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1.
Sci Prog ; 107(2): 368504241262195, 2024.
Article in English | MEDLINE | ID: mdl-38872447

ABSTRACT

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner-Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable.


Subject(s)
Hearing Aids , Neuroma, Acoustic , Humans , Neuroma, Acoustic/surgery , Male , Middle Aged , Hearing Loss, Sensorineural/surgery , Hearing Loss, Sensorineural/rehabilitation , Hearing Loss, Sensorineural/etiology , Quality of Life , Hearing Loss/etiology , Hearing Loss/surgery , Hearing Loss/rehabilitation , Postoperative Complications/etiology
2.
Article in English | MEDLINE | ID: mdl-38578503

ABSTRACT

OBJECTIVES: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. METHODS: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. RESULTS: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). CONCLUSIONS: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014).

3.
Auris Nasus Larynx ; 51(2): 347-355, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37788966

ABSTRACT

OBJECTIVE: Asymmetric sensorineural hearing loss (ASHL) is the most common symptom of sporadic vestibular schwannoma (VS). However, there is still no universally accepted MRI protocol for diagnosing VS. This study identified the characteristics of pure tone audiogram (PTA) in patients with VS. METHODS: We conducted a retrospective chart review of patients diagnosed with sporadic unilateral VS. In the analysis, we focused on the shape and interaural differences of PTA, stratified by the mode of onset and patient age. RESULTS: In total, 390 patients met the inclusion criteria. The U-shaped audiogram showed the highest proportion in patients with the onset of sudden sensorineural hearing loss (SSNHL). In patients with SSNHL, U-shaped audiograms were younger than other audiograms, and 86.7 % of patients under 40 had U-shaped audiograms. Patients with VS were more likely to have interaural differences at higher frequencies than at lower frequencies. Patients with SSNHL had a significantly higher percentage of interaural differences at 500-4000 Hz than those with onset other than SSNHL (non-SSNHL patients). In addition, non-SSNHL patients had a significant trend toward a higher percentage of interaural differences at all frequencies with increasing age. CONCLUSION: MRI screening can be considered in patients with SSNHL with U-shaped audiograms under 40 years of age. In ASHL, not SSNHL, MRI screening can be considered for older patients with interaural differences at wider continuous frequencies. Patients with interaural differences at high frequencies had a higher priority than those with interaural differences at low frequencies as indications for MRI screening for VS.


Subject(s)
Hearing Loss, Sensorineural , Hearing Loss, Sudden , Neuroma, Acoustic , Humans , Neuroma, Acoustic/complications , Neuroma, Acoustic/diagnostic imaging , Retrospective Studies , Audiometry , Hearing Tests , Hearing Loss, Sensorineural/diagnosis , Caffeine , Audiometry, Pure-Tone
4.
Ear Nose Throat J ; : 1455613231215173, 2023 Nov 30.
Article in English | MEDLINE | ID: mdl-38032084

ABSTRACT

Relapsing polychondritis (RP) is a rare chronic inflammatory disease characterized by recurrent inflammation of cartilages throughout the body, with treatment-resistant dizziness and hearing loss in 40%-50% of patients with RP. Although rare, severe binaural hearing loss in RP is an indication for cochlear implantation (CI). Therefore, there are only a few reports on CI insertion in cases of RP. This report describes a 68-year-old woman who developed binaural hearing loss due to RP. She was treated with steroids and immunosuppressive drugs; however, her hearing did not improve significantly, and she relied on written communication for conversation. Subsequently, the patient underwent CI in the right ear. The patient showed improvement in speech perception; at 14 months postoperatively, she was able to speak with lipreading, and at 2 years postoperatively, she was able to speak without lipreading. Previous case reports on CI in patients with RP have shown varying degrees of postoperative hearing improvement. Our case demonstrates the effectiveness of CI in improving hearing and speech recognition in patients with RP having semicircular canal calcification. However, previous reports have shown that speech recognition declines 13 years after CI for RP. Therefore, continuous long-term follow-up is necessary.

5.
J Otolaryngol Head Neck Surg ; 52(1): 67, 2023 Oct 06.
Article in English | MEDLINE | ID: mdl-37803428

ABSTRACT

Highly accurate real-time cochlear nerve monitoring to preserve cochlear nerve function is essential for simultaneous cochlear implantation and ipsilateral vestibular schwannoma resection. In the present study, we developed a novel real-time monitoring system that combines dorsal cochlear nucleus action potential monitoring with intracochlear stimulating electrodes (Auditory Nerve Test System, ANTS). We used this system for a case with vestibular schwannoma resection via the translabyrinthine approach. The monitoring system developed in this study detected highly reliable evoked potentials from the cochlear nerve every two seconds continuously during tumor resection. Near-total tumor resection was achieved, and cochlear implantation was performed successfully after confirming the preservation of cochlear nerve function in a case. The patient's hearing was well compensated by cochlear implantation after surgery. Our novel method continuously achieved real-time monitoring of the cochlear nerve every two seconds during vestibular schwannoma resection. The usefulness of this monitoring system for simultaneous tumor resection and cochlear implantation was demonstrated in the present case. The system developed in this study is compatible with continuous facial nerve monitoring. This highly accurate and novel monitoring method will broaden the number of candidates for this type of surgery in the future.


Subject(s)
Cochlear Implantation , Cochlear Nucleus , Neuroma, Acoustic , Humans , Neuroma, Acoustic/surgery , Cochlear Nucleus/surgery , Action Potentials/physiology , Cochlear Implantation/methods , Cochlear Nerve/pathology , Cochlear Nerve/surgery
6.
J Int Adv Otol ; 19(5): 426-430, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37789631

ABSTRACT

Surgery for vestibular schwannoma can be divided into hearing-preserving and nonhearing-preserving surgeries. Hearing-preserving surgery is usually not considered in patients with deafness due to vestibular schwannoma, because hearing is unlikely to improve, and surgery aims to maximize the tumor resection at the expense of hearing. We report an extremely rare case of a 46-year-old man with unilateral profound hearing loss due to a vestibular schwannoma with marked cystic degeneration in the left cistern, which significantly recovered to near-normal hearing levels after hearing-preserving surgery. Hearing loss gradually worsened, and preoperative pure-tone evaluation showed complete hearing loss in the left ear. However, the response to the distortion product otoacoustic emission was preserved, and hearing loss was considered to be retrocochlear. Tumor resection was performed using the retrolabyrinthine approach with continuous monitoring using dorsal cochlear nucleus action potential, auditory brainstem response, and facial nerve function muscle action potential. The cistern portion of the tumor was almost completely resected along with the wall. Postoperatively, the pure-tone threshold on the left side markedly improved. The present case clearly demonstrates the possibility of hearing recovery in patients with retrocochlear hearing loss. We should consider expanding the indications for hearing-preserving surgery.


Subject(s)
Deafness , Hearing Loss , Neuroma, Acoustic , Male , Humans , Middle Aged , Neuroma, Acoustic/complications , Neuroma, Acoustic/surgery , Neuroma, Acoustic/pathology , Hearing/physiology , Otoacoustic Emissions, Spontaneous/physiology , Hearing Loss/etiology , Hearing Loss/surgery
7.
Diagnostics (Basel) ; 13(16)2023 Aug 13.
Article in English | MEDLINE | ID: mdl-37627924

ABSTRACT

Tumoral lesions of the temporal bone include benign or malignant tumors and congenital or inflammatory lesions. Temporal bone lesions are difficult to approach. Therefore, making a preoperative diagnosis and considering whether the lesions require treatment are necessary; if they require treatment, then the type of treatment requires consideration. These tumors cannot be observed directly and must be diagnosed based on symptoms and imaging findings. However, the differentiation of temporal bone lesions is difficult because they are rare and large in variety. In this pictorial review, we divided temporal bone lesions by location such as along the facial nerve, along the internal jugular vein, around the endolymphatic sac, in the internal auditory canal/cerebellopontine angle, petrous apex, middle ear, and mastoid, focusing on the imaging findings of temporal bone lesions. Then, we created a diagnostic flowchart that suggested that the systematic separation of imaging findings is useful for differentiation. Although it is necessary to make comprehensive judgments based on the clinical symptoms, patient background, and imaging findings to diagnose temporal bone mass lesions, capturing imaging features can be a useful differentiation method.

8.
Diagnostics (Basel) ; 13(2)2023 Jan 11.
Article in English | MEDLINE | ID: mdl-36673085

ABSTRACT

Surgery for vestibular schwannoma includes various techniques such as the middle cranial fossa, suboccipital, translabyrinthine, and retrolabyrinthine approaches. The retrolabyrinthine approach does not impair the labyrinth and allows postoperative hearing preservation. Previously, we reported an endoscope-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring for preservation of hearing and facial nerve function. However, the hearing preservation rate was relatively low in patients with long-wave V latency in the auditory brainstem response or poor otoacoustic emission response under this approach. Thus, the hearing preservation rate in such patients remains to be improved. To overcome this limitation, we modified the previous approach. In 26 of the 33 consecutive cases (79%) over the last three years, preservation of hearing equivalent to that before surgery or improved hearing was achieved. Postoperative deafness was observed in only two of the 33 cases (6%). According to previous reports, the rate of hearing preservation using the retrolabyrinthine approach is approximately 30-50%. Therefore, we have achieved a higher hearing preservation rate than that previously reported using the endoscopy-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring. These improvements in our department are considered to be helpful for hearing preservation.

9.
Diagnostics (Basel) ; 12(8)2022 Jul 23.
Article in English | MEDLINE | ID: mdl-35892501

ABSTRACT

There are no established indications for facial nerve schwannoma treatment, including surgery, radiation and follow-up observation, and it is difficult to determine treatment policy uniformly. The treatment policy was examined from each treatment course. Data of patients with facial nerve schwannomas at our hospital from 1987 to 2018 were retrospectively examined. Their age, sex, clinical symptoms, tumor localization, treatment policies and outcomes were reviewed. In total, 22 patients underwent surgery and 1 patient underwent radiotherapy; 22 patients were followed up without treatment. After total resection, there were no tumor recurrences, and most patients had grade 3 or 4 postoperative facial paralysis. After subtotal resection, tumor regrowth was observed in four patients and reoperation was required in two patients. Facial nerve function was maintained in four patients and was decreased in two patients. During follow-up, six patients showed tumor growth. Only one patient had worsening facial nerve paralysis; four patients underwent facial nerve decompression owing to facial nerve paralysis during follow-up. If the tumor compresses the brain or it is prone to growth, surgery may be indicated, and when the preoperative facial nerve function is grade ≤3, consideration should be given to preserving facial nerve function and subtotal resection should be indicated. If the preoperative facial nerve function is grade ≥3, total resection with nerve grafting is an option to prevent regrowth. If there is no brain compression or tumor growth, the follow-up is a good indication, and decompression should be considered in facial nerve paralysis cases.

10.
Ear Nose Throat J ; : 1455613221097198, 2022 Jun 03.
Article in English | MEDLINE | ID: mdl-35656821

ABSTRACT

Thrombosis is a characteristic symptom of coronavirus disease 2019 (COVID-19). Here, we present a case of external ear stenosis caused by arterial thrombosis after COVID-19 infection. To the best of our knowledge, this is the first report of external ear stenosis related to COVID-19. A 62-year-old man presented with left hearing loss. The patient had a history of hospitalization for COVID-19 treatment 11 months prior to visiting our hospital. He had been experiencing ear fullness and tinnitus after COVID-19 treatment. Physical examination revealed severe left external ear canal stenosis with a subcutaneous mass. Surgical removal of the subcutaneous mass was performed. Histopathological analysis revealed that a subcutaneous thrombosis caused the external ear canal stenosis. This case describes an unusual case of external ear canal stenosis after COVID-19. Clinical and pathological findings indicate that COVID-19 affected the external ear canal. In addition, histopathological results confirmed the formation of arterial thrombosis in the temporal bone region after COVID-19 treatment. This case shows the broad range of body sites that can be involved with thrombotic events with COVID including the subcutaneous tissue around the outer ear. This observation would be helpful in investigating or explaining the various otological symptoms of COVID-19.

11.
Diagnostics (Basel) ; 12(5)2022 Apr 21.
Article in English | MEDLINE | ID: mdl-35626200

ABSTRACT

Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve that causes sensorineural hearing loss. This tumor is clinically and oncologically regarded as a benign tumor as it does not metastasize or invade surrounding tissues. Despite being a benign tumor, its management is difficult and controversial due to the potential serious complications, such as irreversible sensorineural hearing loss, of current interventions. Therefore, preventing hearing loss due to the natural course of the disease and complications of surgery is a challenging issue for an otologist. Improvements have been reported recently in the treatment of vestibular schwannomas. These include advances in intraoperative monitoring systems for vestibular schwannoma surgery where the risk of hearing loss as a complication is decreased. Precise genomic analysis of the tumor would be helpful in determining the characteristics of the tumor for each patient, leading to a better hearing prognosis. These procedures are expected to help improve the treatment of vestibular schwannomas. This review summarizes recent advances in vestibular schwannoma management and treatment, especially in hearing preservation. In addition, recent advances in the understanding of the molecular mechanisms underlying vestibular schwannomas and how these advances can be applied in clinical practice are outlined and discussed, respectively. Moreover, the future directions from the bedside to the bench side are presented from the perspective of otologists.

12.
J Med Chem ; 64(16): 11990-12002, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34347478

ABSTRACT

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme, which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGKγ, localized in the brain, plays an important role in the central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGKγ. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGKγ and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable nonspecific binding. The radiolabeling of 9 followed by PET imaging of wild-type and DGKγ-deficient mice and rats indicated that [11C]9 ([11C]T-278) specifically binds to DGKγ and yields a high signal-to-noise ratio for DGKγ in rodent brains.


Subject(s)
Brain/diagnostic imaging , Diacylglycerol Kinase/metabolism , Indoles/chemistry , Radiopharmaceuticals/chemistry , Animals , Brain/enzymology , Carbon Radioisotopes/chemistry , Drug Design , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Male , Mice, Inbred C57BL , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Rats, Sprague-Dawley
13.
ACS Omega ; 5(49): 31984-32001, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-33344853

ABSTRACT

Fragment screening is frequently used for hit identification. However, there was no report starting from a small fragment for the development of an anaplastic lymphoma kinase (ALK) inhibitor, despite the number of ALK inhibitors reported. We began our research with the fragment hit F-1 and our subsequent linker design, and its docking analysis yielded novel cis-1,2,2-trisubstituted cyclopropane 1. The fragment information was integrated with a structure-based approach to improve upon the selectivity over tropomyosin receptor kinase A, leading to the potent and highly selective ALK inhibitor, 4-trifluoromethylphenoxy-cis-1,2,2-trisubstituted cyclopropane 12. This work shows that fragments become a powerful tool for both lead generation and optimization, such as the improvement of selectivity, by combining them with a structure-based drug design approach, resulting in the fast and efficient development of a novel, potent, and highly selective compound.

14.
J Med Chem ; 62(10): 4915-4935, 2019 05 23.
Article in English | MEDLINE | ID: mdl-31009559

ABSTRACT

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1 H-pyrazol-5-yl)imidazo[1,2- b]pyridazin-6-amine 1 guided by a cocrystal structure of compound 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1 H-pyrazol-3-yl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)((2 S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compound. Intraperitoneal administration of compound 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compound 13 could serve as a useful chemical probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Brain/drug effects , Drug Discovery/methods , Protein Kinase Inhibitors/chemical synthesis , Animals , Biological Transport , Brain/metabolism , Crystallography, X-Ray , HEK293 Cells , Humans , Inhibitory Concentration 50 , LLC-PK1 Cells , Mice , Mice, Inbred ICR , Molecular Structure , Phosphorylation , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Swine
15.
Laryngoscope ; 128(11): 2593-2599, 2018 11.
Article in English | MEDLINE | ID: mdl-30079962

ABSTRACT

OBJECTIVES/HYPOTHESIS: Vocal fold polyps and nodules are common benign laryngeal lesions. Currently, the Japanese health insurance system covers surgical interventions. However, the establishment of more cost-effective conservative methods is required, because healthcare costs are viewed as a major concern, and the government and taxpayers are demanding more economical, effective treatments. In this situation, more suitable vocal hygiene education may be important for the success of cost-effective conservative treatment. In this study, we developed a novel reinforced vocal hygiene education program and compared the results of this program with those of previous methods of teaching vocal hygiene. STUDY DESIGN: Multicenter randomized controlled trial. METHODS: Patients who visited a National Hospital Organization (NHO) hospital for the surgical indication of hoarseness were included in the study. Before undergoing surgery, 200 patients with benign vocal fold lesions (vocal fold polyps/nodules) were enrolled and randomly allocated to the NHO-style vocal hygiene educational program (intervention group) or control education program (control group). Two months after enrollment, the patients in both groups underwent laryngeal fiberscopic examinations to determine whether the benign lesions had resolved or whether surgery was indicated for the vocal fold polyps/nodules. RESULTS: After 2 months, in the intervention group, the proportion of lesion resolution (61.3%) was significantly greater than that in the control group (26.3%) (P < .001, Fisher exact test). CONCLUSIONS: Our results clearly indicate that the quality and features of the education program could affect the outcome of the intervention. We found that a reinforced vocal hygiene education program increased the rate of the resolution of benign vocal fold polyps and nodules in a multicenter randomized clinical trial. LEVEL OF EVIDENCE: 1b Laryngoscope, 2593-2599, 2018.


Subject(s)
Conservative Treatment/methods , Hygiene/education , Laryngeal Diseases/therapy , Patient Education as Topic/methods , Polyps/therapy , Program Evaluation , Female , Humans , Laryngeal Diseases/pathology , Laryngoscopy/statistics & numerical data , Male , Middle Aged , Polyps/pathology , Treatment Outcome , Vocal Cords/pathology
16.
Auris Nasus Larynx ; 45(4): 871-874, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29089157

ABSTRACT

Schwanomatosis is the third most common form of neurofibromatosis. Schwanomatosis affecting the vagus nerve is particularly rare. In this report, we describe an extremely rare case bilateral vagus nerve schwanomatosis in a 45-year-old male patient. The patient initially presented with bilateral neck tumors and hoarseness arising after thoracic surgery. We performed left neck surgery in order to diagnose and resect the remaining tumors followed by laryngeal framework surgery to improve vocal cord closure and symptoms of hoarseness. Voice recovery was successfully achieved after surgery. An appropriate diagnosis and surgical tumor resection followed by phonosurgery improved patient quality of life in this rare case.


Subject(s)
Neoplasms, Multiple Primary/diagnostic imaging , Nerve Sheath Neoplasms/diagnostic imaging , Neurilemmoma/diagnostic imaging , Vagus Nerve Diseases/diagnostic imaging , Hoarseness/etiology , Hoarseness/physiopathology , Humans , Laryngoplasty , Male , Middle Aged , Neoplasms, Multiple Primary/complications , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/physiopathology , Nerve Sheath Neoplasms/complications , Nerve Sheath Neoplasms/pathology , Nerve Sheath Neoplasms/physiopathology , Neurilemmoma/complications , Neurilemmoma/pathology , Neurilemmoma/physiopathology , Recovery of Function , Vagus Nerve Diseases/complications , Vagus Nerve Diseases/pathology , Vagus Nerve Diseases/physiopathology , Vocal Cords
17.
Biopharm Drug Dispos ; 38(9): 543-552, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28948605

ABSTRACT

A recent study suggested that the pharmacokinetics (PK) of highly fat distributed compounds can be affected by acute changes in the volume of adipose tissue. The present study investigates possible influences of body composition on the disposition of the highly lipophilic compound TAK-357 in two rat strains. Physiologically based PK (PBPK) modeling and simulation was applied on single and multiple dose PK data of TAK-357 in obese Wistar fatty rats and Wistar lean rats having approximately 45% and 13% body fat, respectively. The observed effects of an elevated fat mass in Wistar fatty rats on the plasma concentrations appeared to be partly compensated for by other differences between the two rat strains. A decrease in the tissue to blood partition coefficients under high body fat conditions was identified as another factor contributing to the difference in PK. A higher lipid content in the plasma in high body fat animals may result in relatively lower tissue to blood partition coefficients. PBPK-based simulations indicate that the plasma concentrations of lipophilic compounds in high body fat conditions can differ by up to two-times at steady-state. This confirms that there is only a small impact of body composition change on the plasma concentration of highly lipophilic drugs and that the need for therapeutic dose adjustments may be limited.


Subject(s)
Adipose Tissue/metabolism , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Lipids/blood , Models, Biological , Piperazines/chemistry , Piperazines/pharmacokinetics , Animals , Body Composition/physiology , Computer Simulation , Male , Rats , Rats, Wistar , Tissue Distribution
18.
Biopharm Drug Dispos ; 38(6): 373-380, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28256717

ABSTRACT

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.


Subject(s)
Adipose Tissue/metabolism , Indenes/pharmacokinetics , Models, Biological , Animals , Computer Simulation , Dogs , Indenes/blood , Indenes/toxicity , Male , Rats, Sprague-Dawley
19.
Brain Stimul ; 10(3): 576-578, 2017.
Article in English | MEDLINE | ID: mdl-28274722

ABSTRACT

BACKGROUND: Vestibular rehabilitation is useful to alleviate chronic dizziness in patients with vestibular dysfunction. It aims to induce neuronal plasticity in the central nervous system (especially in the cerebellum) to promote vestibular compensation. Transcranial cerebellar direct current stimulation (tcDCS) reportedly enhances cerebellar function. OBJECTIVE/HYPOTHESIS: We investigated whether vestibular rehabilitation partially combined with tcDCS is superior to the use of rehabilitation alone for the alleviation of dizziness. METHODS: Patients with chronic dizziness due to vestibular dysfunction received rehabilitation concurrently with either 20-min tcDCS or sham stimulation for 5 days. Pre- and post-intervention (at 1 month) dizziness handicap inventory (DHI) scores and psychometric and motor parameters were compared. RESULTS: Sixteen patients completed the study. DHI scores in the tcDCS group showed significant improvement over those in the sham group (Mann-Whitney U test, p = 0.033). CONCLUSION: Vestibular rehabilitation partially combined with tcDCS appears to be a promising approach.


Subject(s)
Dizziness/therapy , Transcranial Direct Current Stimulation/adverse effects , Vestibular Diseases/therapy , Adult , Aged , Cerebellum/physiology , Dizziness/rehabilitation , Female , Humans , Male , Middle Aged , Neuronal Plasticity , Transcranial Direct Current Stimulation/methods , Vestibular Diseases/rehabilitation , Vestibule, Labyrinth/physiopathology
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