Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence

Objective: To assess cardiovascular (CV) safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design: Two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods: Serious adverse events, serious adverse reactions (SARs), and non-serious adverse reactions (NSARs) were reported by the treating physicians. CV comorbidities at baseline and throughout the studies were also recorded. Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (standard deviation) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. CV comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No CV safety events were recorded in patients with NS. Five CV comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified CV disease, one ruptured abdominal aortic aneurysm and one pulmonary valve stenosis. Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with CV comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with Noonan syndrome and CV disease.

Einsatz von Secukinumab bei Patienten mit Psoriasis und Psoriasis-Arthritis – Ergebnisse einer nichtinterventionellen Studie unter Praxisbedingungen (SERENA-Studie)

<b>Introduction:</b> Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has demonstrated robust efficacy in the treatment of moderate to severe psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with a rapid onset of action, sustained long-term clinical responses and a consistently favourable safety profile across phase 3 trials. Here, we report the clinical data at enrolment from SERENA, designed to investigate the real-world use of secukinumab across all three indications. <b>Methods:</b> SERENA is an ongoing, longitudinal, observational study conducted at 438 sites across Europe in patients with moderate to severe plaque PsO, active PsA or active AS. Patients should have received at least 16 weeks of secukinumab treatment before enrolment in the study. <b>Results:</b> Overall 2800 patients were included in the safety set; patients with PsA (N = 541) were older than patients with PsO (N = 1799) and patients with AS (N = 460); patients with PsO had a higher mean body weight than patients with PsA and patients with AS; and patients with PsO and patients with AS were predominantly male. Time since diagnosis was longer in patients with PsO compared with patients with PsA and patients with AS, and about 40% of patients were either current or former smokers. The proportion of obese patients (body mass index ≥ 30 kg/m²) was similar across indications. Patients were treated with secukinumab for a mean duration of 1 year prior to enrolment (range 0.89–1.04). The percentages of patients with prior biologics exposure were 31.5% PsO, 59.7% PsA and 55% AS. The percentages of patients prescribed secukinumab monotherapy were 75% (n = 1349) in PsO, 48.2% (n = 261) in PsA and 48.9% (n = 225) in AS groups. <b>Conclusion:</b> Baseline demographics of the study population are consistent with existing literature. This large observational study across all secukinumab indications will provide valuable information on the long-term effectiveness and safety of secukinumab in the real-world setting.

Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms “ischemic stroke brain” in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood–brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.

PEG-BCT-100 in Combination With Capecitabine and Oxaliplatin (PACOX) in Patients With Advanced Hepatocellular Carcinoma: A Phase I Study Results

Introduction: We investigated the safety and efficacy of PEG-BCT-100 in combination with oxaliplatin and capecitabine (PACOX) in advanced HCC patients.Methods: This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: IV PEG-BCT-100 2.7 mg/kg on day 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1-14 of each cycle and IV oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied.Results: Seventeen patients were enrolled at 3 doses of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had local-regional chemotherapy or target therapy such as sorafenib, but no systemic chemotherapy. Most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36% (5/14); most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs (3/6 or 50%). The median TTP, PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the third cohort.Conclusion: The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.

Einsatz von Secukinumab bei Patienten mit Psoriasis und Psoriasis-Arthritis – Ergebnisse einer nichtinterventionellen Studie unter Praxisbedingungen (SERENA-Studie)

<b>Introduction:</b> Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has demonstrated robust efficacy in the treatment of moderate to severe psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with a rapid onset of action, sustained long-term clinical responses and a consistently favourable safety profile across phase 3 trials. Here, we report the clinical data at enrolment from SERENA, designed to investigate the real-world use of secukinumab across all three indications. <b>Methods:</b> SERENA is an ongoing, longitudinal, observational study conducted at 438 sites across Europe in patients with moderate to severe plaque PsO, active PsA or active AS. Patients should have received at least 16 weeks of secukinumab treatment before enrolment in the study. <b>Results:</b> Overall 2800 patients were included in the safety set; patients with PsA (N = 541) were older than patients with PsO (N = 1799) and patients with AS (N = 460); patients with PsO had a higher mean body weight than patients with PsA and patients with AS; and patients with PsO and patients with AS were predominantly male. Time since diagnosis was longer in patients with PsO compared with patients with PsA and patients with AS, and about 40% of patients were either current or former smokers. The proportion of obese patients (body mass index ≥ 30 kg/m²) was similar across indications. Patients were treated with secukinumab for a mean duration of 1 year prior to enrolment (range 0.89–1.04). The percentages of patients with prior biologics exposure were 31.5% PsO, 59.7% PsA and 55% AS. The percentages of patients prescribed secukinumab monotherapy were 75% (n = 1349) in PsO, 48.2% (n = 261) in PsA and 48.9% (n = 225) in AS groups. <b>Conclusion:</b> Baseline demographics of the study population are consistent with existing literature. This large observational study across all secukinumab indications will provide valuable information on the long-term effectiveness and safety of secukinumab in the real-world setting.

New possibilities of systemic therapy of plaque psoriasis with the IL23p19 inhibitor risankizumab

Introduction. There is a trend towards rising incidence of psoriasis and increase in the degree of incidence of severe, atypical and treatment-resistant clinical forms of psoriasis in the Russian Federation. In this regard, cases of early disability of patients and deterioration of their quality of life are recorded, which determines the medical and social significance of this disease. In the last few years, a much deeper understanding of the pathogenesis of psoriasis has been gained. This is especially true of the role of T-helper 17 cells, the role of the IL-23 cytokine in the development of the disease, which has resulted in the development of new classes of biological drugs, which creation introduced significant changes in the treatment of psoriasis that has become more effective, safer and convenient for patients. More new biologics undergo clinical trials and receive approvals with each passing year. Among them is risankizumab, interleukin-23 inhibitor, which is a safe and effective drug for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adult patients. Interleukin-23 inhibitors are not required to be administered as often as interleukin-17 inhibitors and may have a more favourable safety profile without an increased risk of candidiasis or inflammatory bowel disease. Overall, these highly effective drugs contribute to the improvement of the long-term efficacy of psoriasis therapy due to relief of skin lesions and joint symptoms, as well as to the enhancement of patients’ quality of life and lengthening of remissions.Purpose. To analyse key information about risankizumab using the results of clinical trials published in the current scientific literature.Materials and methods. This analysis used literature sources from the international medical databases: PubMed, Cochrane Library, MEDLINE.Results. Presently, a number of phase III registrational trials of risankizumab in 2,109 patients with plaque psoriasis have been published: UltIMMa-1, UltIMMa-2, IMMvent and IMMhance, as well as an additional side by side comparative study of risankizumab with secukinumab (IMMerge) in 327 patients with plaque psoriasis. The results of these studies were used as the grounds for approval of risankizumab for the treatment of patients with moderate to severe plaque psoriasis and psoriatic arthritis by the Russian Ministry of Health on September 14, 2020. There have also been several reports of interim results of the open-label enhanced LIMMitless study, which included patients from pivotal studies. Our records show that the percentage of patients receiving risankizumab for 3 years (172 weeks) and maintaining PASI 90 and PASI 100 was 88 and 63%, respectively, and the percentage of those maintaining sPGA 0/1 was 88%.Conclusion. The analysed data showed that risankizumab is one of the most effective target drugs for the treatment of psoriasis and psoriatic arthritis, it has a favourable safety profile and a more convenient dosage regimen as compared with other genetically engineered biologic drugs (GEBD) (the recommended dose of Skyrizi is 150 mg (two 75 mg injections) administered by subcutaneous injection at week 0, week 4, and every 12 weeks thereafter).

Buspirone in obsessive-compulsive disorder: a potential dark horse?

AimsPharmacological management of Obsessive-Compulsive Disorder (OCD) presents a challenge in modern psychiatry. While most patients respond preferably to serotonin re-uptake inhibitors (SRI), the response is usually delayed by several weeks leading to an insufficient short term management of anxiety. It is also frequently inadequate and needs higher doses and augmentation in many instances. Investigating newer pharmacological strategies to address such treatment gaps has always been of interest. Buspirone is a novel anxiolytic medication with additional weak antidepressant and poor anti-psychotic effects. It is the only medication in its category, i.e. azapriones. It has comparable anti-anxiety efficacy to that of benzodiazepines without their sedating or habit forming effects, and has been demonstrated to moderate serotonin and other monoamine neurotransmission with a favourable safety profile.MethodWe reviewed the literature pertaining to the use of Buspirone in OCD for both as a primary anti-obsessive agent and for a potential secondary role in management of chronic anxiety and/or anxiety disorders comorbid to OCD.ResultThe results of a number of case reports and open trials have been positive while controlled trials have shown contradictory results. In a double blind RCT comparing clomipramine and buspirone, significant improvement was found in both groups with no differences between the two. Further two trials observing buspirone augmentation of clomipramine and fluoxetine treatment respectively, in a double-blind placebo controlled design reported significant improvement in the treatment as opposed to the placebo arm. Another double-blind placebo controlled study of buspirone augmentation of fluvoxamine resistant patients did not show significant benefits as an anti-obsessional agent, but notable anxiolytic effects were reported. In all the trials buspirone was largely well tolerated and did not pose any significant interactions with other psychotropic agents or dependence potential.ConclusionBuspirone is a pharmacologically unique agent with a good safety profile. Given the robust anxiolytic effects of this Peron along with complex neurotransmission modulatory effects coupled with a favourable tolerance and dependents profile might make buspirone an attractive novel pharmacological agent for augmentation in OCD . Further controlled studies to better establish effectiveness and deciphering if certain patients may respond to its use over others, are warranted

Venlafaxine as an analgesic in the treatment of chronic pain in patients with depression – scientific evidence and clinical cases

Depression is sometimes referred to as the state of “mental pain” as its symptoms generate a state of generalised suffering. Mental distress is very often accompanied by physical pain. The prevalence of somatic symptoms in the population of patients with depression varies significantly depending on the study population and ranges from 30 to 95%. The incidence and severity of pain are correlated with the aging process and they tend to increase with age. The most common pain symptoms in depression include headache, back and lower back pain, pain of joints and limbs, migraine headaches and abdominal pain. The pain may sometimes mask depression by coming to the fore in the clinical picture and making it difficult to establish an accurate diagnosis. The fact that antidepressants are effective in chronic pain syndromes, while not all antidepressants show the same analgesic efficacy, is the direct evidence for the common pathogenetic mechanisms of chronic pain and depression. Tricyclic antidepressants were the first antidepressants to be used in the treatment of pain symptoms in various disease states. Numerous studies have confirmed the analgesic efficacy of serotonin and noradrenaline reuptake inhibitors, which are characterised by a much better tolerance and a more favourable safety profile compared to tricyclic antidepressants; however, their analgesic effect is clearly marked only at doses that, in addition to the effect on serotonergic transmission, also affect the noradrenergic transmission. The article summarises the scientific evidence for the purposefulness of the use of venlafaxine in the treatment of chronic pain, in particular pain syndromes associated with depression, and presents two clinical cases with a commentary.

Herbal Medicine “Shulifenxiao” Formula for Nephrotic Syndrome of Refractory Idiopathic Membranous Nephropathy

Background: Treatment for adult patients with refractory idiopathic membranous nephropathy (RIMN) by conventional immunosuppressive regimens is not satisfactory. This study aims to evaluate the effectiveness of Chinese herbal medicine, Shulifenxiao formula, as a promising regimen.Methods: A total of 31 RIMN patients resistant to corticosteroid or immunosuppressive agents were retrospectively analyzed. Shulifenxiao treatment lasted a minimum of 12°months in all patients and extended to 24°months in 11 patients. The primary outcomes [the complete remission (CR) and partial remission (PR)] and secondary outcomes (the serum creatinine and estimated glomerular filtration rate (eGFR) levels) were measured at 6, 12, 18, and 24°months.Results: The data provided an average follow-up of 21 ± 9.16°months from baseline. The remission was attained in 25/31 patients (80.7%: CR 29.0% and PR 51.6%) at 12°months and in 10/11 patients (90.9%: CR 54.6% and PR 36.4%) at 24°months, respectively. Proteinuria reduced from 6.02 g/d at baseline to 0.98 g/d at 12°months (p &lt; 0.001) and to 0.27 g/d at 24°months (p = 0.003); serum albumin increased from 28 g/L to 37.2 g/L at 12°months (p &lt; 0.001) and to 41.3 g/L at 24°months (p = 0.003); eGFR improved from 100.25 ml/min/1.73 m2 to 118.39 ml/min/1.73 m2 at 6°months (p &lt; 0.001) and finally to 111.62 ml/min/1.73 m2at 24°months (p = 0.008). Only two patients developed subsequent relapse.Conclusion: Shulifenxiao formula as a clinical cocktail therapy serves as an alternative therapeutic option for steroid and immunosuppressant-resistant RIMN patients, with a favourable safety profile, though further studies are warranted.Clinical Trial registration:http://www.chictr.org.cn, Chinese Clinical Trials Registry [ChiCTR1800019351].

State of the science: cannabis and cannabinoids in palliative medicine—the potential

Cannabinoids are chemicals derived naturally from the cannabis plant or are synthetically manufactured. They interact directly with cannabinoid receptors or share chemical similarity with endocannabinoids (or both). Within palliative medicine, cannabinoid receptors (CB1 and CB2) may modulate some cancer symptoms: appetite, chemotherapy-induced nausea and vomiting, and mood, pain and sleep disorders. Opioid and cannabinoid receptors have overlapping neuroanatomical receptor distribution, particularly at the dorsal horn, dorsal striatum and locus coeruleus. They have a favourable safety profile compared with opioids, and cannabis-based medicines help chronic pain. While cannabidiol (CBD) has anti-inflammatory properties, tetrahydrocannabinol (THC) is the psychoactive substance for issues such as mood and sleep. Nabiximols (Sativex), a CBD:THC combination, is Food and Drug Administration approved for some multiple sclerosis symptoms and epilepsy. There has been a swift societal evolution in attitudes about use of cannabis and cannabinoid medicines for chronic pain. In the USA, 33 states have now legalised prescription-based medical cannabis for several medical conditions; Canada has had legislation since 2001 authorising medical use. The European Union (EU) recently declared all EU citizens must have access to medical cannabis over the next 4 years. The integration into medicine and routine clinical use of cannabis is fraught with information gaps, regulatory issues and scarcity of research. Each patient should have a comprehensive assessment and risk–benefit discussion before any cannabis-based intervention to avoid possible complications such as hallucinations, psychosis and potential cardiac harm.