Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Epilepsy and cannabidiol: a guide to treatment.

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

A perspective on cannabinoids for treating epilepsy: Do they really change the landscape?

With the licensing of cannabidiol for drug resistant seizures in Dravet and Lennox Gastaut syndromes in the United states in 2018, interest in the potential for cannabis-based-medicinal products to meet currently unmet needs for people with epilepsy continues to grow. This review summarizes current knowledge and discusses the implications for future research and practice. Both cannabidiol and tetrahydrocannabinol, the main components, have been extensively studied in animal models, with multimodal mechanisms of action proposed. Only pure cannabidiol formulations have been rigorously evaluated in controlled trials thus far, with modest but significant improvements in motor seizures. Adverse effects include diarrhoea, somnolence and reduced appetite, with mostly acceptable tolerability, but a not insignificant (up to 1 in 23) risk of serious adverse events. Recognized drug interactions include with valproate (increased risk of hepatotoxicity) and clobazam (contributing to somnolence, increased secretions, probably chest infections, and potentially efficacy). Whilst there is public (and producer) interest in products also containing tetrahydrocannabinol, clinicians have justifiable concerns about exposing a group already vulnerable to mental health and neurobehavioural comorbidities to the associated additional risks in these domains. Artisanal preparations, with often inconsistent/unknown constituents are frequently used but not recommended. A gulf exists between the actual evidence, including a lack of comparative studies and public beliefs, fuelled by media and anecdote. Continued education of the public, policymakers, researchers and healthcare providers about what is and isn't yet known, together with on-going good quality research is essential to mitigate against future potential risks, particularly in relation to vulnerable populations. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy.

OBJECTIVE: With the exception of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDTs) are unknown. We aimed to determine whether common variation across the genome influences the response to KDT for epilepsy. METHODS: We genotyped individuals who were negative for glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Genotyping was performed with the Infinium HumanOmniExpressExome Beadchip. Hospital records were used to obtain demographic and clinical data. KDT response (≥50% seizure reduction) at 3-month follow-up was used to dissect out nonresponders and responders. We then performed a genome-wide association study (GWAS) in nonresponders vs responders, using a linear mixed model and correcting for population stratification. Variants with minor allele frequency <0.05 and those that did not pass quality control filtering were excluded. RESULTS: After quality control filtering, the GWAS of 112 nonresponders vs 123 responders revealed an association locus at 6p25.1, 61 kb upstream of CDYL (rs12204701, P = 3.83 × 10-8 , odds ratio [A] = 13.5, 95% confidence interval [CI] 4.07-44.8). Although analysis of regional linkage disequilibrium around rs12204701 did not strengthen the likelihood of CDYL being the candidate gene, additional bioinformatic analyses suggest it is the most likely candidate. SIGNIFICANCE: CDYL deficiency has been shown to disrupt neuronal migration and to influence susceptibility to epilepsy in mice. Further exploration with a larger replication cohort is warranted to clarify whether CDYL is the causal gene underlying the association signal.

Interictal activity is an important contributor to abnormal intrinsic network connectivity in paediatric focal epilepsy.

Patients with focal epilepsy have been shown to have reduced functional connectivity in intrinsic connectivity networks (ICNs), which has been related to neurocognitive development and outcome. However, the relationship between interictal epileptiform discharges (IEDs) and changes in ICNs remains unclear, with evidence both for and against their influence. EEG-fMRI data was obtained in 27 children with focal epilepsy (mixed localisation and aetiologies) and 17 controls. A natural stimulus task (cartoon blocks verses blocks where the subject was told "please wait") was used to enhance the connectivity within networks corresponding to ICNs while reducing potential confounds of vigilance and motion. Our primary hypothesis was that the functional connectivity within visual and attention networks would be reduced in patients with epilepsy. We further hypothesized that controlling for the effects of IEDs would increase the connectivity in the patient group. The key findings were: (1) Patients with mixed epileptic foci showed a common connectivity reduction in lateral visual and attentional networks compared with controls. (2) Having controlled for the effects of IEDs there were no connectivity differences between patients and controls. (3) A comparison within patients revealed reduced connectivity between the attentional network and basal ganglia associated with interictal epileptiform discharges. We also found that the task activations were reduced in epilepsy patients but that this was unrelated to IED occurrence. Unexpectedly, connectivity changes in ICNs were strongly associated with the transient effects of interictal epileptiform discharges. Interictal epileptiform discharges were shown to have a pervasive transient influence on the brain's functional organisation. Hum Brain Mapp 38:221-236, 2017. © 2016 Wiley Periodicals, Inc.

Integrated care for childhood epilepsy: ongoing challenges and lessons for other long-term conditions.

Epilepsy care has been identified as a major global issue-and there are many recognised concerns in the UK for children and young people with the condition. A proposed new model could help to increase multisector integration, facilitate better outcomes and offer lessons for improving care of other long-term conditions.

Advancing the management of childhood epilepsies.

Childhood epilepsies comprise a heterogeneous group of disorders and syndromes that vary in terms of severity, prognosis and treatment requirements. Effective management requires early, accurate recognition and diagnosis, and a holistic approach that addresses each individual's medical and psychosocial needs within the context of their overall health status and quality of life. With increasing understanding of underlying aetiologies, new approaches to management and treatment are emerging. For example, genetic testing is beginning to provide a tool to aid differential diagnosis and a means of predicting predisposition to particular types of epilepsy. Despite the availability of an increasing number of antiepileptic drugs (AEDs)--due not only to the development of new AEDs, but also to changes in regulatory requirements that have facilitated clinical development--seizure control and tolerability continue to be suboptimal in many patients, and there is therefore a continuing need for new treatment strategies. Surgery and other non-pharmacological treatments (e.g. vagus nerve stimulation, ketogenic diet) are already relatively well established in paediatric epilepsy. New pharmacological treatments include generational advances on existing AEDs and AEDs with novel modes of action, and non-AED pharmacological interventions, such as immunomodulation. Emerging technologies include novel approaches allowing the delivery of medicinal agents to specific areas of the brain, and 'closed-loop' experimental devices employing algorithms that allow treatment (e.g., electrical stimulation) to be targeted both spatially and temporally. Although in early stages of development, cell-based approaches (e.g., focal targeting of adenosine augmentation) and gene therapy may also provide new treatment choices in the future.

The effect of the classical and medium chain triglyceride ketogenic diet on vitamin and mineral levels.

BACKGROUND: The risk of nutritional deficiency in children on restrictive dietary treatments and a lack of ketogenic diet (KD)-specific UK supplements raises concerns about micronutrient status. Vitamin A, E, zinc, selenium and magnesium levels were therefore examined in children with intractable epilepsy treated with the KD. METHODS: Plasma vitamins A and E, zinc, selenium and magnesium levels were measured at baseline and after 3, 6 and 12months on the classical (n=46) or medium chain triglyceride (MCT) (n=45) KD in children aged 2-16years, as part of a randomised trial, and pairwise comparisons with baseline were performed. RESULTS: Data were available from 91 children. From baseline to 12months, mean plasma vitamin A decreased from 1.41µmol L(-1) to 1.13µmol L(-1) in the classical group (P<0.001) but increased from 1.52µmol L(-1) to 1.81µmol L(-1) in the MCT group (P<0.001). Mean plasma vitamin E increased from 22.7µmol L(-1) to 33.2µmol L(-1) in the classical group (P<0.001) and from 22.3 µmol L(-1) to 23.3µmol L(-1) in the MCT group (P<0.05). No significant change in plasma zinc was seen at 12months, although mean plasma selenium decreased from 0.95µmol L(-1) to 0.88µmol L(-1) in the group as a whole (P<0.05). Mean plasma magnesium decreased from 0.87mmol L(-1) to 0.83mmol L(-1) in the group as a whole (P<0.001); when subdivided by KD type, this was limited to the classical group. CONCLUSIONS: Changes in plasma vitamins A and E and the decline in magnesium status after 12months of KD treatment suggest that micronutrient status may be suboptimal in this group and that available formulations for KD supplementation may need reviewing.

A randomised controlled equivalence trial to determine the effectiveness and cost-utility of manual chest physiotherapy techniques in the management of exacerbations of chronic obstructive pulmonary disease (MATREX).

OBJECTIVES: To estimate the effect, if any, of manual chest physiotherapy (MCP) administered to patients hospitalised with chronic obstructive pulmonary disease (COPD) exacerbation on both disease-specific and generic health-related quality of life. To compare the health service costs for those receiving and not receiving MCP. DESIGN: A pragmatic, randomised controlled trial powered for equivalence. It was not possible to blind participants, clinicians or research staff to study arm allocation during the intervention. SETTING: Four UK hospitals in Norwich, Great Yarmouth, King's Lynn and Liverpool. PARTICIPANTS: 526 participants aged 34-91 years were recruited between November 2005 and April 2008; of these, 372 provided evaluable data for the primary outcome. All persons hospitalised with COPD exacerbation and evidence of sputum production on examination were eligible for the trial providing there were no contraindications to performing MCP. INTERVENTIONS: Participants were allocated to either MCP or no MCP on an intention-to-treat (ITT) basis. However, active cycle of breathing techniques (ACBT) was used in both arms. Participants allocated to the intervention were guided to perform ACBT while the physiotherapist delivered MCP. Participants allocated to the control arm received instruction on ACBT only. MAIN OUTCOME MEASURES: The primary outcome was COPD-specific quality of life, measured using the St George's Respiratory Questionnaire (SGRQ) at 6 months post randomisation. The European Quality of Life-5 Dimensions (EQ-5D) questionnaire was used to calculate the quality-adjusted life-year (QALY) gain associated with MCP compared with no MCP. Secondary physiological outcome measures were also used. RESULTS: Of the 526 participants, 261 were allocated to MCP and 264 to control, with 186 participants evaluable in each arm. ITT analyses indicated no significant difference at 6 months post randomisation in total SGRQ score [adjusted effect size (no MCP - MCP) 0.03 (95% confidence interval, CI -0.14 to 0.19)], SGRQ symptom score [adjusted effect size 0.04 (95% CI -0.15 to 0.23)], SGRQ activity score [adjusted effect size -0.02 (95% CI -0.20 to 0.16)] or SGRQ impact score [adjusted effect size 0.02 (95% CI -0.15 to 0.18)]. The imputed ITT and per-protocol results were similar. No significant differences were observed in any of the outcome measures or subgroup analyses. Compared with no MCP, employing MCP was associated with a slight loss in quality of life (0.001 QALY loss) but lower health service costs (cost saving of 410.79 pounds). Based on these estimates, at a cost-effectiveness threshold of lambda = 20,000 pounds per QALY, MCP would constitute a cost-effective use of resources (net benefit = 376.14 pounds). There was, however, a high level of uncertainty associated with these results and it is possible that the lower health service costs could have been due to other factors. CONCLUSIONS: In terms of longer-term quality of life the use of MCP did not appear to affect outcome. However, this does not mean that MCP is of no therapeutic value to patients with COPD in specific circumstances. Although the cost-effectiveness analysis suggested that its use was cost-effective, much uncertainty was associated with this finding and it would be difficult to justify providing MCP therapy on the basis of cost-effectiveness alone. Future research should include evaluation of MCP for patients with COPD producing high volumes of sputum, and an evaluation of the effectiveness of ACBT in COPD exacerbation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13825248.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society.

RECOMMENDATION 1: Clinicians should conduct a focused history and physical examination to help place patients with low back pain into 1 of 3 broad categories: nonspecific low back pain, back pain potentially associated with radiculopathy or spinal stenosis, or back pain potentially associated with another specific spinal cause. The history should include assessment of psychosocial risk factors, which predict risk for chronic disabling back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 2: Clinicians should not routinely obtain imaging or other diagnostic tests in patients with nonspecific low back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 3: Clinicians should perform diagnostic imaging and testing for patients with low back pain when severe or progressive neurologic deficits are present or when serious underlying conditions are suspected on the basis of history and physical examination (strong recommendation, moderate-quality evidence). RECOMMENDATION 4: Clinicians should evaluate patients with persistent low back pain and signs or symptoms of radiculopathy or spinal stenosis with magnetic resonance imaging (preferred) or computed tomography only if they are potential candidates for surgery or epidural steroid injection (for suspected radiculopathy) (strong recommendation, moderate-quality evidence). RECOMMENDATION 5: Clinicians should provide patients with evidence-based information on low back pain with regard to their expected course, advise patients to remain active, and provide information about effective self-care options (strong recommendation, moderate-quality evidence). RECOMMENDATION 6: For patients with low back pain, clinicians should consider the use of medications with proven benefits in conjunction with back care information and self-care. Clinicians should assess severity of baseline pain and functional deficits, potential benefits, risks, and relative lack of long-term efficacy and safety data before initiating therapy (strong recommendation, moderate-quality evidence). For most patients, first-line medication options are acetaminophen or nonsteroidal anti-inflammatory drugs. RECOMMENDATION 7: For patients who do not improve with self-care options, clinicians should consider the addition of nonpharmacologic therapy with proven benefits-for acute low back pain, spinal manipulation; for chronic or subacute low back pain, intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitive-behavioral therapy, or progressive relaxation (weak recommendation, moderate-quality evidence).

Managing genital infection in community family planning clinics: an alternative approach to holistic sexual health service provision.

OBJECTIVE: To pilot and evaluate sexually transmitted infection (STI) management in community family planning clinics (FPCs). METHODS: Number of STI tests taken, positive results, infections treated, contacts traced/treated, referrals to specialist services and time from testing to treatment were documented as well as age and sex of the population tested. RESULTS: STI tests taken increased from 233 to 308/month and male clients seen increased from 114 to 147/month across all clinics. Chlamydia prevalence rates in one large clinic increased from 6.7% to 11.9%. 82% of those with STIs in this clinic were treated. Of 44 clients treated for chlamydia, 84% had partner notification performed, 0.43 contacts were treated for every client with chlamydia and referrals to specialist services decreased. 70% of STIs were detected in clinic users under the age of 25 and 45.5% of clients tested under the age of 16 had an STI. Before STI treatment was available at FP clinics 52% of clients with STIs attended specialist services after referral and time from testing to treatment was 19 days. Managing STIs in the community increased treatment rates to 82% with a testing to treatment time of 10 days. CONCLUSIONS: The management of uncomplicated genital infection in community FPCs working in partnership with specialist services is a feasible and effective approach to holistic sexual health service provision.

Reduction of vancomycin-resistant enterococcal infections by limitation of broad-spectrum cephalosporin use in a trauma and burn intensive care unit.

Both vancomycin and third-generation cephalosporin use are believed to contribute to a rise in vancomycin-resistant enterococci (VRE) infections. In 1998, the largest number of VRE infections in our hospital occurred in the trauma/burn intensive care unit (TBICU), accounting for nearly 20% of hospital infections. In an attempt to control the VRE infection rate, antibiotic protocols for prophylaxis, empiric, and definitive therapy were initiated during the final quarter of 1998 to minimize cephalosporin use by the introduction of piperacillin/tazobactam. Therefore, we undertook a study of the VRE infection rate for the TBICU in relation to vancomycin, piperacillin/tazobactam, piperacillin, third-generation cephalosporin, and total cephalosporin use before and after efforts to limit cephalosporins. These data were compared to those in the medical and surgical intensive care units. During 1998, seven VRE infections occurred in the TBICU. Following initiation of antibiotic protocols, one case of VRE infection occurred in the subsequent month and no cases in the 17 months since. The decrease in the VRE infection rate corresponded with a significant increase in the use of piperacillin/tazobactam and a reduction in third-generation and total cephalosporin use. In contrast, cephalosporin use in the medical and surgical intensive care units remains significantly higher than in the TBICU, and neither unit has had a reduction in their VRE infection rates.

Drug-resistant pathogens in community- and hospital-acquired pneumonia.

Antimicrobial resistance has been a problem since the early days of the antibiotic era, but in recent years, this resistance has increased in the hospital and is being recognized more in the community setting. Respiratory pathogens such as S. pneumoniae and H. influenzae, for example, have developed resistance to traditional antimicrobial therapy, often over a very short period of time. This increase in resistance patterns requires physicians to closely monitor antimicrobial resistance in their community and to appreciate that some antimicrobial resistance mechanisms may result in resistance for a complete class of antibiotics or different classes of antibiotics with similar mechanisms of action.

Antigen-induced (Dumonde Glynn) arthritis in the sheep: a large joint animal model of arthritis.

OBJECTIVE: To determine if the Dumonde Glynn model of arthritis can be established in sheep since a larger model would facilitate injection and the measurement of joints. METHODS: Three groups of sheep were immunised with ovalbumin in Freund's adjuvant. Arthritis was induced in group 1 (n = 10, by the injection of 5 mg ovalbumin in 0.5 ml to the right hock joint. Control groups received saline (n = 10) or no treatment (n = 6). RESULTS: Following joint injection the mean AP diameter increased so that there was a 32% difference between the right and left joints at 24 hr (p < 0.001) declining gradually to 12% (p < 0.01) 19 days after the induction of arthritis. The level of haptoglobin in group 1 prior to the induction of arthritis was 0.04 +/- 0.01. Haemoglobin binding capacity (mg/ml) peaked on day 3 at 0.33 +/- 0.13 (p < 0.01), and was 0.110 +/- 0.05 thirteen days after joint injection. Features observed included proliferation of the joint lining, fibrin deposition and early erosion of cartilage. Synovial membrane showed an infiltrate of inflammatory cells identified as monocytes/macrophages and lymphocytes. Synovial histology scores were 1.8 +/- 0.2 for the left joint and 9.3 +/- 0.73 for the arthritic right joint. CONCLUSION: We conclude that this is a model of mono-arthritis particularly useful when a larger joint is required for intra-articular injection or repeated joint measurements such as in a clinical trial.

Streptomycin and alternative agents for the treatment of tularemia: review of the literature.

Because of the recent lack of availability of streptomycin--currently considered the drug of choice for the treatment of tularemia--we reviewed the literature on alternative drugs that have been used for this purpose. In addition, we reviewed data on the in vitro susceptibility of Francisella tularensis to a wide variety of agents. The rate of cure for streptomycin was 97%, with no relapses. For gentamicin and tetracycline, respectively, the rates of cure were 86% and 88%, the rates of relapse were 6% and 12%, and the rates of failure were 8% and 0. The duration of therapy with gentamicin and a delay in its initiation may have affected outcome in severe cases. For chloramphenicol and tobramycin, cure rates were 77% and 50%, respectively; relapse rates were 21% and 0; and failure rates were 2% and 33%, respectively. Treatment with imipenem/cilastatin was successful in one case, and that with ciprofloxacin or norfloxacin was successful in six cases; in contrast, therapy with ceftriaxone was ineffective in eight cases. On the basis of this review, we conclude that gentamicin is an acceptable alternative to streptomycin for the treatment of tularemia.

Tularemia: treatment failures with outpatient use of ceftriaxone.

Tularemia, an infection caused by the coccobacillus Francisella tularensis, can be a difficult disease process to diagnose and treat. The difficulty in treating this disease is related to the pathophysiology of the infection and the toxicity of the antimicrobial agents presently recommended for treatment. Recent in vitro data have suggested that antimicrobial drugs other than standard agents (streptomycin, gentamicin, chloramphenicol, or tetracycline) may be effective. We present eight cases of documented failure of outpatient use of ceftriaxone in the treatment of tularemia. Our data suggest that while ceftriaxone may have excellent MICs in vitro, these MICs do not necessarily correlate with successful in vivo outcomes.

Spirituality: integral to quality care.

Caring is the medium through which nursing knowledge, skill, and touch are operationalized. Caring is a profound act of hope (White T. 1986. Unpublished data) that contributes to the spiritual well-being of others. In order to assure quality care, the impact of identifying and meeting patient spiritual needs must be taken into account.

Brain GABAB binding sites in depressed suicide victims.

Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain samples (frontal cortex, temporal cortex, and hippocampus) from a group of suicide victims and a group of sex- and age-matched controls. Retrospective psychiatric diagnosis was performed, and only suicide victims with clear evidence of depression in the absence of symptoms of other psychiatric or neurological disorders were studied. There were no significant differences between depressed suicides and controls in the number or affinity of GABAB binding sites in the frontal or temporal cortex and no difference in GABAB binding (measured at two concentrations) in the hippocampus. Thirteen of the depressed suicides had not been prescribed antidepressant drugs recently, and none were found in their blood at postmortem. The number of GABAB binding sites in the frontal and temporal cortex and GABAB binding in the hippocampus did not differ significantly between these drug-free suicides and matched controls. The Kd was higher, however, in the temporal cortex of the drug-free suicides than in the controls. A significant negative correlation was found between age and the number of GABAB binding sites in the temporal cortex (on the basis of pooled data from suicides and controls). These results indicate that GABAB binding sites are unaltered in the brains of depressed suicide victims.

Panuramine, a selective inhibitor of uptake of 5-hydroxytryptamine in the brain of the rat.

The neurochemical profile of the novel inhibitor of uptake of 5-hydroxytryptamine (5-HT) panuramine (Wy 26002) has been investigated in the rat. In vitro, panuramine was found to be a potent and selective inhibitor of uptake of 5-HT with an IC50 of 22 +/- 4 nM. The IC50 for inhibition of uptake of noradrenaline was 848 nM and that for uptake of dopamine greater than 10 micron. Panuramine, in concentrations up to 10 micron did not displace the specific binding of either [3H]spiroperidol or [3H]5-HT and had no effect on the spontaneous or potassium-evoked release of 5-HT, suggesting that the compound had little effect on serotonergic transmission other than the inhibition of uptake of 5-HT. Panuramine also produced a dose-related antagonism of the depletion of 5-HT in brain induced by p-chloroamphetamine, confirming the ability of the drug to inhibit uptake of 5-HT in vivo.