Physical and pharmacokinetic characterization of Soluvec™, a novel, solvent-free aqueous ivermectin formulation.

Purpose: To describe application of the Quicksol™ solvent-free approach to solubilize ivermectin (IVM). Methods: Lyophilized IVM complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was resolubilized in aqueous polysorbate-80, generating Soluvec™. Lyophilizate was examined by Fourier-transform infrared spectroscopy and differential scanning calorimetry; Soluvec, by dynamic light scattering. Pharmacokinetics was evaluated in dogs allocated to subcutaneous (SC) or intramuscular (IM) Soluvec or oral IVM. Results: IVM in Soluvec was tightly bound by HPßCD, forming nearly monodisperse 28 nm particles with solubility ∼2500-times that of free IVM. SC and IM Soluvec increased IVM exposure, peak IVM and extended duration of IVM exposure, versus oral dosing. Conclusion: The Quicksol method generated Soluvec, a concentrated aqueous parenteral IVM formulation with pharmacokinetic properties suitable for veterinary or human use.

Ivermectin (IVM) kills insects and worms that cause disease. Because it doesn't dissolve well, blood IVM can be low. We found a new way to dissolve IVM, using simple, common materials. Dogs receiving our IVM (Soluvec™) had high blood IVM levels for longer, compared with tablet IVM. Next, we hope to learn the best ways to dose Soluvec in animals and people.

Obesity in South and Southeast Asia-A new consensus on care and management.

Obesity is a chronic disease in which the abnormal or excessive accumulation of body fat leads to impaired health and increased risk of mortality and chronic health complications. Prevalence of obesity is rising rapidly in South and Southeast Asia, with potentially serious consequences for local economies, healthcare systems, and quality of life. Our group of obesity specialists from Bangladesh, Brunei Darussalam, India, Indonesia, Malaysia, Philippines, Singapore, Sri Lanka, Thailand, and Viet Nam undertook to develop consensus recommendations for management and care of adults and children with obesity in South and Southeast Asia. To this end, we identified and researched 12 clinical questions related to obesity. These questions address the optimal approaches for identifying and staging obesity, treatment (lifestyle, behavioral, pharmacologic, and surgical options) and maintenance of reduced weight, as well as issues related to weight stigma and patient engagement in the clinical setting. We achieved consensus on 42 clinical recommendations that address these questions. An algorithm describing obesity care is presented, keyed to the various consensus recommendations.

Acute infusion effects in relapsing multiple sclerosis patients receiving alemtuzumab under a modified prophylaxis regimen.

BACKGROUND: Use of alemtuzumab in relapsing multiple sclerosis (RMS) is limited by safety concerns, notably risk of rare, serious vascular events. Along with other vital sign (VS) changes, acute increase in systolic blood pressure (SBP) is monitored as a marker of vascular risk. Peri-infusion prophylaxis is used to manage clinical risk by moderating cytokine release; protocols are not fully specified and vary across sites. Here, we report a modified prophylaxis regimen developed at Maritime Neurology. This single-center observational cohort study (NCT04633967) aimed to examine acute responses (VS events and infusion-associated reactions) in RMS patients receiving alemtuzumab infusion under this regimen. In a post hoc analysis, we examined incidence of acute SBP increase at this clinic versus the Bayshore network of Canadian infusion centers, where a standard prophylaxis regimen is used. METHODS: Alemtuzumab was infused on 5 consecutive days (Course 1; n = 29) and 3 consecutive days one year later (Course 2; n = 28). In addition to intravenous methylprednisolone 500mg on each infusion day, patients received daily prophylactic treatment with oral prednisone 50mg from 5 days before to 5 days after treatment (infusion days excepted) and oral H1 and H2 antihistaminics from 7 days before to 7 days after treatment. Excursions in SBP and other VS were relative to prespecified ranges; persistent excursions were those for which two sequential measurements were outside these ranges. In comparing VS events at Maritime Neurology and the Bayshore centers, acute SBP increase was defined as ≥20 mmHg increase in mean SBP, or any SBP reading ≥20% over patient's pre-course baseline. RESULTS: Mean (SD) VS were within range at pre-course and all other daily baselines. VS changes, including persistent excursions, were generally subclinical; all infusion-associated reactions were mild. One patient discontinued treatment after Course 1 due to immune thrombocytopenia purpura. Acute SBP increase occurred in 11/28 (39%) Maritime Neurology versus 367/610 (60%) Bayshore (p = 0.028). CONCLUSION: The modified peri-infusion prophylaxis regimen was well tolerated and may reduce incidence of acute SBP increase. FUNDING: This project was funded by Sanofi, Canada.

Transition of Topical Therapy Formulation in Psoriasis: Insights from a Canadian Practice Reflective.

Patient preferences for psoriasis treatment may affect treatment adherence and disease control; changing topical formulation may improve adherence and patient acceptance of treatment. This study explored dermatologists' reasons for transitioning psoriasis patients from an ointment or gel (Dovobet®) formulation to an aerosol foam (Enstilar®) formulation of calcipotriol and betamethasone dipropionate (Cal/BD), and to assess the success of this transition. Medical records of 81 Canadian patients from 9 dermatologists were retrospectively reviewed for symptoms affecting quality of life, reasons for transitioning treatment, and whether transition was successful. Reasons for transition included efficacy, quality of life, and patient adherence. At follow-up, median psoriasis severity and body surface area affected had decreased from baseline, and patients experienced improved quality of life. Itch and itch-related sleep loss, which were identified as burdensome in 63% of patients at baseline, had resolved in 33% and improved in 54% of patients at follow-up. Dermatologists deemed the transition successful in 85% of patients, with the most common reasons being patient-reported success, clearance of signs/symptoms, and continued prescription refills. Transition from Cal/BD ointment or gel to aerosol foam was generally deemed successful by patients and dermatologists, and was associated with improved quality of life and improved itch control.

Treatment Choices in a National Cohort of Canadian Women With Symptomatic Uterine Fibroids.

OBJECTIVES: To describe treatment choices made at the time of enrollment in CAPTURE, a Canadian patient registry for women with symptomatic uterine fibroids (UFs), and to define demographic and clinical characteristics that independently predict these choices. METHODS: Women arranging appointments for UF care were eligible to enrol. At the time of the enrollment visit, women's self-reported treatment histories were noted, along with their clinical characteristics. Tretment options were discussed and chosen during that visit. Patients could choose medical and/or surgical treatment, or they could opt for no active treatment (i.e., "watchful waiting"); treatment decisions were not binding. RESULTS: The most common medication proposed and chosen was ulipristal acetate (UPA), and the most common procedure was myomectomy. These treatments were also the most commonly identified in patients' histories. Medication alone and medication in combination with surgery were the most common treatment approaches chosen (46% and 26%, respectively). Surgery alone and watchful waiting were chosen by 14% and 13% of patients, respectively. Significant predictors of active treatment included patient pregnancy plans, overall symptom severity, and prior treatment history (medical and surgical). Other parameters, including patient age and history of specific UF symptoms, appear to influence the choice of medical therapies (UPA, gonadotropin-releasing hormone agonists, or other options) and procedures (myomectomy or hysterectomy). CONCLUSIONS: This real-world study documents the patient factors associated with the treatment decisions of women seeking care for symptomatic UFs in contemporary Canadian gynaecology practice. Subsequent analyses will follow the outcomes of these treatments over two years in this population.

Canadian Patients' Preferences in Topical Psoriasis Care: Insights From the PROPEL Surveys.

BACKGROUND: Patients with psoriasis of all severities employ topical treatment, either alone or in combination. Promoting Patient Engagement at the Leading Edge of Topical Psoriasis Treatment (PROPEL) surveyed Canadian dermatologists and their patients about their attitudes toward topical care. OBJECTIVES: To identify gaps between patients and dermatologists regarding the burden of psoriasis, the burden of treatment, and priorities for topical care to Canadian patients with psoriasis. METHODS: Two parallel surveys explored patient attitudes toward psoriasis and their experience with topical care, as expressed by patients or as perceived by their dermatologists. A third survey, addressed to patients, included additional questions regarding treatment adherence to current topical treatment regimens. RESULTS: PROPEL dermatologists underestimated the burden associated with psoriatic itch. Otherwise, they were well aligned with patients' views, including their preference for maintaining topical care of their psoriasis over other treatment modalities, the nature of good psoriasis control, and desirable features of topical medications. Despite holding generally positive views of topical therapy, many patients self-identified as poorly adherent. CONCLUSIONS: Long-term adherence to psoriasis topical care remains a challenge. Formulations with improved acceptability might help patients maintain good adherence.

Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses.

BACKGROUND: Actinic keratosis (AK) and cheilitis (AC) are lesions that develop on photodamaged skin and may progress to form invasive squamous cell carcinomas (SCCs). OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of AKs and ACs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). RESULTS: Treatment of AKs allows for secondary prevention of skin cancer in sun-damaged skin. Because it is impossible to predict whether a given AK will regress, persist, or progress, AKs should ideally be treated. This chapter discusses options for the management of AKs and ACs. CONCLUSIONS: Treatment options include surgical removal, topical treatment, and photodynamic therapy. Combined modalities may be used in case of inadequate response. AKs are particularly common following the long-term immunosuppression in organ transplant patients, who should be monitored frequently to identify emerging lesions that require surgery.

Non-melanoma Skin Cancer in Canada Chapter 1: Introduction to the Guidelines.

BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy. OBJECTIVE: The aim of this document is to provide guidance to Canadian health care practitioners on NMSC management. METHODS: After conducting a literature review, the group developed recommendations for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas, and actinic keratoses. These tumour types are considered separately in the accompanying articles. The Grading of Recommendations Assessment, Development and Evaluation system was used to assign strength to each recommendation. RESULTS: This introduction describes the scope and structure of the guidelines and the methods used to develop them. The epidemiology of NMSC is reviewed, as are the pathophysiologic changes occurring with damage to the skin, which lead to the formation of actinic keratoses and invasive squamous or basal cell carcinomas. CONCLUSIONS: This introduction describes the need for primary prevention and offers an overview of treatment options that are discussed in later chapters of the guidelines.

Non-melanoma Skin Cancer in Canada Chapter 4: Management of Basal Cell Carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy. Growth of BCCs leads to local destruction of neighbouring healthy skin and underlying tissue and can result in significant functional and cosmetic morbidity. OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of BCCs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying Introduction. RESULTS: Although BCCs rarely metastasize, they can be aggressive and disfiguring. This chapter describes the natural history and prognosis of BCCs. Risk stratification is based on clinical features, including the site and size of the tumour, its histologic subtype (nodular vs sclerosing), and its history of recurrence. CONCLUSIONS: Various options should be considered for BCC treatment, including cryosurgery, curettage, and topical or photodynamic approaches, as well as fixed-margin surgery and Mohs micrographic surgery. Stratification of recurrence risk for individual BCCs determines the most appropriate therapeutic course.

Non-melanoma Skin Cancer in Canada Chapter 5: Management of Squamous Cell Carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) is the second-most common form of non-melanoma skin cancer (NMSC). OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of SCCs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). RESULTS: SCCs are sometimes confined to the epidermis, but they can also invade nearby tissues and, in some cases, metastasize to neighbouring lymph nodes or other organs. This chapter discusses the natural history, staging, prognosis, and management of SCC--a tumour type that is less common but typically more aggressive than BCC. For this reason, margin control is strongly preferred in treating SCCs. CONCLUSIONS: Although approaches such as cryosurgery and radiation therapy may be considered for some patients, surgical excision--sometimes coupled with radiation--remains the cornerstone of SCC management. Patients with high-risk SCC may also be considered for referral to an appropriate multidisciplinary clinic.

Non-melanoma Skin Cancer in Canada Chapter 2: Primary Prevention of Non-melanoma Skin Cancer.

BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma (BCC and SCC), represents the most common malignancy. OBJECTIVE: To provide guidance to Canadian health care practitioners regarding primary prevention of NMSC. METHODS: Structured literature searches were conducted, using search terms including prevention, sunscreen, and sun prevention factor. All recommendations concern guidance that physicians should regularly discuss with their patients to help establish photoprotection habits. The GRADE system was used to assign strength to each recommendation. RESULTS: Ultraviolet exposure is the major modifiable risk factor for NMSC. Aspects of photoprotection, including effective sunscreen use and avoidance of both the midday sun and artificial tanning, are discussed. Several widespread misunderstandings that undermine responsible public health measures related to sun safety are addressed. CONCLUSIONS: Photoprotection represents both an individual priority and a public health imperative. By providing accurate information during routine patient visits, physicians reinforce the need for ongoing skin cancer prevention.

Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus.

Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations.

Practical approaches to the use of lenalidomide in multiple myeloma: a canadian consensus.

In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20-40 mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered.

Topical psoriasis therapy in the age of biologics: evidence-based treatment recommendations.

BACKGROUND: Although the range of therapeutic options has expanded dramatically in recent years, topical agents remain ubiquitous and indispensable tools for treating psoriasis at all levels of severity. The 2009 Canadian psoriasis guidelines considered evidence supporting various monotherapies and combination regimens. OBJECTIVE: Here we review all approved topical agents, including corticosteroids, calcineurin inhibitors, vitamin D analogues, and retinoids, used in psoriasis and develop additional treatment recommendations, using the Scottish Intercollegiate Guidelines Network (SIGN) system to evaluate strength of evidence, as in the original guidelines. CONCLUSION: We propose that topical treatments have a place in the long-term management of patients with moderate to severe plaque psoriasis, including those receiving concomitant photo- or systemic therapy. Topical agents are effective and appropriate treatments for psoriasis as long as the physician is attentive to signs of local adverse events and seeks opportunities to reduce the dose or treatment frequency during chronic use.

Barriers to effective insulin treatment: the persistence of poor glycemic control in type 2 diabetes.

BACKGROUND: Contrary to longstanding recommendations on type 2 diabetes (T2D) management, the de facto standard of care in Canada includes lag times of many years prior to introducing effective glycemic control. Even patients transitioned to insulin may continue to experience poor glycemic control, with attendant diabetic complications, suggesting poor adherence or inadequate dose titration. OBJECTIVE: To identify barriers to timely and effective use of insulin in T2D. METHODS: PubMed searches were conducted to find research articles on insulin initiation, adherence and intensification. Also, because recent data on the consequences of intensive glycemic control may be taken as justification for relaxing glycemic targets, a secondary search on this literature was conducted, including the UKPDS and ACCORD trials, plus post hoc and meta-analyses of these data. No formal evaluation of level of evidence was conducted while researching this narrative literature review. FINDINGS: Timely, effective glycemic control remains an important clinical goal but is complicated by patient, physician and treatment factors. Patient barriers to accepting insulin initiation include fear of hypoglycemia, injections and weight gain, and reluctance to accommodate the inflexible timing of scheduled insulin doses. Adherence issues, including dose omission, are common and are associated with some of the same factors. Fear of hypoglycemia also underlies many physicians' reluctance to prescribe insulin. Caregivers' failure to provide training or answer questions about insulin's risks and benefits was also associated with low patient adherence. Poor communication may also be at fault when patients on insulin fail to titrate or intensify their treatment adequately. Conversely, glycemic control can be significantly improved by facilitating ongoing communication between patients and caregivers. DISCUSSION: Although innovations in injectable therapy for T2D may help address the current pattern of poor glycemic control, improved communication between patients and caregivers is also a powerful approach and can be implemented with existing therapies.

Canadian guidelines for the management of plaque psoriasis: overview.

New clinical treatment guidelines for plaque psoriasis, written by a panel of 16 Canadian dermatologists, were recently published online. These Canadian Guidelines for the Management of Plaque Psoriasis are evidence based and free of any influence from corporate sponsors and have been endorsed by the Canadian Dermatology Association (CDA). The Guidelines offer treatment recommendations for mild and moderate to severe body psoriasis, as well as for psoriasis affecting specific areas of the skin, such as the facial, flexural, and genital areas; nails; scalp; and palms and soles. The present overview describes the genesis and contents of the Guidelines, which are available in full through the CDA at (English) or (French).

Simple enzymatic means to neutralize DNA contamination in nucleic acid amplification.

Reverse transcription PCR (RT-PCR) is prone to false positives when contaminating DNA molecules are present at the start of a reaction. Contaminants that derive from earlier work using a given primer pair (carryover PCR products) are of particular concern when those primers are used routinely, as in clinical diagnostics or environmental monitoring. In addition, contamination by genomic DNA can significantly interfere with quantitative and qualitative analysis of RNAs by RT-PCR. Here we describe contaminant restriction (ConR), a method that can be used to neutralize carryover and genomic DNA contamination in RT-PCR studies. Restriction enzymes (REs) added to the amplification cocktail cleave contaminant DNA molecules while sparing the intended target nucleic acid. Restriction, reverse transcription, and amplification steps all take place in the same sealed vessel, thus avoiding any danger of recontamination. ConR eliminates carryover contamination in PCR without compromising target sequence amplification. Because the method is effective against both genomic and carryover contamination, it can be employed routinely in one-step RT-PCR, whatever the RNA target or the nature of the potential DNA contaminant. A variation of this decontamination method, amplicon primer site restriction (APSR), is effective specifically against carryover contamination. APSR, unlike ConR, can be applied during PCR-based amplification of DNA target molecules.