Commun Biol. 2023 Aug 24;6(1):870. doi: 10.1038/s42003-023-05243-w.

ABSTRACT

Adverse Drug Reactions (ADRs) have a direct impact on human health. As continuous pharmacovigilance and drug monitoring prove to be costly and time-consuming, computational methods have emerged as promising alternatives. However, most existing computational methods primarily focus on predicting whether or not the drug is associated with an adverse reaction and do not consider the core issue of drug benefit-risk assessment-whether the treatment outcome is serious when adverse drug reactions occur. To this end, we categorize serious clinical outcomes caused by adverse reactions to drugs into seven distinct classes and present a deep learning framework, so-called GCAP, for predicting the seriousness of clinical outcomes of adverse reactions to drugs. GCAP has two tasks: one is to predict whether adverse reactions to drugs cause serious clinical outcomes, and the other is to infer the corresponding classes of serious clinical outcomes. Experimental results demonstrate that our method is a powerful and robust framework with high extendibility. GCAP can serve as a useful tool to successfully address the challenge of predicting the seriousness of clinical outcomes stemming from adverse reactions to drugs.

PMID:37620651 | PMC:PMC10449791 | DOI:10.1038/s42003-023-05243-w

Sci Rep. 2023 Aug 24;13(1):13817. doi: 10.1038/s41598-023-40376-2.

ABSTRACT

Because fascial entrapment neuropathy can occur in multiple locations, ultrasound-guided nerve hydrodissection has become a key component of the treatment of cervical radicular pain. In this paper, we propose a combination of injectates used for nerve hydrodissection of the cervical nerve roots and compare the clinical outcomes of this treatment among patients with different severities of stenosis. This is a retrospective cohort study designed to compare outcomes between patients with mild stenosis and moderate to severe stenosis. Forty-four patients with mild cervical stenosis and 30 patients with moderate to severe cervical stenosis were consecutively enrolled into two groups. A 10-mL mixture in a single level consisting of 5% in Dextrose, 0.2% lidocaine (Xylocaine), and 4 mg betamethasone (Rinderon) was used for nerve roots hydrodissection. The two groups were compared with regard to their numeric rating scales (NRS) of pain, proportion of patients who exhibited a favorable outcome (a reduction of pain ≥ 50%), duration of patient exhibited a favorable outcome, and occurrence of serious complications and minor side effects. The follow-up period ranged from 3 to 20 months. The NRS of both groups improved significantly by 1 week, 1 month, 3 months, and final follow-up after the initial injection. Differences in the groups' NRS, proportion of patients who exhibited a favorable outcome, duration of patient exhibited a favorable outcome, and occurrence of serious complications and minor side effects were nonsignificant. There were 4 patients (5.4%) experienced dizziness in that resolved without further treatment. Ultrasound-guided nerve hydrodissection of cervical nerve roots is a safe procedure that reduces pain associated with cervical radicular pain, even in patients with moderate to severe stenosis.

PMID:37620404 | PMC:PMC10449834 | DOI:10.1038/s41598-023-40376-2

Front Immunol. 2023 Aug 8;14:1148632. doi: 10.3389/fimmu.2023.1148632. eCollection 2023.

ABSTRACT

OBJECTIVE: To address a novel lower-dose rituximab (RTX) therapy strategy based on our clinical experience and assess its efficacy and safety in neuromyelitis optica spectrum disorder (NMOSD).

METHODS: A multicenter, open-label, self-controlled, prospective follow-up study. Totally, 108 NMOSD patients were enrolled and a lower-dose RTX strategy was applied including 100 mg weekly for 3 weeks and then reinfusions every 6 months. Annualized relapse rate (ARR), the expanded disability status scale (EDSS) score and length of spinal cord lesions were included to evaluate the efficacy. Side effects were recorded to assess the safety profile.

RESULTS: Of 108 patients, 80 (74.1%) initiated low-dose RTX therapy immediately after acute attack treatment and 33 (30.6%) initiated it after the first attack. During a median treatment period of 35.5 (22.0-48.8) months, significant decreases were observed in median ARR (1.1 [0.8-2.0] versus 0 [0-0.2], p < 0.001), EDSS score (3.5 [2.5-4.0] versus 2.0 [1.0-3.0], p < 0.001) and spinal cord lesion segments (5.0 [4.0-8.0] versus 3.0 [1.0-6.0], p < 0.001). The cumulative risk of relapses significantly decreased during the post- versus pre-RTX period (HR 0.238, 95%CI 0.160-0.356, p < 0.001) and on early therapy initiated within 24 months after disease onset versus delayed therapy (HR 0.506, 95%CI 0.258-0.994, p = 0.041). No serious side effects were recorded and all the subjects did not discontinue treatment due to RTX-related side effects.

CONCLUSION: Our research provided evidence supporting the lower-dose RTX strategy in treating NMOSD and reopened the issues of optimal dosage and therapy initiation timing.

PMID:37614240 | PMC:PMC10442836 | DOI:10.3389/fimmu.2023.1148632

Hum Vaccin Immunother. 2023 Aug 1;19(2):2246542. doi: 10.1080/21645515.2023.2246542.

ABSTRACT

A good safety and immunogenicity profile was reported in Phase I and II clinical trials of inactivated SARS-CoV-2 vaccines. Here, we report two cases associated with vaccine-associated adverse events, including one patient with fever and another with anaphylactic shock resulting from inactivated SARS-CoV-2 vaccination. Cell sub-types and the importance of genetic characteristics were assessed using single-cell mRNA sequencing and machine learning. Overall, the patient with fever showed a significant increase in the numbers of cytotoxic CD8 T cells and MKI67high CD8 T cells. A potential concurrent infection with the Epstein-Barr virus enhanced interferon type I responses to vaccination against the virus. STAT1, E2F1, YBX1, and E2F7 played a key role in the transcription regulation of MKI67high CD8 T cells. In contrast, the patient with allergic shock displayed predominant increases in the numbers of S100A9high monocytes, activated CD4 T cells, and PPBPhigh megakaryocytes. The decision tree showed that LYZ and S100A8 in S100A9high monocytes contributed to the degranulation of neutrophils and activation of neutrophils involved in allergic shock. PPBP and PF4 were major contributors to platelet degranulation. These findings highlight the diversity of adverse reactions following inactivated SARS-CoV-2 vaccination and show the emerging role of cellular subtypes and central genes in vaccine-associated adverse reactions.

PMID:37614152 | DOI:10.1080/21645515.2023.2246542

Sr Care Pharm. 2023 Sep 1;38(9):378-390. doi: 10.4140/TCP.n.2023.378.

ABSTRACT

Objective Community pharmacists play an important role in providing many essential services to older adult patients. This study aimed to assess participants' awareness and utilization of current services provided by the community pharmacy and to identify preferences for innovative strategies and services related to healthy aging. Design This is community-based research using interviews with older people in community pharmacies. Student pharmacists performed the interviews, asking 11 questions developed by the research team. The interview questions included services currently provided by the community pharmacy to determine patient awareness and use. Setting One-on-one structured interviews with participants 50 years of age and older were conducted at community pharmacies in Arizona. Results A total of 53 older people (54.7% female) participated, with most patients knowledgeable about current pharmacy services and 69.7% using at least one service. When asked if they would participate in innovative services, more than half of those interviewed (56.6%) were interested in medication side effect screening and education, and 54.7% would want to participate in medication review with drug interaction screening. Almost half were interested in lifestyle education for healthy aging in nutrition and physical activities (49.1%) and medication disposal (47.2%). Most participants preferred to communicate in person with their pharmacists, but some showed interest in mobile phone texts and calls. Conclusion Community pharmacies may be a viable setting to provide novel services to promote healthy aging among older people, particularly medication side effect and drug interaction screenings and education.

PMID:37612848 | DOI:10.4140/TCP.n.2023.378

Reg Anesth Pain Med. 2023 Aug 24:rapm-2023-104880. doi: 10.1136/rapm-2023-104880. Online ahead of print.

NO ABSTRACT

PMID:37620115 | DOI:10.1136/rapm-2023-104880

Drug Ther Bull. 2023 Aug 24:dtb-2023-000043. doi: 10.1136/dtb.2023.000043. Online ahead of print.

NO ABSTRACT

PMID:37620134 | DOI:10.1136/dtb.2023.000043

Drug Ther Bull. 2023 Aug 24:dtb-2023-000044. doi: 10.1136/dtb.2023.000044. Online ahead of print.

NO ABSTRACT

PMID:37620133 | DOI:10.1136/dtb.2023.000044

IEEE/ACM Trans Comput Biol Bioinform. 2023 Aug 24;PP. doi: 10.1109/TCBB.2023.3308094. Online ahead of print.

ABSTRACT

Side effects of drugs have gained increasing attention in the biomedical field, and accurate identification of drug side effects is essential for drug development and drug safety surveillance. Although the traditional pharmacological experiments can accurately detect the side effects of drugs, the identifying process is time-consuming, costly, and may lead to incomplete identification of side effects. With the expanding of various biomedical databases, many computational methods have been developed for the task of drug-side effect associations (DSAs) prediction. However, existing methods have the following three drawbacks: 1). multiple drug-related databases are not fully used; 2). the complex semantics among drugs and side effects are not effectively captured; 3). the explainability of the predicted DSAs is missed for most existing methods. Therefore, there is an urgent need to find a more effective method for predicting DSAs. To address these issues, we propose a novel meta-path-based graph neural network model for drug-side effect associations prediction (MPGNN-DSA). In MPGNN-DSA, a heterogeneous information network is first constructed by combining multiple biological datasets. Then, a meta-path-based feature learning module is utilized for learning high-quality representations of drugs and side effects by capturing the semantics contained in meta-paths of the constructed HIN. With the learned features, the prediction module is conducted to derive the predicted side effects for drugs. In addition, the explainability of the predicted DSAs can be provided as well with the semantics contained in meta-paths. We conduct comprehensive experiments, and the results demonstrate the effectiveness of MPGNN-DSA, suggesting that the proposed method will be a feasible solution to the task of DSAs prediction.

PMID:37616131 | DOI:10.1109/TCBB.2023.3308094

Eur J Clin Pharmacol. 2023 Aug 24. doi: 10.1007/s00228-023-03552-x. Online ahead of print.

ABSTRACT

PURPOSE: This study examines healthcare costs associated with adverse drug reactions (ADR) in an older population admitted acutely to an Irish tertiary hospital.

METHODS: Prospective cohort study involving older persons admitted to hospital with and without an ADR. Data was collected at baseline, during hospitalisation and post-discharge. Participants provided information on healthcare resource use three months before admission (baseline) and three months after discharge (follow-up). For each healthcare resource, unit costs were derived and applied. The average cost (standard deviation (SD)) associated with the hospital admission for the ADR and non-ADR are presented. In addition, baseline and follow-up care costs were compared using difference-in-difference analysis and presented with 95% confidence intervals (CI). Costs by preventability and severity of ADR are also presented.

RESULTS: A total of n = 230 participants were included (n = 93 ADR and n = 137 without ADR). The average cost associated with hospital admission for an ADR was €9538 (SD €10442) and €9828 (SD €11770) for non-ADR. The additional follow-up costs (difference-in-difference) associated with the ADR was estimated at €2047 (95% CI: -€889 to €4983). The mean incremental follow-up cost of definite preventable ADRs was estimated at €1648 (95% CI: -€4310 to €7605), possible preventable ADRs €2259 (95 CI: -€1194 to €5712) and unavoidable ADRs €1757 (95% CI: -€3377 to €6890). The mean incremental follow-up cost associated with moderate severe ADRs was estimated at €1922 (95% CI: -€1088 to €4932) and €3580 (95% CI: -€4898 to €12,058) for severe ADRs. CONCLUSION: ADRs leading to hospital admission are associated with modest incremental healthcare costs during and three months after admission. Severe and possibly preventable ADRs were associated with higher costs.

PMID:37615688 | DOI:10.1007/s00228-023-03552-x

Cureus. 2023 Jul 23;15(7):e42315. doi: 10.7759/cureus.42315. eCollection 2023 Jul.

ABSTRACT

Nivolumab is an immune checkpoint inhibitor used in the treatment of several types of cancer. Among the adverse effects of this drug, immune-mediated colitis (IMC) has been described. However, in contrast to other checkpoint inhibitors, such as ipilimumab, drug-induced colitis due to nivolumab is not commonly reported. We report the case of a 59-year-old male who had undergone surgical resection for gastroesophageal junction adenocarcinoma, had been on nivolumab during the past five months, and presented with worsening diarrhea. Colonoscopy demonstrated local edema and mild colitis in a region of the colonic mucosa located 30 cm distal to the ileocecal valve. Biopsies revealed acute moderate colitis. The patient responded well to loperamide and dietary modifications. Although nivolumab rarely causes IMC, this occurrence requires proper management in order to avoid further complications.

PMID:37614260 | PMC:PMC10442715 | DOI:10.7759/cureus.42315

J Clin Neuromuscul Dis. 2023 Sep 1;25(1):11-17. doi: 10.1097/CND.0000000000000439.

ABSTRACT

OBJECTIVES: Plasmapheresis (PLEX) and intravenous immunoglobulin (IVIg) are commonly used to treat autoimmune neuromuscular disorders, including myasthenia gravis, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, and other autoimmune neurological disorders. The side effect profiles of these therapies vary, and concern has been raised regarding the safety of PLEX in the elderly population. In this study, we have examined the pattern of PLEX and IVIg use for autoimmune neurological disorders at a single facility and in a national database, focusing on the complications in elderly patients.

METHODS: We performed a retrospective chart review of adult patients at our institution receiving PLEX or IVIg for any autoimmune neuromuscular or neuro-immunological disease. Next, we analyzed the National Inpatient Sample database to confirm the trend in IVIg and PLEX use from 2012 to 2018 for a set of neuromuscular and neuro-immunological primary diagnoses.

RESULTS: IVIg was overall favored over PLEX. The adverse effects were similar among elderly patients (age ≥65 years) compared with younger patients (<65 years) in our institution, even after adequate matching of patients based on age, sex, and medical history. We examined the National Inpatient Sample dataset and noted increasingly higher frequency of IVIg use, consistent with the findings from our institution or facility.

CONCLUSIONS: Both PLEX and IVIg are safe therapeutic choices in adult patients with autoimmune neuromuscular disorders and other neuro-immunological diseases and can be safely administered in the appropriate clinical setting.

PMID:37611265 | DOI:10.1097/CND.0000000000000439

PLoS One. 2023 Aug 23;18(8):e0289825. doi: 10.1371/journal.pone.0289825. eCollection 2023.

ABSTRACT

INTRODUCTION: Drug-related problems (DRPs) are common in clinical practice and occur at all stages of the medication process. The major factor contributing to DRPs is prescription, although patients' poor adherence to treatment is also a significant factor. This study evaluated type 2 diabetes outpatients in a hospital in Vietnam for drug-related problems (DRPs) and related variables.

METHODS: A cross-sectional descriptive study was conducted on 495 outpatients who met the criteria and 157 people agreed to participate in the interview. Medication order review and medication adherence review were used to identify DRPs. The types of DRP were based on the Pharmaceutical Care Network Europe (PCNE) categories version 9.0. The identification and assessment DRPs were carried out by clinical pharmacists and get agreed upon by physicians who had not directly prescribed patients who participated in the study.

RESULTS: A total of 762 DRPs were identified via prescribing review process, the average number of DRP on each prescription was 1.54±1.07, while 412 DRPs were determined through patient interviewing. The most frequent DRPs were "ADR (Adverse Drug Reaction) occurring" (68.8%). The main causes were "patient is unable to understand instructions properly" or "patient is not properly instructed", "patient stores insulin inappropriately", "patient decides to use unnecessary drugs" and "patient intentionally uses/takes less drug than prescribed or does not take the drug at all for whatever reason" which accounted for 65.0%, 41.4%, 38.2%, and 28.7%, respectively. From the prescribing review, the most observed DRPs were "Inappropriate drug according to guidelines/formulary" and "No or incomplete drug treatment in spite of existing indication", accounting for 45.0% and 42.9%, respectively. There was a significant association between age (OR 3.38, 95% CI: 1.01-11.30), duration of diabetes (OR 3.61, 95%CI: 1.11-11.74), presence of comorbidity (OR 5.31, 95%CI: 1.97-14.30), polypharmacy (OR: 2.95, 95%CI: 1.01-8.72) and DRPs. In patients, poor knowledge of antidiabetic agents was the main reason to lack adherence and occurring ADR (OR 2.73, 95%CI: 1.32-5.66, p = 0.007 and OR 2.49, 95%CI: 1.54-4.03, p = 0.001 respectively).

CONCLUSION: DRPs occurred in the prescribing stage and relating to patient's behavior of drug administration was high. Clear identification of DRPs and the associated factors are essential for building the intervention process to improve effectiveness and safety in the treatment of type 2 diabetes mellitus patients.

PMID:37611036 | PMC:PMC10446199 | DOI:10.1371/journal.pone.0289825

Rev Med Suisse. 2023 Aug 23;19(838):1508-1512. doi: 10.53738/REVMED.2023.19.838.1508.

ABSTRACT

This article proposes 10 points considered essential on the ethics associated with the practice of psychotherapy assisted by psychedelics (PAP) : 1) respect of the legal framework (LStup) of the use of psychotropic drugs ; 2) adequately manage psychedelics (storage, production and safety) ; 3) announce adverse effects to the competent authority ; 4) guarantee a psychotherapeutic follow-up ; 5) guarantee the safety of the patients during the treatment ; 6) establish indications on the basis of scientific evidence ; 7) do not confuse personal recreational use and strict medical use ; 8) avoid proselytizing or bad medical practices ; 9) do not to consider the personal consumption of psychedelics as a competency in care and 10) ensure that access to care is equitable and reasonable.

PMID:37610195 | DOI:10.53738/REVMED.2023.19.838.1508

Cochrane Database Syst Rev. 2023 Aug 23;8:CD011570. doi: 10.1002/14651858.CD011570.pub2.

ABSTRACT

BACKGROUND: Anorexia nervosa is a psychological condition characterised by self-starvation and fear or wait gain or other body image disturbance. The first line of treatment is specific psychological therapy; however, there is no consensus on best practice for treating people who develop severe and enduring anorexia nervosa (SEAN). Notably, there is no universal definition of SEAN.

OBJECTIVES: To evaluate the benefits and harms of specific psychological therapies for severe and enduring anorexia nervosa compared with other specific therapies, non-specific therapies, no treatment/waiting list, antidepressant medication, dietary counselling alone, or treatment as usual.

SEARCH METHODS: We used standard, extensive Cochrane search methods. The last search date was 22 July 2022.

SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of people (any age) with anorexia nervosa of at least three years' duration. Eligible experimental interventions were any specific psychological therapy for improved physical and psychological health in anorexia nervosa, conducted in any treatment setting with no restrictions in terms of number of sessions, modality, or duration of therapy. Eligible comparator interventions included any other specific psychological therapy for anorexia nervosa, non-specific psychological therapy for mental health disorders, no treatment or waiting list, antipsychotic treatment (with or without psychological therapy), antidepressant treatment (with or without psychological therapy), dietary counselling, and treatment as usual as defined by the individual trials.

DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were clinical improvement (weight restoration to within the normal weight range for participant sample) and treatment non-completion. Results were presented using the GRADE appraisal tool.

MAIN RESULTS: We found two eligible studies, but only one study provided usable data. This was a parallel-group RCT of 63 adults with SEAN who had an illness duration of at least seven years. The trial compared outpatient cognitive behaviour therapy for SEAN (CBT-SEAN) with specialist supportive clinical management for SEAN (SSCM-SE) over eight months. It is unclear if there is any difference between the effect of CBT-SEAN versus SSCM-SE on clinical improvement at 12 months (risk ratio (RR) 1.42, 95% confidence interval (CI) 0.66 to 3.05) or treatment non-completion (RR 1.72, 95% CI 0.45 to 6.59). There were no reported data on adverse effects. The trial was at high risk of performance and detection bias. We rated the GRADE level of evidence as very low-certainty for both primary outcomes, downgrading for imprecision and risk of bias concerns.

AUTHORS' CONCLUSIONS: This review reports evidence from one trial that evaluated CBT-SEAN versus SSCM-SE. There was very low-certainty evidence of little or no difference in clinical improvement and treatment non-completion between the two therapies. There is a need for larger high-quality trials to determine the benefits of specific psychological therapies for people with SEAN. These should take into account the duration of illness as well as participants' previous experience with evidence-based psychological therapy for anorexia nervosa.

PMID:37610143 | DOI:10.1002/14651858.CD011570.pub2

Med Sci Monit. 2023 Aug 23;29:e939858. doi: 10.12659/MSM.939858.

ABSTRACT

BACKGROUND Patients experience severe pain in early postoperative rehabilitation after total knee arthroplasty (TKA). This study aimed to compare the effect of femoral nerve block with different concentrations of chloroprocaine on postoperative rehabilitation in patients with TKA. MATERIAL AND METHODS Ninety patients who only received unilateral TKA were randomly and equally divided into C1 (1% chloroprocaine 0.2 ml/kg), C2 (2% chloroprocaine 0.2 ml/kg), or NS (0.9% sodium chloride solution 0.2 ml/kg) groups. The patients received rehabilitation 3 times a day on days 3-6 after surgery, and femoral nerve block was performed with corresponding solution 10 min before each training session. We recorded the maximum knee flexion angles (MKFA) and maximum knee extension angles (MKEA) during active exercise on day 7 after surgery, as well as the incidence of MKFA ³100°, American knee society (AKS) scores, and postoperative rehabilitation satisfaction. Adverse effects after administration in each group were also recorded. RESULTS Compared with group NS, patients in group C1 and C2 had larger MKFA during active exercise on day 7 after TKA, and had better rehabilitation satisfaction (P<0.05). MKEA, the incidence of MKFA ≥100°, and AKS scores showed no significant differences in the 3 groups. There were more patients with decline of muscle strength in group C2 (P<0.05), and no other adverse reactions were recorded. CONCLUSIONS Chloroprocaine for femoral nerve block can be safely used in rehabilitation after TKA and to improve the knee flexion angle in the early postoperative period. Because they may have fewer adverse effects, 1% chloroprocaine 0.2 ml/kg may be preferred.

PMID:37608539 | DOI:10.12659/MSM.939858

Drug Ther Bull. 2023 Aug 23:dtb-2023-000045. doi: 10.1136/dtb.2023.000045. Online ahead of print.

NO ABSTRACT

PMID:37612130 | DOI:10.1136/dtb.2023.000045

Eur J Hosp Pharm. 2023 Sep;30(5):e26. doi: 10.1136/ejhpharm-2022-003417. Epub 2022 Sep 2.

ABSTRACT

Anthracyclines are associated with cardiotoxic manifestations that are mainly dose-dependent, with onset varying from a few days to many years after stopping treatment. Frequent monitoring for toxic manifestations, early detection, cessation of anthracycline use and appropriate treatment is the key to preventing morbidity and mortality. Complete heart block with doxorubicin use in Hodgkin's lymphoma is rarely reported, and is a severe toxic manifestation necessitating withdrawal or changing of regimen to etoposide + bleomycin + vinblastine + dacarbazine (EBVD), as in this case.

PMID:37611964 | DOI:10.1136/ejhpharm-2022-003417

Methods Mol Biol. 2023;2967:159-171. doi: 10.1007/978-1-0716-3358-8_13.

ABSTRACT

As a powerful tool, polymerase chain reaction (PCR) has been indispensable and widely used in a large array of applications. In practice, many factors may affect the overall performance of a PCR. One such factor is the stability of intramolecular secondary structure formed within single-stranded template. The higher the stability of such a structure, the more likely it will have adverse effects on PCR performance. Traditionally, chemical reagents believed to reduce the stability of nucleic acid secondary structures, such as DMSO and betaine, have been used to mitigate their adverse effects on PCR performance. However, these reagents have apparent downsides including increasing replication error rate, inhibiting polymerase activity, and being ineffective against secondary structures of very high stabilities. Disruptors, a new class of oligonucleotide reagents, do not exhibit such downsides. They are specifically designed to target intramolecular secondary structures only without any effect on the replication of other regions of the template. Their effective concentration range for improving PCR performance is well tolerated by PCR. And they are very effective in improving PCR performance on templates that are notoriously difficult to amplify by PCR even in the presence of DMSO or betaine, e.g., the inverted terminal repeat of adeno-associated virus (AAV-ITR). In this chapter, the application of disruptors in PCR is described with AAV-ITR as the example template.

PMID:37608110 | DOI:10.1007/978-1-0716-3358-8_13

PLoS One. 2023 Aug 22;18(8):e0277718. doi: 10.1371/journal.pone.0277718. eCollection 2023.

ABSTRACT

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."

PMID:37607205 | PMC:PMC10443869 | DOI:10.1371/journal.pone.0277718