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Hereditary angioedema (HAE), an inherited deficiency of functional C1 esterase inhibitor (C1-INH), is characterized by unpredictable recurrent episodes of painful and often disabling swelling in subcutaneous and/or submucosal tissues. We report the case of a 23-year-old woman with type I HAE who had abdominal, facial, and peripheral attacks throughout her first pregnancy. A facial HAE attack occurred at week 38 of her pregnancy, and symptoms improved after self-administration of 50 U/kg of recombinant human C1-INH (total dose, 3500 U), but soon after she had an unusual abdominal sensation. Ultrasonography detected fetal lower lip swelling (∼3 times the normal size) and limb swelling. Physical examination of the mother found cervical dilatation, indicating the final stages of labor. Two hours after treatment of her HAE attack, she spontaneously delivered a healthy male infant. Photographs taken within 2 minutes of delivery revealed resolution of the infant’s facial edema, and the limb edema was resolved within 30 minutes. By 10 minutes postdelivery, the mother’s facial attack had almost completely resolved. Ten months after birth, genetic analysis confirmed that the infant had type I HAE. This is the first documented case of an HAE attack in utero. Treatment of the mother with recombinant human C1-INH was effective for the maternal and fetal attacks, with resolution within approximately 2 to 2.5 hours for both patients.

Background Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS

Background: Ibuprofen is used for the treatment of non-serious pain. This study assessed the efficacy and safety of a new ibuprofen plaster for the treatment of pain associated with acute sports impact injuries/contusions.Methods: In this randomised, double-blind, multi-centre, placebo controlled, parallel group study, adults (n = 130; 18-58 years of age) diagnosed with acute sports-related blunt soft tissue injury/contusion were randomized to receive either ibuprofen 200 mg plaster or placebo plaster. Plasters were administered once daily for five consecutive days. The primary assessment was area under the visual analogue scale (VAS) of pain on movement (POM) over 0 to three days (VAS AUC(0-3d)). Other endpoints included algometry AUC from 0 to three days (AUC(0-3d)) and 0 to five days (AUC(0-5d)), to evaluate improvement of sensitivity at the injured site, and patient and investigator global assessment of efficacy. Safety was monitored throughout the study.Results: The ibuprofen plaster resulted in superior reduction in AUC(0-3d) compared with placebo; the Least Squares (LS) mean difference was 662.82 mm*h in favour of the ibuprofen 200mg plaster (P = 0.0011). The greater improvement in VAS AUC of POM was also observed after 12 h, 24 h, and five days of therapy. Tenderness also significantly improved with the ibuprofen plaster compared with placebo; LS mean difference in algometry/tenderness AUC(0-3d) was 1.87 N/cm(2)*d and AUC(0-5d) was 1.87 N/cm(2)*d (P valuesConclusions: The results of this study indicate 200 mg plaster is effective and safe for the treatment of pain due to acute sports-related traumatic blunt soft tissue injury/contusion in adults.

To investigate the efficacy and safety of a recently developed ibuprofen medicated plaster in the treatment of acute sports impact injuries/contusions.In this double-blind, multi-center, placebo-controlled, parallel group, phase 3 study (EudraCT Number: 2012-003257-2) patients (n = 132; ages 18 to 60 years) diagnosed with acute sports-related traumatic blunt soft tissue injury/contusion to the upper or lower limbs were randomized to receive either ibuprofen 200 mg plaster (n = 64) or placebo plaster (n = 68). Plasters were administered once daily for five consecutive days. The primary assessment was the area under the curve (AUC) of the visual analogue scale (VAS) of pain on movement (POM) over 0 to 72 h (VASThe ibuprofen medicated plaster was associated with a reduction in pain on movement (POM) based on lower VAS AUCThe results of this study indicate that ibuprofen medicated plaster results in rapid and clinically relevant reduction of pain in patients suffering from blunt musculoskeletal injuries or recurrent pain. The ibuprofen medicated plaster was well tolerated.

Summary Background Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. Methods We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Findings Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p Interpretation Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Funding Pharming Technologies.

Introduction The results of a clinical trial published in 2016 showed the efficacy of ivy leaves dry extract EA 575 versus placebo in the treatment of patients suffering from acute cough. A clinical trial with a very similar design was conducted to not only show the reproducibility of former results but also to investigate an alternative dosing scheme. Methods This randomised, placebo-controlled, multicentre, double-blind clinical trial was conducted to assess the efficacy and safety of a liquid containing EA 575 in the treatment of acute bronchitis. A total of 209 patients were treated with a liquid containing EA 575 as an active investigational medicinal product (verum) either two (7.5 mL) or three (5 mL) times a day or placebo in the respective dosing scheme for 1 week, with a total observational period of 2 weeks. The primary efficacy outcome was a change in Bronchitis Severity Score (BSS) of the pooled placebo and pooled verum groups between visits 1 and 5. Additional secondary parameters were assessed, including, for example, change in cough severity as assessed by a visual analogue scale (VAS) and the Verbal Category Descriptive (VCD) score. Results Superiority of verum over placebo was during and at the end of treatment, as measured by BSS. No significant differences between the dosing schemes were observed. VCD scores and VAS measurements also showed the superiority of verum over placebo. Conclusion The existing data on the clinical efficacy of EA 575 were confirmed. Furthermore, a new dosing scheme was shown to be noninferior to the currently used scheme while maintaining the safety and tolerability of the well-established cough liquid containing EA 575., Ivy leaves dry extract EA 575 provides an effective and safe therapeutic option in the treatment of acute bronchitis http://bit.ly/318CZys

Background: The favorable benefit-risk profile of topical nonsteroidal anti-inflammatory drugs (NSAIDs) makes them a preferred treatment for pain relief in soft tissue injuries. Purpose: To assess the efficacy and safety of a novel etofenamate 70-mg medicated plaster in patients with acute uncomplicated ankle sprain. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Patients with grade 1 or 2 ankle sprain of recent onset were randomized to etofenamate or placebo plasters (1:1) applied twice daily for 7 days. Clinical assessments, including ankle pain on movement (POM) in mm on a 100-mm visual analog scale (VAS), were made at predefined intervals during the treatment period. Results: In total, 156 male or female adult patients (mean age, 35.3 ± 11.8 years) were enrolled. The fall in VAS values for POM from baseline to 72 hours was markedly in favor of the etofenamate plaster, with respective reductions of 52.7% and 24.0% for active and placebo plasters (least squares mean treatment difference, 22.1 mm; P value for analysis of covariance < .0001). Similar clinically relevant differences between etofenamate and placebo were seen for POM at the 48-, 96-, and 168-hour visits ( P < .0001). These differences between etofenamate and placebo plasters were reflected in area under the curve for POM, pain at rest, and ankle swelling measured at various time points during the 7 days. Time taken to achieve a meaningful (30%) and optimal (50%) reduction of POM was significantly shorter in the etofenamate group. The responder rate (proportion of patients with at least 50% pain reduction at 72 hours) was 52.5% for the etofenamate plaster and 7.7% for the placebo. A significantly greater proportion of patients randomized to etofenamate rated their progress and/or the treatment as “good” or “very good.” The medicated plasters adhered well over the 12-hour dosing period and were very well-tolerated. Conclusion: With respect to the investigated indication, uncomplicated ankle sprain, the etofenamate plaster has therapeutic efficacy that is similar to that for the best available topical NSAID formulations. Registration: 2016-000252-99 (EudraCT number).

Objective A prospective, randomized, double-blind, placebo-controlled, parallel-group multicentre study to evaluate the efficacy and safety of diclofenac 4% spray gel for the treatment of acute, uncomplicated ankle sprain. Methods Outpatients with acute, uncomplicated, one-sided ankle sprain were randomly assigned to receive diclofenac 4% spray gel or placebo (vehicle) three times daily for 14 ± 1 days. The main efficacy endpoint was the intra-individual response to treatment (≥50% decrease in swelling of the injured ankle after a treatment period of ≤10 days). Results The response rate was significantly higher in the diclofenac group ( n = 118) than the placebo group ( n = 114) (91.5% vs. 82.5%). After 3–4 days’ treatment, diclofenac spray significantly reduced swelling, spontaneous pain, pain on active movement and tenderness compared with placebo. Diclofenac spray was well tolerated, with a low overall rate of adverse events. Conclusions Diclofenac 4% spray gel rapidly relieves pain and improves mobility in patients with acute, uncomplicated ankle sprain and is well tolerated. It may be a useful treatment option for other acute soft tissue injuries.

Background: Acute cough is one of the lead symptoms of respiratory diseases where ivy leaves dry extract preparations provide relief. Aims and objectives: This randomized, placebo-controlled, double-blind trial was conducted to assess the efficacy and safety of ivy leaves cough liquid in the treatment of acute cough. Methods: A total of 181 adult patients with acute cough were treated with ivy leaves cough liquid containing EA 575 ® or with placebo three times a day for a week. The primary efficacy outcome was cough severity (CS) assessed by Visual Analogue Scale (VAS) over the treatment period (area-under-the-curve (AUC 0-168 h ), visit (V)1-5). The secondary endpoints were defined as the CS assessed by VAS over the observation period (V1–V6) and by Bronchitis Severity Score (BSS) and Verbal Category Descriptive (VCD) score. Results: The evaluation of the VAS, BSS and VCD Score revealed that subjects treated with ivy leaves cough liquid showed statistically significant and clinically relevant reductions in CS compared to the placebo group. Furthermore, a remarkable early onset of efficacy was observed as significant reductions of cough severity were detected within 48 hours after the first drug intake. At all following visits and even 7 days after the end of treatment (V6) this significant treatment advantage was detected in comparison to placebo. All adverse events (AEs) in this clinical trial were non-serious and not drug-related. Also >65 years old patients benefitted from the very good tolerability. Conclusions: This clinical trial proved consistent superiority of the ivy leaves cough liquid treatment versus placebo and confirmed the EA 575 ® preparation to be a safe and efficacious option for the treatment of acute cough.

Topical diclofenac diethylamine (DDEA) 2.32% gel achieves lasting efficacy in localized pain with two applications per day, while maintaining the favorable safety profile of topical diclofenac and potentially improving convenience and patient compliance.This randomized double-blind controlled study enrolled patients with acute ankle sprain treated with DDEA 2.32% gel two times per day (bid) (n = 80) or three times per day (tid) (n = 80) or placebo (n = 82). Efficacy (including pain and swelling) and local tolerability were evaluated during 8 ± 1 d.By day 5, the reduction in pain on movement (POM) (primary efficacy variable) with DDEA bid and tid (49.1 and 49.7 mm, respectively; 100-mm visual analog scale) was almost double that with placebo (25.4 mm) (P0.0001). In patients with severe baseline POM (≥ 80 mm), mean change in POM from baseline to day 5 with DDEA bid or tid was 30-40 mm greater than that with placebo, which was double the difference (15-20 mm) in patients with mild-moderate baseline POM (80 mm). More than 70% of all DDEA patients experienced ≥ 50% reduction in POM between days 1 and 5 versus 21% of placebo patients (P0.0001). By study end (day 8), ankle swelling in patients treated with DDEA (0.3 cm) was one-third that in those treated with placebo (0.9 cm) (P0.0001), which had still not achieved the level of ankle joint function seen with DDEA on day 5 (P0.0001). At day 5, treatment satisfaction was "good" to "excellent" in almost 90% of DDEA patients but only "good" or "very good" in 23% of placebo patients (P0.0001). DDEA 2.32% gel was well tolerated.DDEA 2.32% gel twice daily (applied in the morning and evening) was well tolerated and provided lasting relief from pain, improved function, and reduced symptomatic healing time in uncomplicated ankle sprain.

Objectives: A previously published study comparing the efficacy of comfrey extract to a commercial diclofenac (CAS 78213-16-8) preparation in the treatment of unilateral ankle sprains is critically re-evaluated. The study was designed to show non-inferiority of the comfrey extract. The data were re-evaluated for superiority according to CPMP guidelines. The study was an observer-blind, randomised, multi-centre clinical trial with two independent treatment groups “com-frey extract” and “diclofenac gel” (parallel group design) and included a total of 164 patients (82 in the comfrey group and 82 in the diclofenac group, intention-to-treat (ITT) analysis). Key variables were the area under the curve (AUC) from Visits 1 to 2 of the difference of the tenderness values contra-lateral minus injured side (primary variable), pain assessment (Visual Analogue Scale, VAS) at rest and on movement by patient, swelling (figure-of-eight method) and ankle movement (neutral zero method). On average (mean difference comfrey extract minus diclofenac), the AUC was +61.1 h∙N/cm² greater for patients treated with comfrey extract compared to di-clofenac treated patients (95 % confidence interval: 19.08; 103.09 h∙N/cm²). The difference between the two treatment groups was statistically significant (analysis of variance with factors “study drug”, “centre”, and “drug∙centre interaction”). Safety was excellent in both treatment groups. The re-evaluation of the data showed superiority of the plant based ointment over the diclofenac gel in the treatment of distortions. It is encouraging and impressive to realize that a natural product seems to be an effective and safe alternative to the standard topical treatment with diclofenac.

Objective The objective was to show the superiority of comfrey root extract ointment to placebo ointment in patients with acute upper or lower back pain. Design The study was conducted as a double-blind, multicentre, randomised clinical trial with parallel group design over a period of 5 days (SD 1). The patients (n = 120, mean age 36.9 years) were treated with verum or placebo ointment three times a day, 4 g ointment per application. The trial included four visits. Main Outcome Measures The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. The secondary efficacy variables were back pain at rest using assessment by the patient on VAS, pressure algometry (pain–time curve; AUC over 5 days), global assessment of efficacy by the patient and the investigator, consumption of analgesic medication and functional impairment measured using the Oswestry disability index. Results There was a significant treatment difference between comfrey extract and placebo regarding the primary variable. In the course of the trial the pain intensity on active standardised movement decreased on average (median) approximately 95.2% in the verum group and 37.8% in the placebo group. Conclusions The results of this clinical trial were clear-cut and consistent across all primary and secondary efficacy variables. Comfrey root extract showed a remarkably potent and clinically relevant effect in reducing acute back pain. For the first time a fast-acting effect of the ointment (1 h) was also witnessed.

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p

Objective: The present study was designed to investigate the integrated effects of the beta-1-selective blocker with vasodilator properties, nebivolol, on systemic haemodynamics, neurohormones and energy metabolism as well as oxygen uptake and exercise performance in physically active patients with moderate essential hypertension (EH). Design and methods: Eighteen physically active patients with moderate EH were included: age: 46.9 ± 2.38 years, weight: 83.9 ± 2.81 kg, blood pressure (BP): 155.8 ± 3.90/102.5 ± 1.86 mm Hg, heart rate: 73.6 ± 2.98 min−1. After a 14-day wash-out period a bicycle spiroergometry until exhaustion (WHO) was performed followed by a 45-min submaximal exercise test on the 2.5 mmol/l lactate-level 48 h later. Before, during and directly after exercise testing blood samples were taken. An identical protocol was repeated after a 6-week treatment period with 5 mg nebivolol/day. Results: Nebivolol treatment resulted in a significant (P < 0.01) decrease in systolic and diastolic BP and heart rate at rest and during maximal and submaximal exercise. Maximal physical work performance, blood lactate and rel. oxygen uptake (rel. VO2) before and after nebivolol treatment at rest and during maximal and submaximal exercise remained unaltered. Free fatty acid, free glycerol, plasma catecholamines, beta-endorphines and atrial natriuretic peptide (ANP) increased before and after treatment during maximal and submaximal exercise but remained unaltered by nebivolol treatment. In contrast, plasma ANP levels at rest were significantly higher in the presence of nebivolol, endothelin-1 levels were unchanged. Conclusions: Nebivolol was effective in the control of BP at rest and during exercise in patients with EH. Furthermore, nebivolol did not negatively affect lipid and carbohydrate metabolism and substrate flow. The explanation for the effects on ANP at rest remain elusive. This pharmacodynamic profile of nebivolol is potentially suitable in physically active patients with EH.

Background Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP. Methods In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM), pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after 48 h). Adverse events (AEs) were recorded throughout the study. Results The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm) vs. placebo (56.9 mm) (p

Objectives:To investigate the clinical efficacy and safety of a newly developed diclofenac patch in the topical treatment of blunt impact injuries.Methods:This was a randomised, placebo controlled, double blind, multicentre study in 120 patients with traumatic blunt soft tissue injury. Within 3 h of the injury participants of sport competitions and training camps were enrolled and treated twice daily with the diclofenac or a placebo patch over a period of 7 days. Patients were randomised (1:1) to two parallel groups. Tenderness produced by pressure was measured twice daily during the first 3 days after enrolment as well as at day 7. Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient.Results:The primary efficacy variable was the area under the curve for tenderness over the first 3 days. The diclofenac patch was significantly more effective than placebo (p2(95% confidence interval 48.7 to 80.9) between diclofenac and placebo patches. These results were supported by all secondary efficacy variables. The diclofenac patch produced rapid pain relief as reflected by the time to reach resolution of pain at the injured site which was significantly shorter compared to placebo (pConclusions:A newly developed diclofenac patch is effective and safe for the treatment of blunt impact injuries.

Objectives: To investigate the clinical efficacy and safety of escin-containing gels in the topical treatment of blunt impact injuries. Methods: Competitors in soccer, handball, or karate competitions were enrolled within two hours of sustaining a strain, sprain, or contusion and treated three times with the trial gel within a period of eight hours. Patients were randomised to three parallel groups consisting of two active treatment gels, containing escin (1% or 2%), 5% diethylammonium salicylate, and 5000 IU heparin, or placebo gel. Tenderness produced by pressure was measured at 0 (baseline), 1, 2, 3, 4, 6, and 24 hours after enrolment (within two hours of the injury). Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient. Results: A total of 158 patients were enrolled; 156 were evaluated in the intention to treat analysis. The primary efficacy variable was the area under the curve for tenderness over a six hour period. The gel preparations containing 1% and 2% escin were significantly more effective (a priori ordered hypotheses testing controlling the multiple α = 5% significance level) than placebo (p1 = 0.0001 and p2 = 0.0002 respectively). The treatment effects were 5.7 kp h/cm 2 (95% confidence interval (CI) 2.9 to 8.5) and 5.9 kilopond (kp) h/cm 2 (95% CI 2.9 to 8.8) between 1% escin and placebo and between 2% escin and placebo respectively. These results were supported by secondary efficacy variables. The time to reach the baseline contralateral tenderness value (resolution of pain) at the injured site was shorter in the treatment groups than in the placebo group (p