Conventional Oral Treatment Research Articles

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. Allergan (now AbbVie).

Nanoplatforms: The future of oral cancer treatment.

Cytotoxicity is a key disadvantage of using chemotherapeutic drugs to treat cancer. This can be overcome by encapsulating chemotherapeutic drugs in suitable carriers for targeted delivery, allowing them to be released only at the cancerous sites. Herein, we aim to review the recent scientific developments in the utilization of nanotechnology-based drug delivery systems for treating oral malignancies that can lead to further improvements in clinical practice. A comprehensive literature search was conducted on PubMed, Google Scholar, ScienceDirect, and other notable databases to identify recent peer-reviewed clinical trials, reviews, and research articles related to nanoplatforms and their applications in oral cancer treatment. Nanoplatforms offer a revolutionary strategy to overcome the challenges associated with conventional oral cancer treatments, such as poor drug solubility, non-specific targeting, and systemic toxicity. These nanoscale drug delivery systems encompass various formulations, including liposomes, polymeric nanoparticles, dendrimers, and hydrogels, which facilitate controlled release and targeted delivery of therapeutic agents to oral cancer sites. By exploiting the enhanced permeability and retention effect, Nanoplatforms accumulate preferentially in the tumor microenvironment, increasing drug concentration and minimizing damage to healthy tissues. Additionally, nanoplatforms can be engineered to carry multiple drugs or a combination of drugs and diagnostic agents, enabling personalized and precise treatment approaches. The utilization of nanoplatforms in oral cancer treatment holds significant promise in revolutionizing therapeutic strategies. Despite the promising results in preclinical studies, further research is required to evaluate the safety, efficacy, and long-term effects of nanoformulations in clinical settings. If successfully translated into clinical practice, nanoplatform-based therapies have the potential to improve patient outcomes, reduce side effects, and pave the way for more personalized and effective oral cancer treatments.

Cost-effectiveness analysis of epidural morphine/ropivacaine treatment in patients with cancer pain.

Cancer pain is one of the main causes of human suffering, which can generate disabilities and compromise quality of life, giving rise to several psychosocial and economic consequences. This quantitative study sought to perform a cost-effectiveness pharmacoeconomic analysis to assess the impact of implanting epidural morphine associated with ropivacaine treatment in gastrointestinal cancer patients with pain that is difficult clinical control, compared with conventional oral treatment. The study population consisted of 24 patients with gastrointestinal neoplasia who underwent treatment for cancer pain that was difficult to clinically control. 12 patients each were recruited into the control and intervention groups, respectively. While patients in the control group were administered drug treatment orally, patients in the intervention group underwent a surgical procedure for subcutaneous implantation of a catheter that allowed epidural administration of morphine and ropivacaine. For pain assessment, the Visual Analogue Scale was applied. Data analysis had a descriptive character of costs, taking into account the costs for the year 2021. The study perspective was the Brazilian public healthcare provider, referred to as the Unified Health System (Sistema Único de-SUS in Portuguese). Costs were computed over the time horizon corresponding to the duration of treatment, from the first medical consultation (when the treatment was defined) to the end (end of treatment, disease progression, or death). Treatment duration was divided into three phases (first 60 days, support with palliative care, and end-of-life care). To assess the robustness of the economic analysis, sensitivity analyses were performed, considering the effectiveness of pain reduction on the Visual Analogue Scale, and a comparison of results using the median prices of pharmaceutical components used in the study. The mean age of patients was 59.3 years. The results from the cost-effectiveness analysis showed the epidural morphine/ropivacaine treatment to be more effective with regard to pain reduction on the pain scale, particularly for end-of-life care, when compared to the conventional oral treatment, however, at a significantly higher cost. From the accomplishment of this research, it was observed that the application of the pain assessment scale is a way to better interpret and understand the patient's pain, facilitating care planning and decision-making by health professionals, as well as monitoring the effectiveness of the proposed new treatment. To present a better cost-effectiveness ratio, a reduction in the cost of the new epidural technology or an increase in the value of the existing oral intervention would be required. However, the latter is not feasible and unlikely to occur. A value judgement to decide whether the incremental benefit associated with the use of the new intervention is worth the extra cost will have to be made by the healthcare provider. Interventions that can relieve cancer pain symptoms should be investigated continuously, in search of evidence to support clinical practice and promote better quality of life for patients.

Nanomedicine in the Management of Alzheimer's Disease: State-of-the-Art.

Alzheimer's disease (AD) is a deadly, progressive, and irreversible brain condition that impairs cognitive abilities. Globally, it affects 32.6 million individuals, and if no viable therapies are available by 2050, that figure might rise to 139 million. The current course of treatment enhances cognitive abilities and temporarily relieves symptoms, but it does not halt or slow the disease's development. Additionally, treatments are primarily offered in conventional oral dosage forms, and conventional oral treatments lack brain specialization and cause adverse effects, resulting in poor patient compliance. A potential nanotechnology-based strategy can improve the bioavailability and specificity of the drug targeting in the brain. Furthermore, this review extensively summarizes the applications of nanomedicines for the effective delivery of drugs used in the management of AD. In addition, the clinical progress of nanomedicines in AD is also discussed, and the challenges facing the clinical development of nanomedicines are addressed in this article.

Suboptimal Clinical and Quality of Life Outcomes in Patients with Psoriasis Undertreated with Oral Therapies: International Physician and Patient Survey.

Psoriasis is a chronic, inflammatory, immune-mediated disease. This study assessed the time at which patients switched from a conventional oral systemic treatment to a biologic therapy; patient clinical and quality of life (QoL) outcomes associated with oral systemic treatments; and the proportion of patients who persisted on oral therapy (nonswitchers), despite reported suboptimal clinical and QoL outcomes. This data analysis used the Adelphi Real World Psoriasis Disease Specific Programme, a non-interventional, retrospective, cross-sectional survey conducted in the USA, France, Germany, and United Kingdom (August 2018-April 2019). Kaplan-Meier (KM) analysis assessed switching from oral to biologic therapy in patients treated ≥ 3years at survey completion (n = 597). The severity of psoriasis was reported by physicians as the percentage of body surface area (BSA) affected by psoriasis. Dermatology Life Quality Index (DLQI) scores were calculated for three groups: nonswitchers who met treatment failure criteria, nonswitchers who did not meet failure criteria, and switchers to a biologic therapy. In KM analysis, approximately 50% of the patient population switched by 24months. A substantial portion of nonswitchers continued to have moderate-to-severe psoriasis. Among nonswitchers, 57-77% had BSA ≥ 3% and 16-24% had BSA ≥ 10% at the time of the survey compared with 37% of switchers who had BSA of ≥ 3% and 9% who had BSA of ≥ 10%. QoL was poor among nonswitchers. The mean [standard deviation (SD)] DLQI scores for nonswitchers meeting treatment failure criteria, nonswitchers not meeting failure criteria, and switchers were 6.11 (4.55), 2.62 (3.29), and 2.25 (4.23), respectively. There is a clear unmet need for more effective oral therapies, and further research into the reasons for patients remaining undertreated, which may include patient preference for oral treatments (despite lack of response), contraindications, or insurance/formulary-related barriers to access, are needed.

Patients with Hypocortisolism Treated with Continuous Subcutaneous Hydrocortisone Infusion (CSHI): An Option for Poorly Controlled Patients.

Despite appropriate oral glucocorticoid replacement therapy, patients with hypocortisolism often suffer from impaired health and frequent hospitalizations. Continuous subcutaneous hydrocortisone infusion (CSHI) has been developed as an attempt to improve the health status of these patients. The objective of this study was to compare the effects of CSHI to conventional oral treatment on hospitalizations, glucocorticoid doses, and subjective health status. Patients. Nine Danish patients (males: 4 and females: 5) with adrenal insufficiency (AI) were included, with a median age of 48 years, due to Addison (n = 4), congenital adrenal hyperplasia (n = 1), steroid induced secondary adrenal insufficiency (n = 2), morphine induced secondary adrenal insufficiency (n = 1), and Sheehan's syndrome (n = 1). Only patients with severe symptoms of cortisol deficit on oral treatment were selected for CSHI. Their usual oral hydrocortisone doses varied from 25-80 mg per day. The duration of follow-up depended on when the treatment was changed. The first patient started CSHI in 2009 and the last in 2021. A retrospective case series comparing hospitalizations and glucocorticoid doses before and after treatment with CSHI. In addition, patients were retrospectively interviewed about their health-related quality of life (HRQoL) after the change of treatment modality. Patients significantly reduced their daily dose of glucocorticoids by 16.1 mg (p = 0.02) after changing to CSHI. The number of hospital admission due to adrenal crisis decreased by 1.3 per year on CSHI, which was a 50% reduction (p = 0.04). All patients found it easier to handle an adrenal crisis with CSHI, and almost all patients found it easier to overcome everyday activities and had fewer symptoms of cortisol deficit such as abdominal pain and nausea (7-8 out of 9 patients). The change of treatment from conventional oral hydrocortisone to CSHI resulted in a reduced daily dose of glucocorticoids and a reduced number of hospitalizations. Patients reported regain of energy, achievement of better disease control, and better handling of adrenal crisis.

Iron Therapies For Iron Deficiency In Chronic Kidney Disease: A Literature Review

Chronic kidney disease is a condition when kidney function fails gradually due to kidney damage. One of the causes of anemia in CKD is iron deficiency. Conventional oral iron treatment is not effective to treat iron deficiency anemia due to poor absorption and various side effects. Newer oral iron therapies with better tolerability and offer the potential to normalize iron without the need for intravenous iron. To review the currently available status oral iron therapies and summarizes the latest clinical trial evidence for their use. We researched Google Scholar and PubMed using keyword "iron" OR "ferri" OR "Ferro" OR "iron therapy" AND "Iron deficiency" AND "renal insufficiency, chronic" OR "chronic kidney disease" OR "kidney failure, chronic" OR "chronic renal disease" of last ten years. Total 8 articles recorded the identification stage by the criteria for inclusion. The articles are randomized controlled trials. Total 2.674 patients CKD of various types with or without anemia, age range 18-72 years were treated with oral iron therapies (ferric citrate, ferrous sulfate, sucroferric oxyhydroxide, ferric carboxymaltose) with varying doses. The most side effects of the therapies are gastrointestinal intolerance. Oral iron therapies are considered safe but drug development is still needed to minimize side effects.

Are Intravesical Aminoglycosides the New Gold Standard in the Management of Refractory Urinary Tract Infection: A Systematic Review of Literature.

Background: Antibiotic resistance in urinary pathogens is increasingly common, leading to rising cases of complicated urinary tract infections. Conventional antimicrobial treatment may be insufficient in these cases and broad-spectrum systemic antibiotics contribute to the problem. Intravesical aminoglycoside instillation is an alternative treatment option that delivers localized and high-dose treatment to the source of infection. This study summarizes the existing evidence for the efficacy and safety of this treatment. Methods: A systematic search was conducted of worldwide literature according to PRISMA methodology and Cochrane standards for systematic review. Studies were included if they reported outcome data for the prevention and reduction in urinary tract infections, eradication of antimicrobial-resistant organisms, or change in sensitivities allowing conventional oral antimicrobial treatment after the administration of intravesical aminoglycoside with or without polymyxin therapy. Results: The search identified 826 articles, of which, 19 were included in the final data analysis and narrative synthesis. A successful outcome was identified in 80.7% (n = 289) of patients treated with aminoglycoside alone and 79.5% (n = 163) treated with an aminoglycoside in combination with polymyxin. Discontinuation was noted in 6.2% of patients. An increase in antimicrobial sensitivity was seen in 15.3% (n = 55) and 16.3% (n = 36) in the aminoglycoside and aminoglycoside/polymyxin groups, respectively. Conclusions: Current evidence supports the use of intravesical aminoglycoside instillation as an efficacious and safe treatment for refractory UTIs. Nevertheless, data is limited, and larger volume studies with longer follow-up periods are required.

Protective manifestation of herbonanoceuticals as antifungals: A possible drug candidate for dermatophytic infection.

Background and AimsFungal dermatophytosis or Tinea is a predominance in about 20%–25% of all total world populations. Dermatophyte infections are mainly caused by fungi belonging to Trichophyton, Epidermophyton, and Microsporum genera along with some other fungi. This epidemiological distribution may change with migration, lifestyle, immunosuppressive state, drug therapy, and socioeconomic conditions.MethodsThe present review indicated the bioefficacy of herbal and herbonanoconjugate as safe management of fungal dermatophytic infection.ResultsIt also emphasized the action mechanism as fungicidal and fungistatic with different harmful impacts indicating the need for alternative therapeutics. Simultaneously, the herbal and herbonanoconjugate approaches proved better to manage the prevalence of hepatotoxicity, nephrotoxicity, nausea, altered taste, anemia, GI upsets, hair loss, and so forth. due to conventional oral treatment approaches.ConclusionAdoption of the remedial approach can be recommended after preclinical trials' approval as a safe treatment.

A comparative study of Botulinum toxin type A versus conventional oral therapy as a second-line treatment of diabetic neuropathy

BackgroundDiabetes mellitus is commonly complicated by diabetic peripheral neuropathy. Poor adherence to medication is common in diabetic peripheral neuropathy mainly due to common side effects and poor tolerance to medication. Botulinum toxin A intradermal injection has proved efficacy in cases of diabetic peripheral neuropathy, however there is a need to compare its effect to other lines of treatment. The aim of the study was to compare Botulinum toxin type A versus conventional oral treatment as a second-line treatment of painful diabetic peripheral neuropathy. The current study was a comparative study on 30 patients with type 2 diabetes mellitus. Diabetic peripheral neuropathy was proved by nerve conduction study. All patients were on carbamazepine. Patients were divided randomly into three groups. First group was add-on duloxetine, second group was add-on gabapentin and the third group was injected intradermal with Botulinum toxin A.ResultsOur study showed that Botulinum A intradermal injection, gabapentin and duloxetine add-on therapy decreased the VAS and PSQI over a 12-week study period and this was statistically significant at p < 0.001*. Botulinum A intradermal injection also decreased the mean of PSQ1 from 17.3 ± 1.8 to 10.9 ± 3.1 in 12 weeks constituting the highest decline in PSQ1 among the three groups and this was statistically significant at p < 0.001*.ConclusionBotulinum toxin A injection had a comparable if not superior efficacy to duloxetine and gabapentin as a second-line treatment of diabetic peripheral neuropathy.

Another possible determinant for ischemic stroke with nonvalvular atrial fibrillation other than conventional oral anticoagulant treatment: The relationship between whole blood viscosity and stroke☆

ObjectivesPatients with nonvalvular atrial fibrillation (NVAF) still experience ischemic stroke despite recommended medications and this could be the consequence of increased whole blood viscosity (WBV). We evaluated the predictive value of WBV for stroke in patients with NVFA despite receiving oral anticoagulant (OAC) therapy. MethodsOne thousand and forty-three NVAF patients on OAC medication were followed up for median 36.13 ± 18.31 months. WBV was calculated according to the validated de Simone's formula. ResultsWBV was significantly higher in stroke group when compared to non-stroke group at both low shear rate (LSR) and high shear rate (HSR). Multiple regression analysis demonstrated an independent association between WBV and stroke when adjusted for other risk factors. ConclusionsWBV appears to be a profitable predictor of ischemic stroke in patients with NVAF receiving OAC.

Changes in Bone Mineral Density Following Conventional Oral Phosphonate Treatment of Hypophosphatemic Osteomalacia: A Non-Randomized Controlled Study.

PurposeThere are limited clinical studies aimed at solving the problem of the efficiency of conventional treatment with oral phosphate and calcitriol in adults with hypophosphatemic osteomalacia (HO). In addition, there still had no good non-hazardous markers to evaluate the severity of bone loss of osteomalacia before and after treatment. Therefore, the purpose of this study was to assess the efficacy of conventional treatment with a self-blended phosphate supplementation and calcitriol on patients with HO and whether bone mineral density (BMD) can be helpful for monitoring the efficacy.Patients and MethodsA total of 21 HO patients and 105 healthy controls were enrolled. All patients were tested for serum biomarkers and BMD of the lumbar spine (L1–L4), femoral neck, and total left hip. After three years of treatment, 11 of 21 HO patients were recalled for BMD measurement. According to the administration of drugs, HO patients with calcium and calcitriol were divided into three phosphate treatment groups: patients in group A (n = 3) received continuous phosphate supplementation, patients in group B (n = 5) received intermittent phosphate supplementation and patients in group C (n = 3) received no phosphate supplementation.ResultsThe diagnoses of 21 HO patients were 5 cases of hereditary hypophosphatemic rickets, 4 cases of Fanconi syndrome with the features of renal tubular acidosis and vitamin D deficiency, and 12 cases of hereditary vitamin D abnormality. The average initial serum phosphorus level of the patient group was approximately 50% lower than that of the control group. Lower BMD was significantly observed in the HO group than the control group at the lumbar spine and total hip. Continuous treatment with the phosphate supplement could increase BMD in the lumbar spine and total hip by 33.4–52.3% and in the femoral neck increased by 43.2–79.3% compared with baseline, and the effect appears to be continued once treatment is discontinued.ConclusionThese findings suggest that conventional therapy can improve bone mineral defects in patients with HO, especially in the femoral neck. Detection of BMD in HO patients is a good tool to assess the extent of bone defects and the therapeutic effect.Trial RegistrationChinese Clinical Trial Registry, ChiCTR-OOC-16010095. Registered 7 December 2016. Retrospectively registered.

Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility. Herein, we report the development of dissolving MNs (DMNs) containing ART (MN-ART) and LUM (MN-LUM) as an alternative treatment regimen for malaria in low-resource settings. To incorporate the drugs into the MNs, nanosuspensions (NSs) for both molecules were developed separately to enhance drug solubility. The NSs were freeze-dried and the powder form was incorporated directly in an aqueous polymeric blend with poly-vinyl-pyrrolidone for MN-ART and a sodium hyaluronate hydrogel for MN-LUM. The in vivo bioavailability studies were performed using a MN reapplication scheme (1 × a day for 3 days), illustrating that an extended-release profile was achieved for both drugs when MNs were applied intradermally, and when compared to conventional oral treatment. The ART-LUM oral treatment was used as a positive control. For antimalarial activity, studies with animals infected with 106Plasmodium yoelii 17XNL (12 days) were also conducted using female C57BL/6JUnib mice, demonstrating a 99.5% reduction in parasitemia by day 12 post-infection. By abolishing the infection, MN-ART and MN-LUM may serve as a promising controlled intradermal delivery device for antimalarial drugs to be explored in endemic areas.

Rotigotine Transdermal Patch for Motor and Non-motor Parkinson's Disease: A Review of 12 Years' Clinical Experience.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1–4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.

Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis: a phase 1, randomised, double-blind, placebo-controlled, parallel-group study

Summary Background Blockade of tyrosine kinase 2 (TYK2) signalling has previously shown therapeutic potential in the treatment of psoriasis. The primary objective of this study was to assess the safety and tolerability of the TYK2 inhibitor PF-06826647. Methods This phase 1, randomised, double-blind, placebo-controlled, parallel-group study assessed once daily oral dosing of PF-06826647 in participants with plaque psoriasis, at a single clinical research site in the USA. Eligible participants (aged 18–65 years) had plaque psoriasis covering at least 15% of total body surface area and a psoriasis area and severity index (PASI) score of at least 12 at baseline. Participants received PF-06826647 (100 mg or 400 mg), or placebo once daily for 28 days. Using a computer-generated randomisation schedule with a block size of 3, participants were sequentially randomly assigned into two cohorts by the investigator; in the first cohort, participants were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 400 mg or placebo once daily, whereas participants in the second cohort were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 100 mg or placebo once daily. Site, investigator, Pfizer personnel, and participants, were masked to treatment. The primary endpoint was the safety of multiple-dose PF-06826647 in participants with plaque psoriasis. Secondary endpoints were the characterisation of the pharmacokinetics of multiple-dose PF-06826647 in plasma and the change in PASI score at day 28. Safety analysis was done in all participants who received at least one dose of study drug. Efficacy analysis was done in all participants who received at least one dose of randomised study drug, and had a baseline and at least one post-baseline measurement. This study is registered as a randomised, controlled trial with ClinicalTrials.gov , NCT03210961 and is completed. Findings The trial was done between July 14, 2017, and Jan 25, 2019. Overall from 91 participants assessed, 40 participants with moderate-to-severe psoriasis were randomly assigned to treatment (placebo 14 [35%] of 40; PF-06826647 100 mg, 11 [28%] of 40; PF-06826647 400 mg, 15 [38%] of 40). Treatment-emergent adverse events (TEAEs) were reported in 12 (80%) of 15 participants in the PF-06826647 400 mg group, seven (50%) of 14 in the placebo group and five (45%) of 11 in the 100 mg group. All TEAEs were mild in severity, except one moderate TEAE of vomiting reported in the placebo group. There were no deaths, serious TEAEs, severe TEAEs, dose reductions, or temporary discontinuations. Compared with placebo, the change from baseline in PASI score at day 28 showed a significant reduction in least squares mean difference for the PF-06826647 400 mg group (−13·05; 90% CI −18·76 to −7·35; p=0·00077) but not for the PF-06826647 100 mg group (−3·49; −9·48 to 2·50; p=0·33). Both the area under the concentration–time curve over the dosing interval and the maximum concentration increased in a less than dose proportional manner with increasing dose from 100 mg to 400 mg PF-06826647. Interpretation PF-06826647 showed significant improvement in disease activity within 4 weeks of dosing with an acceptable safety profile. PF-06826647 holds promise over conventional oral treatments for psoriasis that have shown limited efficacy or unfavourable safety profiles. Funding Pfizer.

Post-auricular leech therapy reduced headache &amp; migraine days in chronic migraine

Background: Migraine is an exceedingly common disorder that causes substantial pain, disability and societal burden. Unfortunately, conventional treatments are insufficient, inadequate, or associated with significant risks, such as overuse, abuse or addiction. The Unani system of Medicine has been treating migraine since centuries. Leech therapy (Irsale Alaq) has been employed successfully in severe persistent headache, mania and insomnia since decades.&#x0D; Aim: The purpose of our study was to evaluate the impact of post auricular leech therapy in migraine and to collect data to warrant further clinical trials.&#x0D; Methods: We conducted a case series on 7 patients who had failed conventional oral treatments for the migraine. After informed consent, post auricular leech therapy was done. Patients were asked to keep detailed headache calendars, documenting the number of headache days, migraine days, the intensity of headaches/ migraines and analgesic usage. We compared these parameters before and after 2 months of therapy.&#x0D; Results: We observed a reduction in the number of headache &amp; migraine days and amount of painkillers used without any adverse effects. (P≤ 0.01) Improvement in quality of life was also observed.&#x0D; Discussion: We reviewed the literature related to the medicinal leeches (Hirudo medicinalis), used for the treatment in these cases. Leech saliva contains certain potent anesthetic, anti-inflammatory and vasodilator substances, suggesting plausible mechanisms of action in these cases.&#x0D; Conclusion: The preliminary findings indicate the safe and potential therapeutic role of leech therapy. So further trials should be carried out to explore the therapeutic potential of this therapy in chronic migraine.&#x0D; Keywords: Chronic Migraine, leech therapy, hirudo medicinalis, headache, Unani Medicine, complementary Medicine.

ND4 - COST-EFFECTIVENESS EVALUATION OF THE INTRA-DUODENAL CONTINUOUS LEVODOPA INFUSION IN ADVANCED AND SEVERE PARKINSON’S DISEASE

Motor fluctuations are a common problem in the long-term management of Parkinson’s disease (PD), resulting in disability and impaired quality of life (QoL). The purpose of this analysis was to estimate the cost-effectiveness of Levodopa Continuous Infusion of Gel (LCIG) compared with Optimized Conventional Oral Therapy (OCOT). The prospective, double-blind, placebo-controlled, multicenter trial, long-term study (CECILE) was conducted in routine care with 1-year follow-up at 21 sites in France between December 2010 and March 2016. Patient and family caregivers’ questionnaires were used to collate all outpatient care. The use of resources in hospitals was evaluated using a PMSI survey of the participated centers. Health-related QoL was measured utilizing PDQ-39 and EQ-5D-3L that were administered during every visit. Outcome measure for this analysis were the incremental cost-effectiveness ratio (ICER), defined as the incremental cost divided by the number of QALYs saved and the Net Monetary Benefit (NMB). The uncertainty was apprehended by the bootstrap method approach. The 6-month costs associated with LCIG amounts to €13 189 and generates 0.207 QALYs. The difference of QALYs between two treatment arms was significant. The ICER was negative, LCIG has a lower cost and greater utility compared to OCOT. LCIG dominates OCOT. The NMB of LCIG is always greater than the conventional oral treatment. The dominance of LCIG is clearly demonstrated in the cost-effectiveness acceptability curves: two curves do not intersect which means that treatment of levodopa is the optimal treatment regardless of the willingness-to-pay (WTP) level. Continuous enteral levodopa infusion achieves a reduction of motor fluctuations and dyskinesias improving patients’ QoL, despite the progression of PD motor symptoms and a significant decline in cognitive functions. From a health-economic perspective, LCIG is a cost-effective therapy and could be seen as an alternative treatment to OCOT for the patients with advanced PD.

Pharmacokinetics and Pharmacodynamics of Escalating Doses of SHetA2 After Vaginal Administration to Mice

SHetA2 is a novel compound with strong potential to treat cervical dysplasia, but its low aqueous solubility limits its oral bioavailability. A vaginal suppository achieved SHetA2 cervix concentrations that were severalfold above the predicted therapeutic levels. Thus, we aimed at determining the minimum dose that would achieve SHetA2 therapeutic levels while reducing cyclin D1 levels, the pharmacodynamic end point. The disposition of SHetA2 after vaginal administration of escalating SHetA2 doses and the corresponding reduction in cyclin D1 levels was compared to that after the conventional oral treatment. Vaginal administration of a 15-mg/kg dose achieved an area under the cervix concentration versus time curve (AUCcervix) that was ∼120 times larger than that after a 60 mg/kg administered orally. AUCcervix and Cmax-cervix did not increase proportionally with respect to the dose, with the 30-mg/kg dose resulting in higher AUCcervix and Cmax-cervix (1368.53 μg.mL/h and 155.38 μg/g, respectively) compared to the 15 mg/kg (334.98 μg.mL/h and 121.78 μg/g, respectively) or 60 mg/kg (1178.55 μg.mL/h and 410.38 μg/g, respectively). Likewise, the 30-mg/kg dose caused a larger reduction in cyclin D1 levels than the other doses. Thus, the 30-mg/kg dose was selected for future efficacy studies in a mouse model of cervical neoplasia.

ITCA 650

ITCA 650

Comparing the Effect of Injectable Vitamin B With Conventional Oral Treatment on Aphthous Stomatitis

Background: Recurrent aphthous stomatitis (RAS) is a common condition with recurrent ulcerations limited to the oral mucosa. Different predisposing factors have been proposed, including iron, vitamin B12, and folic acid deficiencies. The aim of this study was to evaluate the effect of injectable vitamin B in comparison with a form of oral therapy on recurrent Aphthous stomatitis. Methods: This randomized clinical trial was performed on 60 patients with RAS, during years 2015 and 2017. All patients were at least 18 years of age without systemic disease associated with RAS. All the study population had a minor type of Aphthous ulcers with two months of maximum recurrence intervals during the last year. Additionally, all patients benefited from a checklist, including demographic data and relapse intervals, and a number of lesions were completed before the start of the study. Also, blood tests were performed to evaluate a complete counting of blood cells, and levels of ferritin, vitamin B12, and folic acid. Next, patients were randomly divided to two groups comprised of those that received eight weeks of injectable vitamin B (a combination of B1, B6, and B12) and those on eight weeks of chewable tablets (a combination of iron, folic acid, vitamin B complex, and vitamin C). Finally, all patients were monitored for 10 months. Results: There were no statistically significant differences between the two groups in terms of deficiencies in ferritin, vitamin B12, and folic acid (P > 0.05). In the injectable form of treatment, the efficacy was excellent in 14, moderate in 12, and low in four patients while in the oral form, the efficacy was moderate in nine and low in 12 patients. It is important to consider that there was no response to treatment in nine patients. Conclusions: The injectable form of Vitamins B that contains a high dose of vitamin B had better efficacy than the oral form. Accordingly, it can be concluded that the injectable form of vitamin B might be an effective treatment as it is considered a simple, inexpensive, and low-risk treatment for patients with RAS, regardless of ferritin, vitamin B12, and folic acid levels.