPs obtained by the Saeed method (26.9 μV vs. 17.0 μV; P < 0.0001). Conclusions: The higher mean amplitude of whole plantar CNAPs obtained by our method suggests that it enables CNAPs to be obtained easily, even in elderly people. Muscle Nerve 53: 209–213, 2016     

Wallace direct versus anti-reflux Le Duc ureteroileal anastomosis: comparative analysis in modified Studer orthotopic neobladder reconstruction

Objectives: To investigate and compare Wallace direct ureteroileal anastomosis with Le Duc anti‐reflux procedure in modified Studer orthotopic neobladder reconstruction after radical cystectomy. Methods: A total of 72 consecutive patients who underwent modified Studer orthotopic bladder reconstruction after a radical cystectomy for bladder cancer were investigated. They were examined for vesicoureteral reflux, hydronephrosis, and pyelonephritis at 6 months after surgery according to the type of ureteroileal anastomosis. Results: Vesicoureteral reflux occurred in 29 ureters (38.2%) after the Wallace procedure compared to six ureters (9.6%) with the Le Duc (P < 0.05). Hydronephrosis was detected in 12 ureters (18.8%) in the Le Duc patients compared to seven (9%) in the Wallace patients (P > 0.05). Six months after the operation, all three patients with vesicoureteral reflux‐related hydronephrosis improved using clean intermittent catheterization in the Le Duc patients; five of seven patients were cured by clean intermittent catheterization and two improved without any treatment in the Wallace patients. Seven of nine cases of ureteroileal anastomosis stenosis causing hydronephrosis were cured without any treatment but one case resulted in a non‐functional kidney despite treatment of the stenosis. Conclusions: Direct ureteroileal anastomosis using the Wallace method is effective for minimizing ureteroileal anastomosis stenosis and it represents a simple surgical procedure when combined with a modified Studer procedure.