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BACKGROUND: Fatigue is an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) used for cancer treatment. Chinese herbal medicines (Ho-zai) are used to treat cancer-related fatigue. However, no interactions between ICIs and Ho-zai have been reported. Herein, we investigated the risk of irAEs associated with the concomitant use of ICIs and Ho-zai. METHODS: We extracted data of patients who used ICI and Ho-zai from the Japanese Adverse Event Reporting Database. The proportional reporting ratio (PRR) was calculated for patients using ICI, Ho-zai, or both. We focused on cases of interstitial lung disease (ILD) and colitis, which were among the most severe cases of irAEs among these patients. The shrinkage method used by the World Health Organization-Uppsala Monitoring Center was used to detect the interactions. RESULTS: Of the 799,670 patients in the database, 77,219, 2060, and 92 were using ICIs, Ho-zai, and combination treatment, respectively. The ILD and colitis groups included 39,388 and 17,522 patients, respectively. ILD signals were detected for both ICIs and Ho-zai. There were 24 cases of patients treated with concomitant ICIs and Ho-zai who developed ILD. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no ILD-related interactions. Colitis signals were detected for ICIs except for atezolizumab, avelumab, and durvalumab. There were eight patients treated with concomitant ICI and Ho-zai who developed colitis. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no colitis-related interactions. CONCLUSION: To our knowledge, this is the first study to investigate interactions between ICIs and Ho-zai. Signals were detected for ILD in both ICI and Ho-zai groups, and colitis in the ICI group. However, the combined use of these treatments did not increase the risk of irAEs.
Subject(s)
Databases, Factual , Drugs, Chinese Herbal , Immune Checkpoint Inhibitors , Neoplasms , Humans , Drugs, Chinese Herbal/adverse effects , Immune Checkpoint Inhibitors/adverse effects , Male , Female , Neoplasms/drug therapy , Middle Aged , Japan/epidemiology , Aged , Drug-Related Side Effects and Adverse Reactions/etiology , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Prognosis , Lung Diseases, Interstitial/chemically induced , Colitis/chemically induced , Follow-Up Studies , AdultABSTRACT
There are many commercially available artificial nerve conduits, used mostly to repair short gaps in sensory nerves. The stages of nerve regeneration in a nerve conduit are fibrin matrix formation between the nerve stumps joined to the conduit, capillary extension and Schwann cell migration from both nerve stumps, and, finally, axon extension from the proximal nerve stump. Artificial nerves connecting transected nerve stumps with a long interstump gap should be biodegradable, soft and pliable; have the ability to maintain an intrachamber fibrin matrix structure that allows capillary invasion of the tubular lumen, inhibition of scar tissue invasion and leakage of intratubular neurochemical factors from the chamber; and be able to accommodate cells that produce neurochemical factors that promote nerve regeneration. Here, we describe current progress in the development of artificial nerve conduits and the future studies needed to create nerve conduits, the nerve regeneration of which is compatible with that of an autologous nerve graft transplanted over a long nerve gap.
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PURPOSE: This study investigated the effects of ice cream consumption on chyle leakage after left lateral neck dissection in patients with thyroid cancer. METHODS: A total of 491 patients with thyroid cancer underwent left lateral neck dissection with identification of the thoracic duct following ice cream consumption. Before closing the wound, the anesthesiologist increased the intrathoracic pressure to observe chyle leakage. If chyle leakage occurred postoperatively, the drain was removed using the drain negative pressure release test. RESULTS: Postoperative chyle leakage was observed in 18 of the 491 patients who underwent left lateral neck dissection. We treated 17 patients conservatively and 1 patient surgically. Drains were removed within five days in all patients. After the drain negative pressure release test had been performed in eight patients, the drainage volume significantly decreased from an average of 175 ml to 31 ml per day. The average number of days until the removal of the drainage tube was 3.2 days. No perioperative complications were associated with ice cream consumption. CONCLUSIONS: In left lateral neck dissection for thyroid cancer, performing surgery following ice cream consumption does not completely prevent chyle leakage; however, early drain removal is possible because there is only mild leakage.
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Arthroscopic partial trapeziectomy with suture-button suspensionplasty was developed for the surgical treatment of thumb carpometacarpal arthritis. However, the relationship between clinical results and radiographic evidence is unclear. Methods: The authors retrospectively reviewed 33 consecutive patients who underwent arthroscopic partial trapeziectomy with suture-button suspensionplasty for thumb carpometacarpal arthritis between 2016 and 2021. Clinical and radiographic outcomes were recorded, and the correlations between them were evaluated. Results: The average patient age at surgery was 69 years. Patient radiologic evidence was Eaton stage â ¡ in three thumbs, â ¢ in 25 thumbs, and â £ in five thumbs. The average trapezial space ratio (TSR) was 0.36 immediately after the operation but declined to 0.32 after 6 months. In contrast, the average joint subluxation was reduced to 0.005 immediately after the operation compared with 0.28 before, and was maintained at 0.04 at final follow-up. A statically significant correlation was detected between grip strength and TSR (P = 0.03), and between pinch strength and TSR (P = 0.02). A significant correlation was detected between TSR and trapezium height (P = 0.0215), which remained after partial trapeziectomy. No correlation was detected between rope position and other clinical or radiographic scores. Conclusions: Suture-button can have an effect on the medialization of the first metacarpal base. Excessive trapeziectomy can result in functional deficiency of the thumb through metacarpal subsidence, which potentially causes loss of grip and pinch strength.
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Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.
Subject(s)
Stroke , Humans , Japan , Lacosamide , Retrospective Studies , Hospitals , SeizuresABSTRACT
BACKGROUND: We newly developed a muscle graft that employs a doxorubicin pretreatment technique. The aims of this study were to reveal the biological and morphological features of the muscle tissue in the second week (Study I), to reveal the regeneration outcomes of functional and kinematic assessments of longer-term follow-up (16 weeks, Study II), and to make assessments of the muscle graft with doxorubicin pretreatment in the critical-sized nerve defect model (20 mm, Study III). METHODS: A total of 26 adult rats were used in this study. Doxorubicin treatment was accomplished by immersion in a doxorubicin solution for 10 minutes followed by a rinsing procedure. The rats were divided into three groups: the muscle graft with and without doxorubicin pretreatment (M-graft-w-Dox and M-graft-w/o-Dox) groups and the autologous nerve graft (N-graft) group. Assays of apoptosis, immunofluorescent histochemistry including CD68 (macrophage marker), scanning electron microscopy (SEM), morphometrical studies of the regenerated axons, nerve conduction studies, and kinematic studies were performed. RESULTS: The M-graft-w-Dox group contained significantly larger numbers of apoptotic cells and CD68-positive cells. SEM revealed the existence of the basal lamina, so called "empty tubes," in the M-graft-w-Dox group. Study II showed contentious maturation of the regenerated axons, especially in the compound muscle action potentials. Study III showed that even at 20 mm, the M-graft-w-Dox group promoted axonal regeneration and functional regeneration. CONCLUSION: The M-graft-w-Dox group showed superior regeneration results, and this easy and short-term procedure can expand the muscle graft clinical indication for the treatment of peripheral nerve defects.
Subject(s)
Nerve Regeneration , Sciatic Nerve , Rats , Animals , Nerve Regeneration/physiology , Sciatic Nerve/surgery , Sciatic Nerve/physiology , Muscles , Axons/physiology , Basement Membrane/physiology , Basement Membrane/transplantation , Doxorubicin/pharmacologyABSTRACT
BACKGROUND: This study represents the clinical results, especially range of motion (ROM) improvement, of arthroscopic partial trapeziectomy with suture-button suspensionplasty for symptomatic grade II and III thumb carpometacarpal arthritis with a minimum 1-year follow-up. METHODS: Thirty-two patients (mean: 67.5 years) with grade II and III thumb carpometacarpal arthritis treated with arthroscopic partial trapeziectomy with suture-button suspensionplasty were retrospectively followed up for at least 1 year. The physical assessments included ROM, pain visual analogue scale (VAS), strength, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. The physical variables were retrospectively compared before surgery and at the final follow-up. RESULTS: Preoperative radial abduction and palmar abduction (45.4 ± 16.4° and 54.3 ± 13.9°, respectively) were significantly increased at the final follow-up (59.7 ± 16.9° and 65.5 ± 14.2°, respectively). Preoperative VAS score, pinch strength, and DASH score (70.5 ± 14.0, 57.2 ± 24.8% and 36.8 ± 14.8, respectively) were also significantly improved at the final follow-up (7.9 ± 9.1, 91.0 ± 39.6%, and 11.7 ± 10.5, respectively). Complications involved 1 case of irritation of the superficial branch of the radial nerve and 1 case of dystonia. Two suture-buttons were removed due to patient discomfort. CONCLUSIONS: A significant increase in ROM and pain relief was obtained after suture-button suspensionplasty with arthroscopic partial trapeziectomy.
Subject(s)
Carpometacarpal Joints , Osteoarthritis , Humans , Osteoarthritis/surgery , Thumb/surgery , Retrospective Studies , Carpometacarpal Joints/surgery , Sutures , PainABSTRACT
BACKGROUND: The anterolateral thigh (ALT) flap has been used in upper extremity reconstruction. However, there is no consensus about the age at which the flap can be used safely, which is a concern when applying ALT flaps for upper extremity reconstruction in older patients. We present the results of the use of ALT flap for upper extremity reconstruction in a series of older patients. PATIENTS AND METHODS: Seventeen patients who underwent ALT flaps for soft tissue defects in the upper extremities from 2010 to 2020 were included. The patients' mean age was 63.5 (range, 26-83) years. Ten of seventeen patients were smokers. Defect locations were the dorsum of the hand in seven patients, palm in two patients, dorsum and palm in two patients, and forearm in six patients. Etiologies of the defect were traumatic in 14 patients and malignant tumor in three patients. The defect size was 8 to 25 × 5 to 11 cm. When dissecting the perforators, we preserved the surrounding small muscular and fatty tissue with the perforators and to harvest them together to prevent intima damage. Flap thinning was performed for 16 flaps to adjust the flap thickness to match defect site requirements. We used an end-to-side or interposition arterial anastomosis to regulate the blood flow. RESULTS: The flap size was 9 to 28 × 5 to 13 cm. One patient had venous congestion and vein re-anastomosis was needed. All flaps survived. One patient had a methicillin-resistant Staphylococcus aureus infection and debridement and irrigation was needed. The mean follow-up period was 20 (range, 13-37) months. Fifteen patients returned their previous activities. The mean DASH score was 30.6 (range, 3-70). CONCLUSIONS: Regardless of patient age or smoking status, the ALT flap was a safe and reliable surgical option for soft tissue defect reconstruction of the upper extremity.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Plastic Surgery Procedures , Soft Tissue Injuries , Humans , Aged , Middle Aged , Thigh/surgery , Thigh/blood supply , Soft Tissue Injuries/surgery , Plastic Surgery Procedures/methods , Upper Extremity/surgery , Upper Extremity/injuries , Treatment OutcomeABSTRACT
Autologous nerve grafting is the gold standard method for peripheral nerve injury with defects. Artificial nerve conduits have been developed to prevent morbidity at the harvest site. However, the artificial conduit regeneration capacity is not sufficient. A Bio 3D printer is technology that creates three-dimensional tissue using only cells. Using this technology, a three-dimensional nerve conduit (Bio 3D nerve conduit) was created from several cell spheroids. We reported the first application of the Bio 3D nerve conduit for peripheral nerve injury. A Bio 3D nerve conduit that was created from several cells promotes peripheral nerve regeneration. The Bio 3D nerve conduit may be useful clinically to treat peripheral nerve defects.
Subject(s)
Peripheral Nerve Injuries , Humans , Peripheral Nerve Injuries/surgery , Nerve Regeneration/physiology , Peripheral Nerves/surgery , Prostheses and Implants , Autografts , Tissue ScaffoldsABSTRACT
BACKGROUND: There is no report of the application of intraoperative computed tomography to the extremities, and its usefulness is not mentioned. CASE PRESENTATION: We present a case of a patient with the elbow pain and loss of the forearm rotation due to the prominent bicipital tuberosity of the radius, which was diagnosed as enthesopathy. Surgical treatment to excise the prominent part of the bicipital tuberosity of the radius was recommended. However, it is difficult to perform the appropriate excision of the abnormal prominent part because of complications such as bicipital tendon rupture. The patient was successfully treated by surgical resection under the control of intraoperative computed tomography. CONCLUSIONS: Intraoperative computed tomography scan is a useful tool to assess the remaining volume of the abnormal bones.
Subject(s)
Enthesopathy/diagnosis , Radius/diagnostic imaging , Surgery, Computer-Assisted/methods , Tendon Injuries/surgery , Tendons/diagnostic imaging , Tomography, X-Ray Computed/methods , Aged , Elbow Joint/surgery , Enthesopathy/etiology , Enthesopathy/surgery , Female , Humans , Tendon Injuries/complications , Tendon Injuries/diagnosis , Tendons/surgeryABSTRACT
BACKGROUND: Although decellularized nerve grafts are often used as a bridging material in nerve defect repair, the lack of perfusion support in this procedure limits the regeneration capacity. To address this, we applied vascularized biogenic conduits, which are fibrous membranes prefabricated around the silicone rod that contain rich vascularity and macrophages, to nerve defect repair procedures using decellularized nerve grafts. The purpose of this study is to investigate the capacity of combining a vascularized biogenic conduit and a decellularized nerve graft for peripheral nerve regeneration using a 10-mm nerve defect model in rats. MATERIALS AND METHODS: Sixteen adult male rats (F344 rats, 10-12 weeks, 200-250 g) were used in this study. For the prefabrication of vascularized biogenic conduits, a silicone rod was transplanted next to the sciatic nerve. After 8 weeks, this silicone rod was enveloped in connective tissue, called a vascularized biogenic conduit. The first rat was used to investigate the histological characteristics of vascularized biogenic conduits through immunofluorescence studies. The remaining 15 rats were divided into three groups to evaluate the efficacy of the combination of a decellularized nerve graft and a vascularized biogenic conduit: a decellularized nerve graft (DNG) group, a decellularized nerve graft with a vascularized biogenic conduit (DNG-w-VBC) group, and an autologous nerve graft (ANG) group. Eight weeks after nerve graft surgery, the assessment results of both functional recovery (electrophysical studies and target muscle atrophy) and morphological recovery (total number, diameter, and myelin thickness of the regenerated axons) of the regenerated nerves were examined. RESULTS: Immunofluorescence studies revealed that the VBC contains extracellular matrix, vascular tissue, and macrophages. The results of the DNG-w-VBC group were superior to the DNG group in electrophysiological studies (CMAP; 6.29 ± 0.80% vs. 4.02 ± 3.35%, MNCV; 50.6 ± 8.4% vs. 25.7 ± 15.6%, p < .05, respectively), regenerated axon number (11,348 ± 812 vs. 7697 ± 2197, p < .05), and mean axon diameter (2.72 ± 0.33 µm vs. 1.64 ± 0.12 µm, p < .05). CONCLUSIONS: Our study confirms that vascularized biogenic conduits supply vascularity and macrophages to nerve defect sites. Combining vascularized biogenic conduits with decellularized nerve grafts to treat nerve defects offers superior functional and morphological recovery of regenerated axons.
Subject(s)
Nerve Regeneration , Sciatic Nerve , Animals , Axons/physiology , Male , Nerve Regeneration/physiology , Rats , Rats, Inbred F344 , Recovery of Function , Sciatic Nerve/pathologyABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Oxaliplatin (L-OHP) is an antineoplastic agent that frequently causes vascular pain. However, the risk factors for vascular pain are unclear, and prevention methods have not been established. We retrospectively investigated patients who were treated with L-OHP to examine the influence of patient characteristics and concomitant analgesic use on the incidence of vascular pain. METHODS: We collected information about the presence or absence of vascular pain, age, sex, treatment dose and analgesic use of patients who received L-OHP at Tokyo Medical University Hachioji Medical Center. We analysed the relevance of each factor between the vascular pain onset and non-onset groups. RESULTS AND DISCUSSION: Thirty-two patients (average age: 68.6 years; 69.8% and 30.2% men and women, respectively) were classified into the vascular pain onset (n = 64) and non-onset groups (n = 68). The multivariate logistic regression analysis revealed that L-OHP concentration (>358.5 mg/L) was an independent determinant of vascular pain development (odds ratio: 2.422, 95% CI: 1.117-5.252). Intergroup differences in age, sex, body mass index, non-steroidal anti-inflammatory drug use, and underlying pain from cancer and other comorbidities were not significant. WHAT IS NEW AND CONCLUSION: High L-OHP concentration was identified as a significant risk factor for L-OHP-induced vascular pain. Our results indicate that the dilution of L-OHP may reduce the incidence of vascular pain.
Subject(s)
Antineoplastic Agents , Aged , Analgesics/adverse effects , Antineoplastic Agents/adverse effects , Female , Humans , Male , Oxaliplatin/adverse effects , Pain/drug therapy , Retrospective Studies , Risk FactorsABSTRACT
Background The number of patients with epilepsy receiving perampanel or lacosamide as an add-on treatment following levetiracetam treatment has increased. Although levetiracetam causes psychiatric disorders, it is unclear whether they occur with the combined use of these antiepileptic drugs. Objective To determine the frequency of psychiatric disorders in patients received lacosamide or perampanel in combination with levetiracetam. Setting A single-center retrospective cohort study. Method Patients who received levetiracetam + lacosamide or levetiracetam + perampanel were selected. Medical records from the start of combination therapy contained characteristics of patients and the incidence of psychiatric disorders. Main outcome measure The frequency of psychiatric disorders, the time to onset, dose reduction or discontinuation following psychiatric disorders, and the clinical course following disorder onset. Results Forty-four patients used levetiracetam + lacosamide and 50 used levetiracetam + perampanel. The incidence of psychiatric disorders was significantly lower (p < 0.001) with levetiracetam + lacosamide (6.8%) than with levetiracetam + perampanel (44%). The incidence of affect lability was significantly higher with levetiracetam + perampanel than with levetiracetam + lacosamide (p = 0.018). The time to the onset of psychiatric disorders was within 1 month of dose initiation or increase in one case (33.3%) with levetiracetam + lacosamide and 16 cases (72.7%) with levetiracetam + perampanel. There was no significant difference in clinical characteristics and antiepileptic drug dosages owing to the presence or absence of psychiatric disorders. Conclusion As the frequency of psychiatric disorders was higher with levetiracetam + perampanel therapy, levetiracetam + lacosamide may be preferable. These disorders tended to develop within 1 month of therapy and were not dose-dependent. Antiepileptic drugs should be cautiously prescribed to avoid psychiatric disorders.
Subject(s)
Anticonvulsants , Mental Disorders , Anticonvulsants/therapeutic use , Drug Therapy, Combination , Humans , Lacosamide , Levetiracetam , Mental Disorders/drug therapy , Mental Disorders/epidemiology , Nitriles , Pyridones , Retrospective Studies , Treatment OutcomeABSTRACT
We present the case of a Tailgut cyst occurring in the retrorectal space that was curatively resected using a posterior approach. A 40-year-old man presented to the Kochi Health Sciences Center with the chief complaint of perineal incongruity. Pelvic magnetic resonance imaging revealed a multilocular cystic lesion in the retrorectal space, with high signal intensity on T2-weighted imaging. After diagnosing a Tailgut cyst, we performed resection of the tumor using a posterior approach. The lesion was removed en bloc with the coccyx. Histopathologically, the lesion was diagnosed as a non-malignant Tailgut cyst, and the surgical margin was negative. The patient is currently doing well without recurrence at 20 months.
Subject(s)
Cysts , Hamartoma , Adult , Cysts/surgery , Humans , Magnetic Resonance Imaging , Male , Neoplasm Recurrence, Local , PerineumABSTRACT
BACKGROUND: We previously reported the development of a scaffold-free Bio three-dimensional (3D) nerve conduit from normal human dermal fibroblasts (NHDFs). The aim of this study was to investigate the regenerative mechanism of peripheral nerve cells using a Bio 3D conduit in a rat sciatic nerve defect model. METHODS: Bio 3D conduits composed of NHDFs were developed, and cell viability was evaluated using a LIVE/DEAD cell viability assay immediately before transplantation and 1-week post-surgery. Tracking analysis using PKH26-labeled NHDFs was performed to assess the distribution of NHDFs within the regenerated nerve and the differentiation of NHDFs into functional Schwann cells (SCs). RESULTS: The assessment of the viability of cells within the Bio 3D conduit showed high cell viability both immediately before transplantation and 1-week post-surgery (88.56 ± 1.70 and 87.58 ± 9.11, respectively). A modified Masson's trichrome staining of the Bio 3D conduit revealed the formation of a prominent extracellular matrix (ECM) in between the cells. We observed, via tracking analysis, that the tube-like distribution of the NHDFs remained stable, the majority of the regenerated axons had penetrated this structure and PKH26-labeled cells were also positive for S-100. CONCLUSION: Abundant ECM formation resulted in a stable tube-like structure of the Bio 3D conduit with high cell viability. NHDFs in the Bio 3D conduit have the potential to differentiate into SCs-like cells.
Subject(s)
Nerve Regeneration , Sciatic Nerve , Animals , Axons , Fibroblasts , Humans , Rats , Schwann CellsABSTRACT
We previously reported that a nerve conduit created from fibroblasts promotes nerve regeneration in a rat sciatic nerve model. This study aims to determine whether a nerve conduit created from bone marrow stromal cells (BMSCs) can promote nerve regeneration. Primary BMSCs were isolated from femur bone marrow of two Lewis rats, and cells at passages 4-7 were used. We created seven Bio 3D nerve conduits from BMSCs using a Bio-3D Printer. The conduits were transplanted to other Lewis rats to bridge 5-mm right sciatic nerve gaps (Bio 3D group, n = 7). We created two control groups: a silicone group (S group, n = 5) in which the same nerve gap was bridged with a silicone tube, and a silicone cell group (SC group, n = 5) in which the gap was bridged with a BMSC injection. Twelve weeks after transplantation, nerve regeneration was evaluated functionally and morphologically. In addition, PKH26-labeled BMSCs were used to fabricate a Bio 3D conduit that was transplanted for cell trafficking analysis. Electrophysiological study, kinematic analysis, wet muscle weight, and morphological parameters showed significantly better nerve regeneration in the Bio 3D group than in the S group or SC group. In immunohistochemical studies, sections from the Bio 3D group contained abundant S-100-positive cells. In cell trafficking analysis, PKH26-positive cells stained positive for the Schwann cell markers S-100, p75NTR, and GFAP. Bio 3D nerve conduits created from BMSCs can promote peripheral nerve regeneration in a rat sciatic nerve model through BMSC differentiation into Schwann-like cells.
Subject(s)
Guided Tissue Regeneration , Mesenchymal Stem Cells/cytology , Nerve Regeneration/physiology , Peripheral Nerves/physiopathology , Action Potentials , Animals , Biomechanical Phenomena , Cell Survival , Cell Tracking , Male , Muscles/pathology , Organ Size , Rats, Inbred LewABSTRACT
5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.
Subject(s)
Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Intestine, Small/drug effects , Models, Biological , Nausea/prevention & control , Receptors, Serotonin, 5-HT3/drug effects , Serotonin 5-HT3 Receptor Antagonists/pharmacokinetics , Vomiting/prevention & control , Antineoplastic Agents/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/blood , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cisplatin/administration & dosage , Constipation/chemically induced , Creatinine/urine , Granisetron/blood , Granisetron/pharmacokinetics , Humans , Hydroxyindoleacetic Acid/urine , Intestine, Small/metabolism , Intestine, Small/physiopathology , Isoquinolines/blood , Isoquinolines/pharmacokinetics , Nausea/chemically induced , Nausea/metabolism , Oxazines/blood , Oxazines/pharmacokinetics , Palonosetron , Quinuclidines/blood , Quinuclidines/pharmacokinetics , Receptors, Serotonin, 5-HT3/metabolism , Serotonin/metabolism , Serotonin 5-HT3 Receptor Antagonists/adverse effects , Serotonin 5-HT3 Receptor Antagonists/blood , Vomiting/chemically induced , Vomiting/metabolismABSTRACT
5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.
Subject(s)
Antiemetics/urine , Granisetron/urine , Receptors, Serotonin, 5-HT3/metabolism , Serotonin Antagonists/urine , Aged , Antiemetics/pharmacokinetics , Antiemetics/therapeutic use , Creatinine/urine , Female , Granisetron/pharmacokinetics , Granisetron/therapeutic use , Humans , Hydroxyindoleacetic Acid/urine , Intestine, Small/metabolism , Male , Middle Aged , Models, Biological , Nausea/blood , Nausea/drug therapy , Nausea/urine , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/urine , Serotonin/metabolism , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/therapeutic useABSTRACT
BACKGROUND: The aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT(3) receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT(3) receptor occupancies, based on receptor occupancy theory. METHODS: We analyzed interindividual differences of 5-HT(3) receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT(3) receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron. RESULTS: The interindividual difference between maximum and minimum 5-HT(3) receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%. CONCLUSION: Interindividual differences in the clinical effects of 5-HT(3) receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.