Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until June 30, 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51% to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2% to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Extemporaneous combination therapy with nebivolol/amlodipine for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVE: The investigation of the real-world use of the extemporaneous combination of nebivolol and amlodipine (NA-EXC) in adult patients diagnosed with hypertension in Europe. METHODS: Retrospective analysis of data extracted from seven databases of patient medical records and prescriptions from Italy, Germany, France, Hungary, and Poland, to determine the prevalence and incidence of NA-EXC use and to estimate the number of patients potentially eligible for a single-pill combination of the two antihypertensives. Secondary objectives included: the description of the population of NA-EXC users and the assessment of their adherence to treatment based on the proportion of days covered. RESULTS: The use of NA-EXC was found to be common in Europe and ranged between 2.9% to 9.9% of all patients identified in the databases with a prescription of nebivolol and/or amlodipine. The estimated numbers of patients potentially eligible in 2019 for a single-pill combination of nebivolol and amlodipine in Italy and Germany were, respectively, 178,133 and 113,240. Users of NA-EXC were mostly aged 70-79 years, had metabolic disorders and other comorbidities; >70% of them had received ≥2 concomitant medications before starting NA-EXC. Adherence to NA-EXC was defined as high only in 15.6% to 35% of patients. CONCLUSIONS: The extemporaneous combination of nebivolol and amlodipine is commonly prescribed in Europe, however adherence to the therapy is poor. The development of a single-pill combination of nebivolol and amlodipine may improve adherence by reducing the number of pills administered to patients and thus simplifying treatment regimens.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - part 4: Solidago virgaurea-Vitis vinifera.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph - now (since 2014) called a 'European Union herbal monograph' - has been produced. The present part 4 addresses species from Solidago virgaurea L. to Vitis vinifera L.

Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - Part 3: Mentha × piperita - Solanum dulcamara.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph - now (since 2015)(†) called a European Union herbal monograph - has been produced. Part 3: Mentha × piperita L.-Solanum dulcamara L.

Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens: A meta-analysis of 18 randomized controlled clinical trials.

The anti-Epidermal Growth Factor Receptor monoclonal antibodies (anti-EGFR MoAbs) are beneficial in the treatment of wild type (WT) KRAS colorectal cancer, but are burdened by serious toxicities. We conducted a systematic review and meta-analysis to determine incidence and relative risk (RR) of severe and life-threatening diarrhoea and mucositis in colorectal cancer patients and WT-KRAS subpopulation. PubMed and Embase were searched for trials comparing the same therapeutic regimens with or without anti-EGFR for colorectal cancer. Data on severe and life-threatening diarrhoea and mucositis were extracted from 18 studies involving 13,382 patients. Statistical analyses calculated incidence of AEs, RRs and 95% confidence intervals by using either random or fixed effects models. Patients receiving anti-EGFR MoAbs showed an increased risk of diarrhoea (RR: 1.66, CI 1.52-1.80) and mucositis (RR: 3.44, CI 2.66-4.44). The risk was similar among WT-KRAS patients. Prevention and risk reduction strategies of these AEs are mandatory to optimize clinical outcomes.

Serenoa repens as an Endocrine Disruptor in a 10-Year-Old Young Girl: A New Case Report.

Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population.

Review of Clinical Pharmacology of Aloe vera L. in the Treatment of Psoriasis.

Aloe vera L., is a plant used worldwide as folk remedy for the treatment of various ailments, including skin disorders. Its gel is present in cosmetics, medicinal products and food supplements. Psoriasis, an immune-mediated chronic inflammatory disease, involving mainly the skin, affects about the 2-3% of general population. Conventional pharmacological treatments for psoriasis can have limited effectiveness and can cause adverse reactions. For this reason often psoriatic patients look for alternative treatments based on natural products containing Aloe vera. We conducted a systematic review of clinical trials assessing effectiveness and safety of aloe for the treatment of psoriasis. Clinical studies published in English were considered; a total of four clinical trials met inclusion criteria. Studies were also evaluated by using the Jadad scale and Consort Statement in Reporting Clinical trials of Herbal Medicine Intervention. Quality and methodological accuracy of considered studies varied considerably, and some crucial information to reproduce clinical results was missing. We conclude that administration of aloe as cutaneous treatment is generally well tolerated, as no serious side effects were reported. Results on the effectiveness of Aloe vera are contradictory; our analysis reveals the presence of methodological gaps preventing to reach final conclusions.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - part 2: Echinacea purpurea-Lavandula angustifolia.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph has been produced. Part 2: Echinacea purpurea Moench-Lavandula angustifolia Mill.

Clinical pharmacology of melatonin in the treatment of tinnitus: a review.

PURPOSE: We performed a review with the purpose to summarise, analyse and discuss the evidence provided by clinical studies evaluating effectiveness of melatonin in the cure of tinnitus. Due to the fact that there is no satisfactory treatment for tinnitus, clinical research has explored new therapeutic approaches. METHODS: A search of Pubmed, Medline, Embase, Central and Google Scholar was conducted to find trials published prior March 2014 on melatonin in the treatment of tinnitus. Design of the studies, randomization, allocation concealment procedures and diagnostic instruments (scales for tinnitus evaluation) were critical evaluated. RESULTS: Five clinical studies have been included. Three of them tested effectiveness of melatonin alone, the remaining two along with sulpiride and sulodexide respectively. Considered clinical trials adopted various experimental designs: single arm, randomised placebo-controlled and randomised placebo-controlled followed by crossover. These studies were characterised by several methodological weaknesses. CONCLUSION: Confirmation of melatonin clinical effectiveness in the treatment of tinnitus cannot be given in the light of the biases observed in the considered evidence. Melatonin seems to improve sleep disturbance linked to tinnitus.

Montelukast-induced adverse drug reactions: a review of case reports in the literature.

BACKGROUND: Montelukast, a leucotriene receptor antagonist, binds the cysteinyl leucotriene type 1 receptor. Montelukast is commonly prescribed to asthma patients as add-on therapy to inhaled corticosteroids. Several clinical trials emphasized that montelukast can be considered a safe drug. However, recent evidence reconsidered the benefit/risk ratio of the use of montelukast for both paediatric and adult patients. SUMMARY: The present review analyzed the previous published case reports regarding montelukast-induced adverse drug reactions (ADRs). They included agitation, anxiety, depression, sleep disturbance, hallucinations, suicidal thinking and suicidality, tremor, dizziness, drowsiness, neuropathies and seizures. The immune system can be involved, in particular, cases of Churg-Strauss syndrome have been published. Furthermore, it can induce hypersensitivity reactions, including anaphylaxis and eosinophilic infiltration. In addition, hepatobiliary, pancreatic and uropoietic disorders have been observed. Some of these cases are characterized by severe prognosis (i.e. neurological deficit and fatal hepatotoxicity). Key Message: The use of montelukast can be burdened by several ADRs, of which physicians should be aware in their clinical practice. A better understanding of the mechanisms causing ADRs after using montelukast could help researchers and clinicians in defining a risk-reduction strategy aimed to lessen montelukast toxicity. More accurate epidemiological studies, in order to discover risk factors favouring montelukast-associated ADRs, are demanded.

Systematic review of clinical trials assessing pharmacological properties of Salvia species on memory, cognitive impairment and Alzheimer's disease.

Salvia officinalis L. and Salvia lavandulaefolia L. have a longstanding use as traditional herbal remedies that can enhance memory and improve cognitive functions. Pharmacological actions of S. officinalis and S. lavandulaefolia on healthy subjects and on patients suffering of cognitive decline have been investigated. Aim of this review was to summarize published clinical trials assessing effectiveness and safety of S. officinalis and S. lavandulaefolia in the enhancement of cognitive performance in healthy subjects and neurodegenerative illnesses. Furthermore, to purchase a more complete view on safety of S. officinalis and S. lavandulaefolia, we collected and discussed articles regarding toxicity and adverse reactions. Eight clinical studies investigating on acute effects of S. officinalis on healthy subjects were included in the review. Six studies investigated on the effects of S. officinalis and S. lavandaeluaefolia on cognitive performance in healthy subjects. The two remaining were carried out to study the effects of sage on Azheimer's disease. Our review shows that S. officinalis and S. lavandulaefolia exert beneficial effects by enhancing cognitive performance both in healthy subjects and patients with dementia or cognitive impairment and is safe for this indication. Unfortunately, promising beneficial effects are debased by methodological issues, use of different herbal preparations (extracts, essential oil, use of raw material), lack of details on herbal products used. We believe that sage promising effects need further higher methodological standard clinical trials.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - part 1: Achillea millefolium-Curcuma longa.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph has been produced. Part 1: Achillea millefolium L.-Curcuma longa L.

Research and development for botanical products in medicinals and food supplements market.

Botanical products sold in the health area are generally intended as drugs, medicinal products, food supplements or substances for therapeutic use. Use of botanicals for improving or to care human health has evolved independently in different countries worldwide. Regulatory issues regarding botanical products designed for the food supplements or medicinal market and their influence on research and development are discussed. European Union (EU) and United States (US) policies regulating these products are focused with comments on the legislations delivered during the last ten years and differences existing in rules between these countries are emphasized. Research and development on botanical products nowdays strongly influenced by the product destination in the market. Addressed and differentiated research for either food supplements or medicinal markets is necessary to purchase data really useful for assessment of safe and effective use for both the categories. The main objective is to catalyze interest of academic and companies' researchers on crucial aspects to be taken into account in the research for the development of botanical products.

Attitudes and opinion about adverse drug events of women living in a city of south Italy.

BACKGROUND/AIM: Perception of risk of adverse drug events (ADEs) is different between health and nonhealth professionals, but these differences have not been investigated sufficiently in the general population. Women are more affected by ADEs. With the aim to investigate ADE risk perception in a sample of nonhealth professional women of South Italy, we carried out a phone survey. METHODS: Phone survey based on a structured questionnaire on educational level, type of work, lifestyle, comorbidity, and medication used of 1,050 inhabitants of the city of Messina (Italy). RESULTS: 744 responders, divided into an ADE group (n = 162) and a non-ADE group, were analyzed. Most used drugs were nonsteroidal anti-inflammatory drugs (37.0%) and antibiotics (29.6%). Reported disorders related to drug intake were general malaise (25.9%), gastrointestinal complaints (24.1%), and skin reactions (20.4%). Younger age and higher educational level, along with allergic diseases and food intolerances were more frequently reported in the ADE group. Women from the ADE group were better informed about drug risks (p < 0.001). CONCLUSIONS: Higher risk perception for ADEs in women is associated with higher educational level, food intolerance/allergic diseases, and choice of alternative or complementary medicines. Difference in perception of risk exists within the female population, which can cause overreporting or underreporting of ADEs.

Hot flashes in a young girl: a wake-up call concerning Serenoa repens use in children.

Extracts of the plant Serenoa repens are widely used in male adults for the treatment of benign prostatic hyperplasia. Recently, therapy with S repens has been proposed as a "natural" alternative to conventional treatments for male androgenetic alopecia as well as for other hair disorders. Telogen effluvium is a form of alopecia characterized by abnormality of hair cycling, resulting in excessive loss of telogen hair. We report the case of an 11-year-old girl presenting hot flashes that appeared after treatment of telogen effluvium with a food supplement containing S repens that lasted for ~2 months. When use of the product was discontinued, the hot flashes no longer occurred. Four months after the start of S repens intake and 45 days from the cessation of therapy, the girl experienced menarche at the age of 11 years. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the appearance of hot flashes and the intake of S repens. A correlation between exposure to S repens and the onset of menarche is not certain, but it cannot be excluded. Medicinal products or food supplements containing S repens are generally well tolerated in male adults, but we believe that their use in pediatric patients should be better evaluated.