Intrathecal Drug Administration Research Articles

Ultrasound assisted versus landmark based intrathecal administration of nusinersen in adults with spinal muscular atrophy disease: A randomized trial.

Nusinersen intrathecal administration can be challenging in spinal muscular atrophy (SMA) adults. We aimed to determine if the ultrasound (US)-assistance reduces the number of needle attempts and needle redirections needed for intrathecal drug administration and its impact on the procedure time, the incidence of adverse events (AEs), and patient satisfaction in these patients. Fifty-eight patients aged 18 years and older scheduled for intrathecal nusinersen injection were enrolled and randomized (1:1 ratio) into Group 1 (nusinersen infusion with US-assisted technique) or Group 2 (nusinersen infusion with landmark-based technique). The number of attempts, number of redirections, periprocedural time, AEs and patient satisfaction were reported. Continuous variables were compared with the Student t-test or Wilcoxon rank sum test. Categorical variables were evaluated with the Chi-square test or Fisher's exact test in case of expected frequencies <5. The p-values <.05 were considered statistically significant. There were no statistical differences in the number of attempts, AEs, or patient satisfaction between the two groups. The number of needle redirections was significantly lower in the ultrasound group versus landmark-based group (p < .05) in both the overall group of patients and in the subgroup with difficult spines. The periprocedural time was about 40 seconds longer in US-group versus landmark-based group (p < .05). In SMA adults, US assistance reduces the number of needle redirections needed for intrathecal drug administration. These results suggest that the US assistance may be advantageous for nusinersen therapy to reduce the therapeutic burden of intrathecal infusion.

Revisiting intrathecal thiotepa: Efficacy and safety in secondary CNS malignancies.

Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.

Continuous intrathecal infusion of nivolumab in advanced melanoma with leptomeningeal disease.

9522 Background: The prognosis of melanoma patients with leptomeningeal disease (LMD) remains poor (median OS of 3.5 months). Intrathecal (IT) drug administration could bypass the blood-cerebrospinal fluid (CSF) barrier and has been explored in many cancers using chemotherapies or monoclonal antibodies. According to a recent phase I trial (PMID36997799), nivolumab IT delivery appears safe while its efficacy remains to be further investigated. Methods: We retrospectively reviewed melanoma patients with LMD treated with continuous IT administration of nivolumab (after decision in multidisciplinary tumor boards) at 2 institutions from February 2021 to October 2023. Patients received 10 to 13.5 mg/day of IT nivolumab delivered through a catheter (cath) connected to an implanted pump. Nivolumab concentrations were monitored in spinal CSF via an independent access port. All patients were enrolled in the MelBase cohort. Results: 11 patients (5 females, median age 52) were treated with continuous IT nivolumab with median (IQR) time to follow-up of 2.5 (1.1-6.3) months (m). Nivolumab was delivered through a spinal (n=10) and ventricular (n=1) cath. All patients had progressed on systemic immunotherapy (ipilimumab + nivolumab n=10, nivolumab n=1). Five patients had symptomatic LMD. All patients were ECOG 0 or 1 except one patient ECOG 3 (due to neurological deficit). Primary tumors were cutaneous (n=8), mucosal (n=1) and unknown (n=2). Tumors were BRAFV600 (n=10) and NRASQ61-mutated (n=1). All but 3 patients had stable extracranial disease. Concomitant systemic therapies were the following: corticosteroids (n=5), intravenous nivolumab (first 3 months of IT therapy) (n=1), and targeted therapies (n=4). The median duration of IT treatment was 1.5 (0.5-2.7) m. The median overall survival (OS) was 2.5 (1.1-NA) m. OS at 3, 12 and 19 m were 36.4 % (16.6-79.5), 27.3 % (10.4-71.6) and 13.6 % (10.4-71.6), respectively. Three patients had prolonged survival (19 m n=2, 12 m n=1). Treatment-related adverse events (all reversible) occurred in 5 patients: hemorrhage on cath path (n=1, grade 2), immune-mediated meningoencephalitis (n=1, grade 3), intracranial hypotension syndrome (n=3, grade 2). Steady state was obtained after 3 weeks of continuous IT infusion. Pharmacokinetics data are summarized in Table. Conclusions: Survival data are slightly inferior to those previously published. However 3 patients had prolonged survival (&gt;=1 year). Median nivolumab concentrations in CSF were comparable to through plasma concentrations at steady state after 3mg/kg IV infusion. High plasma concentrations suggest rapid clearance of nivolumab from the CSF, possibly related to reverse transcytosis of immunoglobulins. [Table: see text]

Comparison of 0.5% Hyperbaric Bupivacaine with Midazolam Versus 0.5% Hyperbaric Bupivacaine Alone Intrathecally: Prospective Observational Study

Context: Neuraxial anesthesia is the preferred choice for infraumbilical surgeries due to its advantages. The incorporation of midazolam alongside local anesthetic drugs in spinal anesthesia has demonstrated positive outcomes. This study was undertaken to assess the effectiveness of midazolam in terms of analgesic and anesthetic efficacy, as well as potential adverse effects, in patients undergoing infraumbilical surgeries. Aims: To compare the analgesic and anaesthetic effect of mixture of midazolam - bupivacaine as compared to bupivacaine alone in patients undergoing infra-umbilical surgeries under spinal anaesthesia. Settings and Design: The present study is a prospective, observational study. Methods and Material: Fifty patients posted for elective infra-umbilical surgery were randomly divided into two groups of 25 each for intrathecal drug administration. (n=25). After administration of block, patients were assessed for analgesic and anesthetic effect of the drug. Statistical Analysis used: The study analyzed through the statistical programming software SPSS-22 and it involved the application of the student’s t-test, with a significance threshold set at a P value of &lt;0.05. Results: Analgesic duration of patients in Midazolam Group was signiÞcantly longer compared to Bupivacaine Group for sensory block. More patients in the midazolam group were sedated and easily arousable. Conclusions: This study concludes that the addition of intrathecal preservative-free midazolam to hyperbaric bupivacaine improved intra - operative anaesthesia and prolonged duration of analgesia. Also, it was observed that there was a significant reduction in the consumption of analgesics during the postoperative period in patients undergoing infra-umbilical surgeries without causing any significant haemodynamic changes.

A multimodal approach to prevent spinal cord ischemia in patients undergoing thoracoabdominal aortic aneurism repair - from pathophysiology to anesthesiological management

Thoraco-abdominal aortic aneurysm (TAAA) open repair is a high-risk surgery further burdened with both mortality and morbidity. Despite numerous experimental endeavors and technical advancements, spinal cord ischemia (SCI) is still the most formidable morbidity to be resolved, irrespective of the open or endovascular surgical approach. It presents a spectrum of severity, ranging from temporary or permanent paraparesis to paraplegia with or without autonomic dysfunction. The timing of SCI occurrence is a crucial factor, with approximately 15% of cases manifesting intraoperatively, 50% within 48 h post-surgery, and the remaining 35% classified as late SCI, occurring more than 48 h after the procedure. The mechanism responsible for SCI is complex and multifactorial; hence, understanding its underlying pathophysiology is essential for its effective management. Over the last decade, strategies to enhance spinal cord perfusion and minimize the risk of SCI during TAAA open repair have been implemented. These include optimization of hemodynamics, hemoglobin levels, cardiac function, and cerebrospinal fluid pressure, ensuring collateral vascular network stability and distal aortic perfusion and intrathecal administration of drugs. A multimodal approach involving anesthesiologists and surgeons can lead to improved neurological recovery and a reduced incidence and severity of SCI.

Determination of spinal tracer dispersion after intrathecal injection in a deformable CNS model.

Background: Traditionally, there is a widely held belief that drug dispersion after intrathecal (IT) delivery is confined locally near the injection site. We posit that high-volume infusions can overcome this perceived limitation of IT administration. Methods: To test our hypothesis, subject-specific deformable phantom models of the human central nervous system were manufactured so that tracer infusion could be realistically replicated in vitro over the entire physiological range of pulsating cerebrospinal fluid (CSF) amplitudes and frequencies. The distribution of IT injected tracers was studied systematically with high-speed optical methods to determine its dependence on injection parameters (infusion volume, flow rate, and catheter configurations) and natural CSF oscillations in a deformable model of the central nervous system (CNS). Results: Optical imaging analysis of high-volume infusion experiments showed that tracers spread quickly throughout the spinal subarachnoid space, reaching the cervical region in less than 10min. The experimentally observed biodispersion is much slower than suggested by the Taylor-Aris dispersion theory. Our experiments indicate that micro-mixing patterns induced by oscillatory CSF flow around microanatomical features such as nerve roots significantly accelerate solute transport. Strong micro-mixing effects due to anatomical features in the spinal subarachnoid space were found to be active in intrathecal drug administration but were not considered in prior dispersion theories. Their omission explains why prior models developed in the engineering community are poor predictors for IT delivery. Conclusion: Our experiments support the feasibility of targeting large sections of the neuroaxis or brain utilizing high-volume IT injection protocols. The experimental tracer dispersion profiles acquired with an anatomically accurate, deformable, and closed in vitro human CNS analog informed a new predictive model of tracer dispersion as a function of physiological CSF pulsations and adjustable infusion parameters. The ability to predict spatiotemporal dispersion patterns is an essential prerequisite for exploring new indications of IT drug delivery that targets specific regions in the CNS or the brain.

P16.03.A DEVELOPMENT OF INTRATHECAL DRUG DELIVERY PLATFORM TO CURE BREAST CANCER LEPTOMENINGEAL DISEASE BY DENDRITIC CELL VACCINE IN PRECLINICAL MODEL

Abstract BACKGROUND Leptomeningeal disease (LMD) is a rare form of metastasis in the meninges, a membrane surrounding the brain and spinal cord. Approximately 5% of advanced stage breast cancer (BC) will develop LMD and currently there is no cure. One reason for poor prognosis is the issue of drug accessibility to tumor sites due to the blood brain barrier (BBB) and blood-cerebral spinal fluid (CSF)-barrier. While the Ommaya reservoir is used clinically to overcome this challenge, there has not been an optimized preclinical model that allows researchers to adequately test novel therapies in the CSF space. MATERIAL AND METHODS The Forsyth lab have recently developed an MRI-compatible device called the “murine Ommaya” which mimics the Ommaya reservoir and allows repeated intrathecal (IT) administration of drugs in 3-7μl volume directly into CSF, bypassing BBB. In a joint effort with Dr. Czerniecki, whose lab have developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and subsequently generating tumor-targeting dendritic cells (DC), we have created a platform to IT deliver peptide-pulsed DCs directly targeting BC-LMD. RESULTS Currently, we have tested the efficacy of treatment in HER2+ LMD and triple negative breast cancer (TNBC) LMD models and found a very favorable response; LMD mice that received IT DC therapy exhibited reduced tumor burden and prolonged survival, and is more superior than systemic therapy. About 70% of mice from HER2+ LMD and 30% from TNBC LMD were cured of disease. Cured mice also exhibited resistance against LMD recurrence. CONCLUSION Our preliminary data suggest IT DC immunotherapy is effective against the incurable BC-LMD. We are currently investigating the mechanism(s) by which IT DC-initiated CD4 Th1 adaptive immune response against LMD. By using single-cell RNA-sequencing technique, we are analyzing the immune landscape in CSF tumor microenvironment in response to IT DC. FDA-approved phase I clinical trial has been funded by the US Department Of Defense. Future approach includes employing our IT DC vaccine platform in other cancer types, such as LMD from melanoma.

The Efficacy of Dural Puncture Epidural Performed by 27-gauge Whitacre Needle in Labour Epidural Analgesia: Randomized Single-Blinded Controlled Study.

Dural puncture epidural technique is refinement of standard epidural technique. Its goal is to overcome drawbacks of standard epidural. We assessed whether dural puncture epidural technique performed by 27-gauge spinal needle would provide higher quality of labour epidural analgesia by using 10 mL epidural bolus of 0.125% bupivacaine. Additionally, the impact of dural puncture epidural on epidural analgesia onset, course of labour and occurrence of maternal side effects was examined. We designed prospective, randomized, single-blind study. A total of 76 healthy nulliparous parturients were randomly allocated to dural puncture or standard epidural group. After identification of epidural space, spinal Whitacre needle was used for dural puncture. Intrathecal drug administration was omitted at that point. Both groups received a bolus of local anaesthetic mixture, followed by a continuous infusion of diluted local anaesthetic via epidural catheter. Pain was assessed by numeric pain rating scale. The number of top-ups and mode of delivery were recorded in both groups. After 10 minutes, there was a statistically significant difference in numeric pain rating scale ≤3 reported (P=0.028), with 97.4% subjects in dural puncture epidural group achieving adequate analgesia after 10 minutes. There was no statistically significant difference in the number of additional boluses, time to delivery, Bromage scale achieved or maternal outcomes between groups. Dural puncture epidural technique appears to be effective in providing faster onset of epidural analgesia. However, the need for additional boluses remains unchanged. It can be safely used in obstetrics, without deleterious effect on the course of labour.

Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

Nosocomial outbreaks of aseptic meningitis: A public health concern

Nosocomial outbreaks of aseptic meningitis: A public health concern

Risk of leptomeningeal metastasis in children with parameningeal rhabdomyosarcoma with intracranial spread

Introduction. Soft tissue tumors account for up to 8 % of all malignant neoplasms in children. According to the international histological classification, about 150 different morphological variants of soft tissue tumors have been registered, of which 45 % are rhabdomyosarcoma (RMS). Most often, RMS occurs in early childhood – the average age of patients at the time of diagnosis is 5 years. The incidence rate of RMS is 0.9 per 100,000 children. In 25 % cases, the initial diagnosis reveals distant metastasis to the lungs, bones, bone marrow, and 8 % – leptomeningeal metastasis. More than 7 % of patients with localized parameningeal RMS develop leptomeningeal metastasis, according to the Rhabdomyosarcoma Study Group. Purpose of the study – report the incidence, prognosis of leptomeningeal metastasis and treatment outcomes in children with intracranial spread of RMS. Materials and methods. The study included 45 patients aged 1 to 17 years with a diagnosis of RMS of parameningeal localization with intracranial spread, who received special treatment from 2003 to 2020. The study included 6 (20 %) patients in whom the tumor developed in early childhood (up to 3 years). The boys predominated – 25 (55.5 %) in the study. The primary tumor spread to the orbit in 7 (15 %) cases, the skull base in 7 (15 %) cases, the middle ear in 4 (8 %) cases, the nasopharynx in 3 (6 %) cases, and the brain substance was affected in 16 (35 %). Metastases in regional lymph nodes were determined in 7 (15 %) patients. Multiple metastatic lesions of bones and bone marrow – 4 (9 %) cases, leptomeningeal metastases – in 2 (4 %). 45 (100 %) patients received drug treatment according to the protocols approved by the Academic Council of the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Medical Research Centerof Oncology, Ministry of Health of Russia. Radiation therapy was performed in 33 (74 %) patients, while total focal dose of 50 Gy was administered to the primary tumor. Affected lymph nodes of the neck were irradiated in 10 (23 %) patients, total focal dose is 45.0 Gy. Surgical treatment was performed in 15 (34 %) patients. Multicomponent treatment was performed in 15 (34 %) patients. Results. During the observation period from 12 months to 14 years, 21 (49 %) patients are alive. 21 (51 %) patients died from tumor progression, 1 (2 %) died from complications of special treatment. Conclusions. The treatment of this group of patients is one of the urgent problems of pediatric oncology, which is based on polychemotherapy, supplemented by intrathecal administration of anticancer drugs and craniospinal irradiation. The development of new therapies requires a multidisciplinary approach to achieve a significant improvement in the survival of children with leptomeningeal metastases RMS of parameningeal localization.

RTID-04. CLINICAL POTENTIAL OF TARGETING TRANSFORMING GROWTH FACTOR BETA 2 WITH OT-101 FOR POST-RADIATION CONSOLIDATION IN DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract Diffuse intrinsic pontine glioma (DIPG) in children has a dismal prognosis with a median overall survival (OS) of 10 months and a 2-year overall survival rate of &amp;lt; 10% after standard radiation therapy. Chemotherapy does offer clinically meaningful benefits. Therefore, there is an urgent need for therapeutic innovations for treatment of pediatric DIPG. High-grade glioma cells, including pediatric glioblastoma and DIPG cells have been shown to produce transforming growth factor beta 2 (TGFB2) which has been implicated both as promoter of glioma cells and as a key contributor to the T-cell hyporesponsiveness of the tumor microenvironment (TME) towards glioma cells. OT-101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive and tumor promoting actions of TGF-B2. At low micromolar concentrations, OT-101 reduces the TGFB2 secretion by human glioma cells, blocks their proliferation as well as migration, and restores the anti-glioma cytolytic function of patient-derived T-cells. In a Phase 2 clinical study, intracerebrally applied OT-101 administered via convection-enhanced delivery showed promising single agent activity in Recurrent/Refractory (R/R) high-grade glioma (HGG) (Uckun et al., Cancers. 2019 28;11(12):1892). The intrathecal administration of antineoplastic drugs directly in the CSF allows to bypass the selective filter of BBB, achieving significant concentrations of the antineoplastic agents in CSF, while reducing the likelihood of systemic toxicity. Informed by favorable safety pharmacology studies of intrathecally delivered OT-101 in rabbits and primates and encouraged by its single agent activity in adult patients with HGG, we decided to embark upon a multi-center, two-part, randomized Phase 1-2 study of OT-101 in pediatric patients with DIPG. Multiple doses of OT-101 will be administered after completion of radiation therapy as intrathecal bolus injections. The study is designed to determine: 1) the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of OT-101, and 2) its efficacy in children with DIPG.

Chronic pain in cancer patients

Background. Pain is a complex clinical sign that is highly variable in both intensity and perception by patients. Often, a combination of symptoms and signs can indicate a pain syndrome specific to oncology. Virtually all patients with malignant diseases experience recurrent episodes of acute pain, which may accompany previous surgery, invasive procedures, or complications such as pathologic fractures or disease progression. Chronic pain is a huge economic burden on society, both in terms of health care and lost productivity.Effective treatment of chronic pain results in significant improvements in general and psychological wellbeing and functioning of cancer patients and reduces the burden of chronic pain on health services.The purpose is to clarify the problems of the prevalence of chronic pain in cancer patients, the complexity and variability of the pathophysiological mechanisms of the development of pain syndrome, to consider modern approaches to the management of patients with chronic pain.Materials and methods. Modern foreign guidelines for the management of cancer patients with pain syndrome, written in English, data from metaanalyses, reviews and clinical studies were used.Conclusions. Data from a 2016 crosssectional study to determine the prevalence and impact of depression on health care costs in patients with complex chronic pain indicated that patients with chronic pain are at increased risk of developing depressive disorder of varying severity. About onethird of the study sample had major depression, and the overall prevalence of depression among individuals with chronic pain was higher than 50% [3].Up to 75% of all cancer patients with chronic pain have nociceptive (somatic or visceral) or neuropathic syndromes, which are a direct consequence of the development and progression of the neoplasm. Other causes include anticancer drugs and disorders unrelated to the disease or its treatment.Several systems are used to classify the pain syndrome, in particular — ECS-CP, IASP, ACTTION-APS.Today, in the management of cancer patients with chronic pain, the WHO threestep analgesic ladder is used: the first two steps are paracetamol and NSAIDs, mild opioids (control of mild and moderate pain), the third is opioids. The selection of opioids, their dosage and titration features should take into account the individual characteristics of the patient in order to avoid overdose and addiction.In addition to the abovementioned drugs, studies are being conducted to determine the effectiveness and feasibility of using medical cannabis as an alternative means, the use of which will improve the general condition of patients by relieving pain, and preventing the development of opioid addiction.Interventional techniques (neurolytic blockades, neuraxial infusions, trigger point injections, spinal cord stimulation, intrathecal drug administration, and vertebral augmentation) are also used to control chronic pain. The application of physical and psychosocial methods in the comprehensive management of such patients is studied.

Comparative study between intrathecal bupivacaine versus intrathecal bupivacaine and fentanyl in elective caesarean sections

Background: Intrathecal administration of adjuvant drugs have been used increasingly for increasing the onset, duration and quality of analgesia. This study was designed to compare the efficacy of intrathecal hyperbaric bupivacaine with that of intrathecal hyperbaric bupivacaine with fentanyl for patients undergoing elective caesarean sections. Materials &amp; methods: 50 aged between 15 to 30 years, whose weight is 45 to 80 kg, belonging to ASA class I and II, scheduled for elective caesarean sections were selected and randomized into 2 groups. Group B received 9mg of hyperbaric bupivacaine 0.5% and group BF received 9mg of hyperbaric bupivacaine 0.5% with 10mcg of fentanyl. The onset of analgesia, onset of motor blockade, the duration of sensory blockade, the duration motor blockade, the quality of blockade, duration of analgesia, Intrathecal Injection to delivery time, APGAR SCORE of neonates, hemodynamic parameters of parturient and side effects were recorded. Results: There was significant difference between the two groups in the meantime to onset of sensory anaesthesia (group BF 3.28±0.73mins, group B 3.84±1.06mins; p value=0.009). The onset of motor blockade was similar in both the groups. Excellent block was achieved in 80% patients in group B compared to 100% of patients in group BF.

The Options for Neuraxial Drug Administration.

Neuraxial drug administration, i.e., the injection of drugs into the epidural or intrathecal space to produce anesthesia or analgesia, is a technique developed more than 120 years ago. Today, it still is widely used in daily practice in anesthesiology and in acute and chronic pain therapy. A multitude of different drugs have been introduced for neuraxial injection, only a part of which have obtained official approval for that indication. A broad understanding of the pharmacology of those agents is essential to the clinician to utilize them in a safe and efficient manner. In the present narrative review, we summarize current knowledge on neuraxial anatomy relevant to clinical practice, including pediatric anatomy. Then, we delineate the general pharmacology of neuraxial drug administration, with particular attention to specific aspects of epidural and intrathecal pharmacokinetics and pharmacodynamics. Furthermore, we describe the most common clinical indications for neuraxial drug administration, including the perioperative setting, obstetrics, and chronic pain. Then, we discuss possible neurotoxic effects of neuraxial drugs, and moreover, we detail the specific properties of the most commonly used neuraxial drugs that are relevant to clinicians who employ epidural or intrathecal drug administration, in order to ensure adequate treatment and patient safety in these techniques. Finally, we give a brief overview on new developments in neuraxial drug therapy.

Intrathecal application of ethosuximide is highly efficient in suppressing seizures in a genetic model of absence epilepsy

Systemic drug application is the main approach in epilepsy treatment. However, the central nervous system (CNS) is a challenging target for drug delivery as the blood-brain barrier (BBB) restricts the transfer of drugs into the brain. Accordingly, there is a general interest in developing new therapeutic strategies to improve CNS drug accessibility. Intrathecal administration of antiseizure drugs (ASDs) e.g. via pumps or advanced materials could be a possible approach to bypass the BBB and increase the availability of neuroactive compounds in the CNS. The aim of this study was the evaluation of intracerebroventricular (i.c.v.) compared to systemic drug application in generalized epilepsy. The i.c.v. administration of the established ASD ethosuximide (ETX) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) caused a robust and dose-dependent reduction of spike-wave discharges (SWDs) without causing obvious behavioral abnormalities. Additionally, we could show that i.c.v. treatment with ETX is significantly more effective in seizure suppression than systemic treatment with the same dose. The localized application resulted in reduced systemic drug exposure compared to standard systemic ETX therapy. The tracing of dye distribution throughout the CNS supported the view that i.c.v. applied drugs cross into brain tissue surrounding the ventricles but largely remain restricted to the site of injection. Our data suggest that intrathecal application represents a possible route for the treatment in generalized epilepsy through direct drug penetration from CSF into brain tissue.

A novel chronic dural port platform for continuous collection of cerebrospinal fluid and intrathecal drug delivery in free-moving mice

BackgroundCerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models.MethodsWe developed a novel chronic dural port (CDP) method without cannulation for CSF collection of mice. This method enables easy and repeated access to the intrathecal space in a free-moving, unanesthetized mouse, thereby enabling continuous long-term CSF collection with minimal tissue damage and providing a large volume of high-quality CSF from a single mouse. When combined with chemical biosensors, the CDP method allows for real-time monitoring of the dynamic changes in neurochemicals in the CSF at a one-second temporal resolution in free-moving mice. Moreover, the CDP can serve as a direct access point for the intrathecal injection of CSF tracers and drugs.ResultsWe established a CDP implantation and continuous CSF collection protocol. The CSF collected using CDP was not contaminated with blood and maintained physiological concentrations of basic electrolytes and proteins. The CDP method did not affect mouse’s physiological behavior or induce tissue damage, thereby enabling a stable CSF collection for up to four weeks. The spatio-temporal distribution of CSF tracers delivered using CDP revealed that CSF metabolism in different brain areas is dynamic. The direct intrathecal delivery of centrally acting drugs using CDP enabled real-time behavioral assessments in free-moving mice.ConclusionsThe CDP method enables the collection of a large volume of high-quality CSF and direct intrathecal drug administration with real-time behavioral assessment in free-moving mice. Combined with animal models relevant to CNS disorders, this method provides a unique and valuable platform for biomarker and therapeutic drug research.

Circadian effects on neural blockade of levobupivacaine and fentanyl intrathecal administration for caesarian section.

Circadian variations in biological rhythms affect the pharmacological properties of many anaesthetic agents, suggesting circadian patterns of local anaesthetics' activity in labour pain analgesia, with important differences among diurnal and nocturnal phases.

Crystalloid preload versus crystalloid co-load for hypotension in parturients undergoing caesarean section under spinal anaesthesia

Abstract Though hypotension is a common complication after spinal anaesthesia, preloading with crystalloids may not be able to prevent it. We aimed to compare the efficacy of crystalloid preload and co-load for the prevention of maternal hypotension in parturients undergoing caesarean section under spinal anaesthesia. Seventy parturients, aged 20 to 40 years of American Society of Anaesthesiologist (ASA) physical status 1/II, scheduled for caesarean section under spinal anaesthesia were divided into two groups. Parturients in group P received 15 ml/kg of ringer's lactate as preload over 20 min before the intrathecal drug administration. Parturients in group C received 15 ml/kg of ringer's lactate over 20 min, just after intrathecal drug administration. Incidence of hypotension, systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, the requirement of ephedrine, and any complications was recorded. 25 (71%) parturients in group P and 15 (42%) parturients in group C developed statistically significant hypotension. 21 (59%) parturients developed nausea and vomiting in group P as compared to 9 (25%) parturients in group C which were statistically significant. The mean number of doses of ephedrine required in group P was 1.8±0.6 and 0.9±0.7 in group C which was statistically significant. The total dose of ephedrine used in group P was 9.6±3.4mg and 5.9± 2.1mg in group C which was statistically significant. Co-loading with 15 ml/ kg of crystalloid-like ringer's lactate was more effective than preloading in preventing spinal-induced maternal hypotension, thereby reducing ephedrine requirement and avoiding complications. Keywords: Anaesthesia, Co-load, Hypotension, Preload, Spinal, Caesarean section.

Development and Validation of an HPLC Method for Analysis of Topotecan in Human Cerebrospinal Fluid and Its Application in Elimination Evaluation of Topotecan after Intraventricular Injection.

Simple SummaryIntrathecal administration of anticancer drugs is an effective strategy to treat meningeal leukemia and lymphoma. Topotecan is an anticancer drug, and its anticancer effect is expected via intrathecal administration. In this study, we developed a method to measure the concentration of topotecan in the cerebrospinal fluid (CSF) for clinical monitoring of personalized medicine. By controlling the unique structural feature of topotecan, a pH-dependent lactone ring-opening/closing reversible reaction, we established a simple high-performance liquid chromatography (HPLC) method to measure the total topotecan concentration in the CSF and confirmed that this method can be applied to clinical samples. In the present situation, wherein the concentrations were monitored, the disappearance of topotecan in the CSF was delayed, and signs of adverse effects were confirmed when a high concentration of topotecan was observed.Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs.