Perioperative Management of Spinal Arteriovenous Malformation Embolization: Delayed Venous Thrombosis and Implications for Severe Back Pain.

BACKGROUND AND PURPOSE: The prognosis of untreated spinal arteriovenous malformations (SAVMs) is poor. Embolization plays an important role in the management of intramedullary SAVMs. Delayed aggravation due to spinal venous thrombosis following successful embolization has been reported; however, perioperative management strategies to prevent thrombosis have not been explored. We present our single-center experience of SAVM embolization and perioperative management, including anticoagulation. MATERIAL AND METHODS: We retrospectively evaluated 18 patients with SAVMs who underwent transarterial embolization. Perioperative anticoagulation therapy was administered to selected patients. We compared the characteristics of the patients, including perioperative management procedures, between those with and without postoperative worsening following embolization. RESULTS: Acute postoperative worsening within 1 week occurred in 4 (22.2%) patients. Of these, immediate worsening was observed in one patient as a procedure-related complication. Delayed worsening after 24 h was observed in 3 patients, caused by delayed venous thrombosis with severe back pain. Rescue anticoagulation for delayed worsening improved symptoms in two patients. A comparison between patients with and without acute postoperative worsening revealed significant differences in age (median 46.5 vs. 26.5 years, p = 0.009) and the presence of postoperative back pain (75.0% vs. 0%, p = 0.005); however, there was no significant difference in use of selective anticoagulation (p = 0.274). CONCLUSION: The results of this study suggest that SAVM embolization can cause acute worsening due to postoperative venous thrombosis with severe back pain, which may be reversed by anticoagulation therapy. Back pain is an important finding that suggests venous thrombosis, and anticoagulation should be urgently administered.

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

Quantitative prediction of CYP3A-mediated drug-drug interactions by correctly estimating fraction metabolized using human liver chimeric mice.

BACKGROUND AND PURPOSE: Fraction metabolized (fm ) and fraction transported (ft ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo fm due to inability to reflect the ft by efflux transporters (ft,efflux ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice. EXPERIMENTAL APPROACH: For estimating human in vitro fm by CYP3A enzyme (fm,CYP3A,in vitro ), six drugs, including CYP3A/P-gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated fm,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo fm,CYP3A (fm,CYP3A,in vivo ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated fm,CYP3A,in vivo using the change of total clearance (CLtotal ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu-PXB and SCID mice with or without ketoconazole. We calculated the change of CLtotal caused by ketoconazole. We compared the CLtotal change in humans with that in Hu-PXB and SCID mice. KEY RESULTS: The fm,CYP3A,in vitro was overestimated compared to the fm,CYP3A,in vivo . Hu-PXB mice showed much better correlation in the change of CLtotal with humans (R2 = 0.95) compared to SCID mice (R2 = 0.0058). CONCLUSIONS AND IMPLICATIONS: CYP3A-mediated DDI can be predicted by correctly estimating human fm,CYP3A,in vivo using Hu-PXB mice. These mice could be useful predicting hepatic fm and ft,efflux .

Pistol Shooting Dystonia Treated with Thalamotomy.

Background: Neurosurgical treatment for pistol shooting dystonia has not been studied. Case report: The patient was a 41-year-old woman who participated in the Olympic Games four times as a shooting player. Five months after the final Tokyo Olympic trials, she developed dystonia of the right index finger when shooting. Stereotactic thalamotomy was performed, and a complete resolution of dystonia was achieved. She garnered her personal best score and placed fifth in the Tokyo Olympics. Discussion: Thalamotomy along with deep brain stimulation can be a surgical modality for patients with task-specific dystonia who fail oral medications or botulinum toxin therapy.

De Novo Radicular Arteriovenous Fistula After Treatment of Spinal Arteriovenous Fistula: A Case Report and Literature Review.

De novo spinal dural arteriovenous fistulas (AVFs) have been reported as metachronous AVFs However, metachronous spinal AVFs are extremely rare, and their pathogenesis remains uncertain. We report a case of de novo radicular AVF (RAVF) following treatment for spinal AVF at the craniocervical junction (CCJ). We also reviewed the literature and discussed the pathogenesis of metachronous spinal AVF. A 64-year-old male patient diagnosed with spinal AVF at the CCJ supplied from the right C1 segmental artery was treated with Onyx-18 (eV3 Inc, CA, USA) trans-arterial embolization, resulting in partial occlusion. Angiography showed a slight residual shunt two weeks after the embolization without another shunt lesion. A five-year follow-up spinal angiography showed de novo RAVF at the C4 level and complete occlusion of the first AVF. The second AVF was not treated because it was asymptomatic, and the patient remained asymptomatic. De novo RAVF was found to develop five years after the embolization of a CCJ-spinal AVF in a patient. This is the first case of de novo RAVF post-treatment of a spinal AVF. This case demonstrated that RAVF could develop as an acquired disease.

Successful embolization of ventricular arteriovenous malformation supplied by the choroidal artery: A case report and literature review.

Background: Ventricular arteriovenous malformations (AVMs) are localized in the ventricles and are mainly fed by the anterior choroidal artery (AChoA) and posterior choroidal artery (PChoA). Surgical resection of ventricular AVMs is difficult as the lesions are localized deep in the brain. Therefore, endovascular treatment is expected to treat ventricular AVMs. However, embolization from the AChoA and PChoA carries the risk of ischemic complications. Even though there are some major reports on embolization strategies from the choroidal arteries, embolization of these arteries remains technically challenging. In this article, we report two successful cases of ventricular AVM embolization using AChoA and PChoA. Case Description: Case 1: A 34-year-old male presented with intraventricular hemorrhage (IVH). Subsequently, ventricular AVM embolization in the anterior horn was performed using n-butyl-2-cyanoacrylate (NBCA) through the AChoA and medial PChoA, and complete obliteration was observed without neurological deterioration. Case 2: A 71-year-old female presented with IVH. Subsequently, ventricular AVM embolization in the lateral ventricle was performed through the AChoA and lateral PChoA with Onyx and NBCA, and partial obliteration was observed without complications. Furthermore, Gamma Knife surgery for residual lesions resulted in complete obliteration. Conclusion: Embolization through the choroidal arteries for ventricular AVMs is an effective curative or adjunctive treatment.

Progress in the Quantitative Assessment of Transporter-Mediated Drug-Drug Interactions Using Endogenous Substrates in Clinical Studies.

Variations in drug transporter activities, caused by genetic polymorphism and drug-drug interactions (DDIs), alter the systemic exposure of substrate drugs, leading to differences in drug responses. Recently, some endogenous substrates of drug transporters, particularly the solute carrier family transporters such as OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K, have been identified to investigate variations in drug transporters in humans. Clinical data obtained support their performance as surrogate probes in terms of specificity and reproducibility. Pharmacokinetic parameters of the endogenous biomarkers depend on the genotypes of drug transporters and the systemic exposure to perpetrator drugs. Furthermore, the development of physiologically based pharmacokinetic models for the endogenous biomarkers has enabled a top-down approach to obtain insights into the effect of perpetrators on drug transporters and to more precisely simulate the DDI with victim drugs, including probe drugs. The endogenous biomarkers can address the uncertainty in the DDI prediction in the preclinical and early phases of clinical development and have the potential to fulfill regulatory requirements. Therefore, the endogenous biomarkers should be able to predict disease effects on the variations in drug transporter activities observed in patients. This mini-review focuses on recent progress in the identification and use of the endogenous drug transporter substrate biomarkers and their application in drug development. SIGNIFICANCE STATEMENT: Advances in analytical methods have enabled the identification of endogenous substrates of drug transporters. Changes in the pharmacokinetic parameters (Cmax, AUC, or CLR) of these endogenous biomarkers relative to baseline values can serve as a quantitative index to assess variations in drug transporter activities during clinical studies and thereby provide more precise DDI predictions.

Subclavian Artery-Carotid Artery Bypass for Subclavian Artery or Common Carotid Artery Severe Stenosis or Occlusion.

Various surgical treatments are available for occlusive subclavian and common carotid artery diseases. Nevertheless, to date, when cerebral endovascular treatment is utilized, revascularization via direct surgery may be required. This study reported five symptomatic cases of revascularization for CCA and SCA occlusive and stenotic lesions that were expected to be challenging to treat with endovascular treatment. We performed subclavian artery-common carotid artery or internal carotid artery bypass using artificial blood vessels or saphenous vein grafts in five patients with subclavian steal syndrome, symptomatic common carotid artery occlusion, and severe proximal common carotid artery stenosis. In this study, good bypass patency was achieved in all five cases. Although there were no intraoperative complications, one patient had a postoperative lymphatic leak. Moreover, there was no recurrence of stroke during postoperative follow-up for an average of 2 years. Conclusively, subclavian artery-common carotid artery bypass can be an effective surgical treatment for common carotid artery occlusion, proximal common carotid artery stenosis, and subclavian artery occlusion.

Postsurgical dural supply to the spinal cord arteriovenous malformation in spinal arteriovenous metameric syndrome.

Dural supply from the external carotid system in cerebral arteriovenous malformations (AVMs) is well known, but actual angiographic evidence of dural supply to spinal cord AVMs (SCAVMs) has not been reported. Here, we report a case of dural supply to the conus SCAVM in the spinal arteriovenous metameric syndrome segment 25-30. Thirteen years after spinal surgery (T12-L2 laminoplasty), spinal angiography showed multiple dural supplies from the dorsal somatic branches, prelaminar arteries, and radiculomeningeal arteries to the SCAVM at the level of the previous spinal surgery. To the best of our knowledge, this is the first reported case with dural supply to the spinal cord. This case demonstrates that the extradural and extraspinal branches can supply the spinal cord in rare instances of spinal dural adhesions following repeated hemorrhages and surgical intervention under a metameric link background.

Angiographic Index for the Treatment Efficacy and Functional Outcomes of Spinal Cord Arteriovenous Shunts: the Vertebral Blush Sign.

BACKGROUND: The functional outcomes in spinal cord arteriovenous shunts (SCAVSs) are usually unpredictable from current assessments of treatment results. We aimed to investigate and propose a new index marker, the vertebral blush (VB) sign, for assessing the treatment efficacy of SCAVSs. METHODS: This retrospective cohort study enrolled patients diagnosed with SCAVSs between June 2012 and May 2021. The VB sign was defined as the angiographic finding of reappearance or enhanced contrast staining of the vertebral bodies fed by shunt-related arteries observed after shunt occlusion. The primary outcome was the improvement in motor/sensory disturbances or sphincter impairments within 1 year after treatment. The secondary outcome was shunt recanalization. VB sign characteristics and associations with outcomes were analyzed. RESULTS: Of 65 patients with SCAVSs, 57 were eligible for VB sign assessment; among these, there were 26 with the VB sign and 31 without the VB sign. Among vascular shunts perimedullary arteriovenous fistula showed the greatest difference in prevalence rate between those with and without the VB sign (33.3%, n = 9/27 versus 10.0%, n = 3/30; P = 0.031). On multivariable logistic regression analysis, SCAVSs with the VB sign had significantly more favorable outcomes than those without the VB sign (adjusted odds ratio, 5.61; 95% confidence interval, 1.48-21.23; P = 0.01). There was no relationship between the VB sign and secondary outcomes (P = 0.35). CONCLUSION: The VB sign is independently associated with functional recovery after shunt occlusion and could be an assessment tool for the treatment efficacy of SCAVSs.

Pure spinal intraosseous arteriovenous fistula: A case report.

Spinal osseous arteriovenous fistula (AVF) is a rare disease with a characteristic angioarchitecture involving an intraosseous venous pouch (VP) of the vertebral body where the feeders are converging. Using spinal angiography alone, it is difficult to distinguish spinal osseous AVF from classical spinal epidural AVF (EDAVF) with fistulas in the epidural VP and bone erosion because both subtypes have an angiographically similar dilated VP appearance. Thus, spinal osseous AVF may be often misdiagnosed as spinal EDAVF. With advancing imaging techniques, it would be possible to determine the exact location of the fistula. Here, we present the case of a 37-year-old woman with a pure spinal thoracic osseous AVF and radiculopathy. She was diagnosed with spinal intraosseous AVF using high-resolution three-dimensional rotational angiography (3D-RA). The fistula was located in the Th1 lateral mass with a VP where multiple osseous feeders were converging. There was paravertebral venous drainage without intradural venous drainage. Transvenous embolization with Onyx and coils was performed through the azygos vein to the lateral epidural venous plexus, resulting in complete obliteration. This case suggests that 3D-RA reconstructed images are essential for accurate diagnosis and successful treatment of this condition. It is important to occlude only intraosseous VPs by accurate subtype diagnosis. Transvenous embolization is a treatment option for spinal intraosseous AVF with paravertebral epidural venous drainage.

FLOW-diverted Glue Embolization to Target lesions (FLOW-GET) technique for spinal vascular diseases: A technical note.

We present and exemplify the flow-diverted glue embolization to target lesions (FLOW-GET) technique for spinal vascular diseases. In this technique, the occlusion of the posterior intercostal artery or dorsal muscular branch by coils diverts the injected glue from the segmental artery to the target lesions. This technique was applied to a ruptured retrocorporeal artery aneurysm and spinal dural arteriovenous fistulas. The FLOW-GET accomplished the complete obliteration of all lesions. This simple and useful technique can be applied to spinal vascular lesions even if a microcatheter is not placed in proper feeders or advanced close to the shunt points or aneurysms.

Optimal guiding catheter position during advancement of the guiding catheter into the carotid artery from the aortic arch via transfemoral approach.

BACKGROUND: Guiding catheter (GC) advancement into the target carotid artery is a crucial step in neuroendovascular therapy. In difficult anatomies, alternative methods have been reported to overcome difficult carotid access for swift GC advancement. However, studies focusing on the positional relationship between the GC and inner catheter (IC) at the aortic arch are lacking. METHODS: We evaluated the impact of the positional relationship between the GC and IC on whether the GC position affects catheter support or system straightening. We retrospectively reviewed 89 patients who underwent neuroendovascular therapy. We assessed the time to carotid access across difficult arch anatomies. The GC position was divided into Position 1, descending aorta level; Position 2, aortic arch level; and Position 3, origin of the left common carotid artery or innominate artery. We also evaluated the GC support and straightening effects in an in vitro vascular model study. RESULTS: The coaxial catheter flexion angle at the aortic arch was significantly larger when the GC was set to Position 3 (p < 0.0001). A significantly shorter time to carotid access was observed with Positions 2 and 3 than with Position 1 in the difficult arch anatomy group. In the in vitro vascular model evaluation, the catheter support effect significantly increased as the GC position became closer to the IC tip (p < 0.0001) and straightening effect significantly increased as the GC moved to Position 2 from Position 1 (p < 0.0001). CONCLUSION: During GC advancement, the GC positional relationship changed the support of the coaxial system with system straightening. The optimal GC position, Position 3, facilitated swift GC advancement.

Bilateral Radiofrequency Ventral Intermediate Thalamotomy for Essential Tremor.

INTRODUCTION: With the advent of MR-guided focused ultrasound, the importance of the efficacy and safety of bilateral ventral intermediate (Vim) thalamotomy for essential tremor (ET) has increased. However, reports on bilateral Vim thalamotomy for ET remain scarce. METHODS: To review the results and complications of bilateral Vim thalamotomy for the treatment of ET in the upper extremities, we retrospectively analyzed the patients with ET who underwent bilateral Vim thalamotomy with radiofrequency (RF) thermal coagulation. As bilateral simultaneous thalamotomy can cause surgical complications, thalamotomy was performed in stages. The interval between the first and second thalamotomies was 21.3 ± 14.7 months. We evaluated the efficacy using the Clinical Rating Scale for Tremor (CRST) before and after the first and second treatments, respectively. We also evaluated the complications before and after the first and second treatments, respectively. Moreover, we assessed the adverse events. RESULTS: Seventeen patients were included in the study. The mean follow-up period following the second thalamotomy was 29.3 ± 15.0 months. The CRST part A + B scores were 34.9 ± 9.7, 20.8 ± 7.0, and 7.4 ± 6.8 before, following the first (40.4% improvement, p < 0.0001) and second thalamotomies (78.6% improvement, p < 0.0001), respectively. Nine patients presented with prolonged adverse events, including dysarthria, dysgeusia, dysphagia, tongue numbness, unsteady gait, and postural instability at the last available evaluation. All adverse events were mild and did not interfere with the patient's daily activities. DISCUSSION/CONCLUSIONS: Bilateral Vim thalamotomy with RF thermal coagulation was an effective treatment for ET in both upper extremities. Despite most possible complications being mild, additional studies with a larger sample size are required to ensure patient safety.

Cerebral venous thrombosis associated with hyperhomocysteinemia and iron-deficiency anemia induced by autoimmune gastritis: A case report and literature review.

Cerebral venous thrombosis (CVT) is a rare disease, occurring in 0.5%-1% of all patients with strokes. Systemic and hereditary diseases and traumas are potential causes of CVT. We report a case of CVT and systemic thromboembolism complicated with hyperhomocysteinemia and iron-deficiency anemia caused by autoimmune gastritis. A 47-year-old female patient was admitted to the emergency department due to difficulty in movement, impaired consciousness, and urinary incontinence. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral thalamic edema associated with venous sinus thrombosis and embolic cerebral infarction in the deep white matter of the bilateral cerebral hemispheres. In addition, contrast enhanced whole-trunk CT scan showed deep femoral thrombosis and pulmonary artery embolism. She had no medical history of diseases or drug use that may cause thrombosis. Blood test results revealed iron-deficiency anemia and hyperhomocysteinemia, which were determined to be the cause of systemic thromboembolism. The patient tested positive for intrinsic factor antibodies. Moreover, the patient was diagnosed with autoimmune gastritis by gastrointestinal endoscopy. Therapies including anticoagulant and replacement with iron and vitamin B12 were administered. The patient was discharged from the hospital without neurological deficits. A favorable clinical course was achieved with anticoagulant administration and replacement therapy with iron and vitamin B12 for cerebral arteriovenous embolism that developed due to autoimmune gastritis.

Cluster Gauss-Newton method analyses of PBPK model parameter combinations of coproporphyrin-I based on OATP1B-mediated rifampicin interaction studies.

Coproporphyrin I (CP-I) is an endogenous biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B). We previously constructed a physiologically-based pharmacokinetic (PBPK) model for CP-I using clinical DDI data with an OATP1B inhibitor, rifampicin (RIF). In this study, PBPK model parameters for CP-I were estimated using the cluster Gauss-Newton method (CGNM), an algorithm used to find multiple approximate solutions for nonlinear least-squares problems. Eight unknown parameters including the hepatic overall intrinsic clearance (CLint,all ), the rate of biosynthesis (vsyn ), and the OATP1B inhibition constant of RIF(Ki,u,OATP ) were estimated by fitting to the observed CP-I blood concentrations in two different clinical studies involving changing the RIF dose. Multiple parameter combinations were obtained by CGNM that could well capture the clinical data. Among those, CLint,all , Ki,u,OATP , and vsyn were sensitive parameters. The obtained Ki,u,OATP for CP-I was 5.0- and 2.8-fold lower than that obtained for statins, confirming our previous findings describing substrate-dependent Ki,u,OATP values. In conclusion, CGNM analyses of PBPK model parameter combinations enables estimation of the three essential parameters for CP-I to capture the DDI profiles, even if the other parameters remain unidentified. The CGNM also clarified the importance of appropriate combinations of other unidentified parameters to enable capture of the CP-I concentration time course under the influence of RIF. The described CGNM approach may also support the construction of robust PBPK models for additional transporter biomarkers beyond CP-I.

Tortuosity of middle cerebral artery M1 segment and outcomes after mechanical thrombectomy.

BACKGROUND: We aimed to quantify the tortuosity of the middle cerebral artery (MCA) and assess its effects on radiological and clinical outcomes in patients with acute MCA occlusions who received mechanical thrombectomy (MT). METHODS: This retrospective study enrolled 53 patients with acute ischemic stroke due to MCA M1 or M2 segment occlusion who underwent MT using stent retrievers (SRs). Tortuosity index (TI) was defined to quantify the tortuosity of the MCA M1 segment using the following formula: (actual distance / straight distance) × 100. For each patient, four TIs were measured in the anteroposterior and caudal views for both ipsilateral and contralateral sides to the occluded site (TI-APi, TI-APc, TI-CAUi, and TI-CAUc, respectively) using magnetic resonance angiography (MRA) or computed tomography angiography (CTA). We defined the first-pass effect (FPE) as first-pass mTICI classification ≥2b reperfusion. RESULTS: Patients who did not achieve FPE had significantly higher TI-APi (112 vs. 106; P = 0.004), TI-APc (111 vs. 105; P = 0.005), TI-CAUi (110 vs. 105; P = 0.002), and TI-CAUc (110 vs. 105; P = 0.001) than those who achieved FPE. In multivariable analysis, higher TI-APi, TI-CAUi, and TI-APc were independently associated with an increased rate of unsuccessful FPE (odds ratio (OR) [95% confidence interval (CI)]: 1.25 [1.02-1.61], 1.21 [1.01-1.45], and 1.27 [1.03-1.73], respectively). TI-CAUi, TI-APc, and TI-CAUc were also independent predictors of the occurrence of intracranial hemorrhage after MT (OR [95% CI]: 1.15 [1.01-1.38], 1.14 [1.01-1.38], 1.25 [1.02-1.52], respectively). CONCLUSIONS: The TIs of the MCA M1 segment on both ipsilateral and contralateral sides were associated with unfavourable outcomes after MT.

Physiologically-based pharmacokinetic model-based translation of OATP1B-mediated drug-drug interactions from coproporphyrin I to probe drugs.

The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP-I) by CysA. In vivo Ki of unbound CysA for OATP1B (Ki,OATP1B ), and the overall intrinsic hepatic clearance per body weight of CP-I (CLint,all,unit ) were optimized to account for the CP-I data (Ki,OATP1B , 0.536 ± 0.041 nM; CLint,all,unit , 41.9 ± 4.3 L/h/kg). DDI simulation using Ki,OATP1B reproduced the dose-dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro Ki,OATP1B failed. The Cluster Gauss-Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP-I (ß, CLint, all , Fa Fg , Rdif , fbile , fsyn , and vsyn ), and Ki,OATP1B and Ki,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CLint, all and Ki,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP-I is a promising translational approach to predict OATP1B-mediated DDIs in drug development.

Effect of Cyclosporin A and Impact of Dose Staggering on OATP1B1/1B3 Endogenous Substrates and Drug Probes for Assessing Clinical Drug Interactions.

This study was designed to assess the quantitative performance of endogenous biomarkers for organic anion transporting polypeptide (OATP) 1B1/1B3-mediated drug-drug interactions (DDIs). Ten healthy volunteers orally received OATP1B1/1B3 probe cocktail (0.2 mg pitavastatin, 1 mg rosuvastatin, and 2 mg valsartan) and an oral dose of cyclosporin A (CysA, 20 mg and 75 mg) separated by a 1-hour interval (20 mg (-1 hour), and 75 mg (-1 hour)). CysA 75 mg was also given with a 3-hour interval (75 mg (-3 hours)) to examine the persistence of OATP1B1/1B3 inhibition. The area under the plasma concentration-time curve ratios (AUCRs) were 1.63, 3.46, and 2.38 (pitavastatin), 1.39, 2.16, and 1.81 (rosuvastatin), and 1.42, 1.77, and 1.85 (valsartan), at 20 mg, 75 mg (-1 hour) and 75 mg (-3 hours) of CysA, respectively. CysA effect on OATP1B1/1B3 was unlikely to persist at the dose examined. Among 26 putative OATP1B1/1B3 biomarkers evaluated, AUCR and maximum concentration ratio (Cmax R) of CP-I showed the highest Pearson's correlation coefficient with CysA AUC (0.94 and 0.93, respectively). Correlation between AUCR of pitavastatin, and Cmax R or AUCR of CP-I were consistent between this study and our previous study using rifampicin as an OATP1B1/1B3 inhibitor. Nonlinear regression analysis of AUCR-1 of pitavastatin and CP-I against CysA Cmax yielded Ki,OATP1B1/1B3,app (109 ± 35 and 176 ± 42 nM, respectively), similar to the Ki ,OATP1B1/1B3 estimated by our physiologically-based pharmacokinetic model analysis described previously (107 nM). The endogenous OATP1B1/1B3 biomarkers, particularly Cmax R and AUCR of CP-I, corroborates OATP1B1/1B3 inhibition and yields valuable information that improve accurate DDI predictions in drug development, and enhance our understanding of interindividual variability in the magnitude of DDIs.

Unilateral pallidothalamic tractotomy at Forel's field H1 for cervical dystonia.

BACKGROUND: Neurosurgical ablation of Forel's field H1 for cervical dystonia, which is currently abandoned, was formerly used in the 1960s-1970s. Regardless of the lack of neuroimaging modalities and objective evaluation scales, the reported efficacy was significant. Although recent studies have reappraised the ablation of the pallidothalamic tract at Forel's field H1 for Parkinson's disease, the efficacy for cervical dystonia has not been investigated well. METHODS: Data of 35 patients with cervical dystonia who underwent unilateral pallidothalamic tractotomy at Forel's field H1 were retrospectively analyzed. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores, the neck score of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), and adverse events were evaluated preoperatively and at the last available follow-up period. RESULTS: The mean clinical follow-up period was 13.9 ± 6.5 months. The mean TWSTRS total scores were 34.3 ± 14.0 preoperatively and 18.4 ± 16.5 at the last available follow-up period (46.4% improvement, p < 0.0001). The BFMDRS neck score also improved significantly from 6.2 ± 2.9 preoperatively to 2.8 ± 2.8 at the last available follow-up period (55.0% improvement on the neck score, p < 0.0001). Reduced hand dexterity in seven patients, hypophonia in five patients, dysarthria in four patients, and executive dysfunction in one patient were confirmed as adverse events at the last available follow-up evaluation. One patient had postoperative hemorrhage. CONCLUSION: The current study confirmed significant improvement in TWSTRS total scores and BFMDRS neck scores at the 13.9-month follow-up after unilateral pallidothalamic tractotomy. The pallidothalamic tract in Forel's field H1 is expected to be an alternative treatment target for cervical dystonia.