Safety Of Available Treatments Research Articles

Antibacterial mechanism of the novel antimicrobial peptide Jelleine-Ic and its efficacy in controlling Pseudomonas syringae pv. actinidiae in kiwifruit.

Bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa) poses a severe threat to kiwifruit production. Because of the insufficient efficacy and environmental safety of available treatments, novel antibacterial agents should be urgently developed. Antimicrobial peptides (AMPs) can be used as antimicrobials for disease control. In this study, we designed a novel AMP, Jelleine-Ic, and evaluated its antibacterial activity and mechanism of action against Psa. Jelleine-Ic with a half maximal effective concentration of 1.67 μg/mL exhibited stronger antibacterial activity than did parent Jelleine-I. Jelleine-Ic targeted the Psa membrane, increased membrane permeabilization, and dissipated membrane potential, resulting in calcium leakage. Electron microscopy revealed that Jelleine-Ic disrupted cell morphology and caused intracellular alterations. Moreover, this AMP penetrated the cell membrane, bound to DNA, and reduced the expression of genes related to DNA replication and repair. Jelleine-Ic also reduced esterase activity and induced intracellular reactive oxygen species generation. This peptide inhibited the development of Psa canker. The control efficiency of Jelleine-Ic against Psa in the leaf discs and leaves of kiwifruit was 81.83% and 70.53%, respectively, which was superior to that of the commercial agricultural streptomycin. Furthermore, Jelleine-Ic upregulated the expression of kiwifruit defense genes (PR-10 and WRKY70a). Jelleine-Ic effectively controls Psa in vitro and in vivo, and may be developed as a bactericide for plant disease control. This article is protected by copyright. All rights reserved.

Lasers, lights, and compounds for melasma in aesthetics

Melasma is a chronic and relapsing skin condition. Although melasma is usually asymptomatic, it can be associated with immense psychosocial stress and greatly impact a patient's quality of life. Over the years, many different treatments have been used, ranging from daily photoprotection, topical lightening creams, and oral agents to laser and light-based therapies; however, efficacy is often limited with such treatments, and there is currently no effective modality to prevent recurrence. Although treatment strategies had originally centered on the use of hydroquinone, newer modalities now include oral tranexamic acid and lasers. We examined previous and ongoing debates related to melasma treatments and have reviewed the current efficacy and safety of available treatments. Critical components essential to the successful management of melasma are the setting of patient expectations and assurance of treatment compliance.

Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide1 Receptor Agonists.

Obesity is a chronic disease associated with many complications. Weight loss of 5–15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Pharmacotherapy can help people with obesity achieve and maintain their target weight loss, thereby reducing the risk of obesity-related complications. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. Reasons for low levels of initiation and long-term use of AOMs may include reluctance of public health and medical organizations to recognize obesity as a disease, lack of reimbursement, provider inexperience, and misperceptions about the efficacy and safety of available treatments. This article aims to inform primary care providers about the mechanism of action of one class of AOMs, glucagon-like peptide 1 receptor agonists (GLP-1RAs), in weight loss and longer-term maintenance of weight loss, and the efficacy and safety of this treatment class. GLP-1RA therapy was initially developed to treat type 2 diabetes. Owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg has been approved, and once-weekly subcutaneous administration of semaglutide 2.4 mg is being investigated in phase III trials, for obesity management. Considerations regarding adverse effects and contraindications for different drug classes are provided to help guide treatment decision-making when considering pharmacotherapy for weight management in patients with obesity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01710-0.

Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs.

Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging survival. At present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate–severe flares, followed by low–moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.

Systemic treatments for eczema: a network meta-analysis.

Systemic treatments for eczema: a network meta-analysis.

Combined analysis of 3 cross-sectional surveys of pain in 14 countries in Europe, the Americas, Australia, and Asia: impact on physical and emotional aspects and quality of life.

Background and aims Recognition of the biopsychosocial aspects of pain is important for a true understanding of the burden of pain and the necessity of pain management. Biopsychosocial aspects of pain may differ between countries and cultures. Market research methods can be well suited and effective for assessing patient perspectives of pain and biopsychosocial differences. We conducted and combined 3 cross-sectional, international surveys to document the impact of pain on physical and emotional aspects of life, as well as quality of life (QOL). Methods Online panelists from 24 countries took part in our surveys in 2014, 2016, and 2017. Fourteen countries (Australia, Brazil, Canada, China, Germany, Italy, Japan, Poland, Russia, United Kingdom, United States, Mexico, Sweden, Saudi Arabia) contributed data in all 3 surveys and comprise the analysis population. A Global Pain Index (GPI) was constructed using 8 questions in 3 categories: Physical (frequency, duration, intensity of pain), Emotional (anxiety, impact on self-esteem, happiness), and Impact on QOL and ability to enjoy life. Each item was scored as the percentage of respondents meeting a prespecified threshold indicative of a substantial pain impact. Scores for the items within each category were averaged to obtain a category score, category scores were averaged to obtain a total score for each survey, and total scores from each survey were averaged to obtain a final combined score. Scores were assessed for the overall population, by individual countries, by age and gender, and by self-identified pain-treatment status (treat immediately, wait, never treat). Results Of the 50,952 adult respondents, 28,861 (56.6%) had ever experienced musculoskeletal pain; 50% of those with pain had pain with a multifaceted impact based on the GPI (Physical: 51%; Emotional: 40%; QOL Impact: 59%). Russia (57%) and Poland (56%) had the highest scores; Mexico (46%), Germany (47%), and Japan (47%) had the lowest. GPI score was higher in women (52%) than men (48%), and initially increased with age through age 54 (18‒24 years: 45%; 25‒34 years: 52%; 35‒44 years: 53%; 45‒54 years: 54%), after which it decreased again (55‒64 years: 51%; ≥65 years: 45%). A majority (65%) of respondents wait to treat their pain, whereas 21% treat their pain immediately and 14% never treat pain. The most common reason for waiting (asked in survey 3 only) was to avoid taking medication. Conclusions In this combined analysis of 3 international surveys using a novel biopsychosocial pain assessment tool, pain had a substantial impact on ~50% of respondents' lives, spanning physical (51%), emotional (40%), and QOL effects (59%). Despite the substantial impact, a majority of patients tried to avoid treating their pain. Implications Clinicians should take a biopsychosocial approach to pain by asking patients not only about the presence and severity of pain, but the extent to which it affects various aspects of their lives and daily functioning. Patients may also need education about the efficacy and safety of available treatments for self-management of pain. The GPI may be a useful new tool for future studies of the biopsychosocial effects of pain in large populations.

New Diagnosis of Acquired Immunodeficiency Syndrome in a Patient With Crohn's Disease.

ABSTRACTThere are limited data on the natural history of Crohn's disease (CD) in the presence of human immunodeficiency virus infection and the safety of available treatments. We report a patient with CD who presented with pneumocystis pneumonia secondary to newly diagnosed acquired immunodeficiency syndrome. One month before his admission, his gastrointestinal symptoms were well controlled without treatment but gradually reappeared after antiretroviral therapy was initiated. Clinical remission was achieved with vedolizumab treatment. We review the management challenges of CD in a patient with human immunodeficiency virus and describe the unique mechanism of anti-α4β7 integrin therapy in this setting.

Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis.

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n=4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial.

BackgroundThere is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.MethodsA multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.Results378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).ConclusionsDue to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.Trial registrationClinicalTrials.gov NCT01310738

Treatment of Pediatric Type 2 Diabetes

To review the current literature for the efficacy and safety of available treatments for type 2 diabetes (T2DM) in the pediatric population. A search from January 1990 to April 2016 was conducted using PubMed and clinicaltrials.gov using the search terms diabetes mellitus, type 2; adolescent; child; and pediatric Bibliographies of chosen articles were reviewed. Relevant articles and preliminary data from clinical trials on metformin, insulin, sulfonylureas, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors for the treatment of pediatric T2DM were reviewed. Studies included randomized controlled, observational, and open-label designs. Metformin, studied in 4 of the reviewed trials, and premixed insulin appear to be safe and effective in pediatric patients with T2DM. TZDs were well tolerated and yielded favorable results, but may have limited applicability. A sulfonylurea had favorable hemoglobin A1C reduction, but was associated with significant weight gain. Studies of incretin-based agents also showed favorable results in the pediatric population but have limited safety and efficacy data. Several trials for other agents are reported on clinicaltrials.gov with unpublished results, but no statistical analyses are reported. Metformin and insulin remain the mainstay of treatment for T2DM in pediatric patients. More robust studies are needed to assist in the provision of evidence-based guidance for the treatment of T2DM in youth.

Pharmacological Agents to Decrease New Episodes of Recurrent Lower Urinary Tract Infections in Postmenopausal Women. A Systematic Review.

The purpose of this systematic review was to evaluate and summarize pharmacological interventions evaluated in randomized clinical trials designed to prevent recurrent episodes of urinary tract infections (UTIs) in postmenopausal women. Excerpta Medica dataBASE, Pubmed, Medline, and Cochrane Library were accessed to search for nonexperimental drugs evaluated in randomized clinical trials published in peer reviewed journals from January 1, 1970, to August 1, 2015, to reduce the number of recurrent UTIs in postmenopausal women. A systematic search yielded 9 articles that met eligibility criteria. Five articles involved the use of systemic or vaginal estrogen therapy and the remainder used oral antibiotics, lactobacilli, or a combination of interventions. Antibiotics were the most efficacious therapy but with a higher incidence of systemic side effects. Oral lactobacillus was noninferior to sulfamethoxazole with trimethoprim with a safer profile in 1 small study. Vaginal estrogen appeared to be inferior to continuous oral antibiotic suppression; however, use of multiple formulations of both treatment options precludes meta-analysis. Oral estrogen use did not decrease UTI recurrence and resulted in local and systemic side effects in up to nearly 30% of the patients. This review supports the use of antibiotic suppression, vaginal estrogen, and oral lactobacillus for prevention of recurrent UTIs in postmenopausal women. However, the overall dearth of data suggests that this is an important but understudied population. Because the effectiveness and safety of available treatments are not well understood, they should be used with caution in older populations, pending further study.

Linagliptin use in older individuals with type 2 diabetes.

Older people have the highest prevalence of type 2 diabetes mellitus (T2DM) of any age group and are thus frequent users of glucose-lowering agents. Because individuals 65 years or older are underrepresented in clinical studies, there is a lack of information regarding the efficacy and safety of available treatments in this population. Additionally, a high prevalence of comorbidities, polypharmacy, and frailty can make treatment of T2DM in this population challenging. Safety is an important consideration when choosing a treatment for older individuals. Renal impairment is quite common in older patients with T2DM and can contribute to hypoglycemia. Hypoglycemia can lead to serious consequences, such as falls and fractures, and cognitive changes. As such, hemoglobin A1c treatment targets, typically <7% in the general population, are less stringent in older people, with the goal being an individualized target that balances efficacy and safety. Many glucose-lowering agents can cause adverse events detrimental to older individuals, such as hypoglycemia (insulin, sulfonylureas), weight gain (sulfonylureas, thiazolidinediones), gastrointestinal events (metformin), and fractures (thiazolidinediones), and are contraindicated or require dose adjustments in those with renal impairment (most oral/injectable agents). Orally administered dipeptidyl peptidase (DPP)-4 inhibitors have a low risk of hypoglycemia and are generally well tolerated. Linagliptin is the only DPP-4 inhibitor excreted through nonrenal pathways and therefore does not require any dose adjustment in older patients with kidney disease. This paper reviews the findings of a recent study by Barnett et al assessing the efficacy and safety of the DPP-4 inhibitor linagliptin in patients with T2DM aged 70 years or older, which concluded that linagliptin may be a useful glucose-lowering option for older patients with T2DM.

PGI46 - Systematic Literature Review in Moderate to Severe Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The objective of this systematic literature review (SLR) was to examine the evidence on the efficacy and safety of all available pharmacological interventions for moderate to severe UC. A systematic literature search using a predefined strategy was performed in Medline®, EMBASE®, Medline-In-Process, Cochrane Library and BIOSIS from 1966 to 2013, to identify randomized controlled trials (RCTs) concerning the efficacy and safety of available treatments in adult patients with moderate to severe UC. Studies reporting on mild-moderate UC patients were included if they reported results for the moderate subgroup separately. No language restrictions were applied to the search. A total of 4344 abstracts were screened based on the predefined selection criteria, of which 4279 were excluded. In total, 65 publications, reporting results from 65 RCTs were included (49 double blind), examining aminosalicylates (n=23), corticosteroids (n=10), immunosuppressants (n=15), biologics (n=16) and kinase inhibitors (n=1). Baseline patient characteristics, study design and outcomes were extracted, including: adverse events (AE) (reported in n=24 studies), serious AE (n=25), deaths (n=23), clinical remission (n=49), clinical response (n=33) and mucosal healing (n=11). Eleven different disease activity scales and four different endoscopic scales were used. The mean age of included patients ranged from 27 to 51, and the percentage of males from 28.6% to 87.5%. Due to large differences and different scales used for reporting efficacy it is not feasible to report the range across different scales. Safety endpoints were also reported inconsistently. The results per outcome are presented in a narrative way per treatment class. A comprehensive SLR performed which identified 65 RCT reporting on the efficacy and safety of pharmacological treatments in moderate to severe UC patients. Differences in patient population, disease severity, disease activity scales and trial duration are explored and presented.

Pharmacologic and Compression Therapies for Postthrombotic Syndrome: A Systematic Review of Randomized Controlled Trials

Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS.We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature.A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score.There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

Osteoporosis: Trials and tribulations

A 30–50% reduction in fracture risk produced by a drug is biologically “worthwhile.” The detection of this benefit, when truly present, is a challenge requiring large studies of 3–5 years' duration, because only a small number of women at risk actually sustain a fracture during this time. For example, in any year, fractures occur in 1–2 per 100 women approximately 65 years of age, 6–10 per 100 women approximately 75 years of age, and only 1–2 per 2,000 of the 15% of women <60 years of age with osteoporosis. An appreciation of this low annual event rate is important because (1) it helps patients to understand their illness, (2) it determines the power of clinical trials, (3) it underscores the large numbers of patients that must be treated to prevent one fracture, and (4) it underscores the need for safety, particularly in groups at low absolute risk of fracture; all are exposed to drug side effects, and the vast majority derive no benefit from treatment because they would not have had a fracture without it, despite being at risk. Few studies have met the design requirements needed to identify the antifracture efficacy of a drug when it really exists, namely, (1) large patient samples randomized to treatment or placebo for 3–4 years, (2) blinding throughout follow-up, (3) statistical analyses of preplanned comparisons using intention to treat, and (4) avoidance of statistical analyses of associations discovered by post hoc analyses. Moreover, (5) few studies have assessed long-term safety and quality of life. Consequently, the uncertainty regarding efficacy and safety of available treatments may be more of a problem of the design, execution, and interpretation of the clinical studies than of the drugs themselves. In the reduction of vertebral fracture risk, the greatest optimism exists for hormone replacement therapy (HRT) and the bisphosphonates. HRT reduces bone turnover, increases bone mineral density (BMD), and decreases vertebral fracture rates by approximately 40%, even in women > 70 years of age. Reduction in hip fracture risk with HRT has been reported in observational studies. Two rigorously conducted studies provide credible evidence that the bisphosphonate alendronate reduces the risk of vertebral and hip fractures by approximately 40–50%. Etidronate, calcitonin, and 1,25-dihydroxyvitamin D 3 may reduce risk of vertebral fracture; however, problems in study design leave uncertainty. Although 2 trials using fluoride suggest a reduction in fracture rates, the more rigorously conducted trials do not, despite having adequate power to do so. Calcium supplements are likely to slow bone loss, but reduction in fracture risk is uncertain. Vitamin D and calcium supplementation reduce risk of hip fracture in nursing home residents but not in community residents. There have been no studies of the efficacy of any treatment to prevent hip or vertebral fractures in men or in corticosteroid-related osteoporosis. The treatment of osteoporosis is becoming a reality. HRT and the bisphosphonates, particularly alendronate, appear to be the best options at present.

Should physicians screen for depression in elderly medical inpatients?: Results of a decision analysis.

We wish to determine whether or not elderly medical inpatients should be screened for depressive disorder using either 1) a self-rated depression scale (Geriatric Depression Scale), 2) "usual clinical assessment," or 3) neither, assuming that treatment with tricyclic antidepressants (TCAs) is the primary mode of intervention. Based on recent data from epidemiological studies on the prevalence and course of depression, the test characteristics of available screening tests, and the efficacy and side-effects of traditional antidepressants, decision analysis is used to help decide whether or not clinicians should screen for depression in this setting. These calculations indicate that if screening is done solely to identify depressed patients for treatment with TCAs, then the highest utility lies in not screening; however, the difference in utilities between that decision and the decisions to either screen with GDS or screen by usual clinical assessment was only .04 units on a 0 to 100 scale, making the decision virtually a toss-up. Furthermore, even a small variation in one of several clinical factors or test characteristics could give screening a higher utility. In particular, if psychotherapy is considered as the primary intervention, then the utility of screening exceeds that of not screening. Characteristics of the screening test, clinical setting, types and safety of available treatments, each impact on the usefulness of screening and must be kept in mind when diagnosing and treating depressed medically ill elders hospitalized in acute care settings.