A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis

Objective: At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted.

Research design and methods: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required.

Main outcome measures: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study.

Results: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old).

Conclusions: No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.     

Modulation of exocrine pancreatic secretion by leptin through CCK(1)-receptors and afferent vagal fibres in the rat

In this report, we determined whether leptin could modify the exocrine pancreatic secretion of anaesthetized rats in vivo. Intravenous injection of recombinant murine leptin resulted in a time- and dose-dependent stimulation of exocrine pancreatic secretion, maximally observed with 30 nmol/kg of leptin. This stimulation of pancreatic water, bicarbonate, and protein output was abolished by atropine, hexamethonium, L364,718 ([3S(-)-N-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine]), a cholecystokinin CCK(1) receptor antagonist or perivagal capsaicin pretreatment, but unaffected by the CCK(2) receptor antagonist L365,260 ([3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3yl)-N'-(3-methylphenyl)urea]). In addition, the physiological dose of 3 nmol/kg leptin, ineffective per se, potentiated the secretory effect of 45 pmol/kg of cholecystokinin octapeptide (CCK-8) on exocrine pancreatic secretion. Furthermore, intraperitoneal leptin induced a rapid increase in plasma CCK levels in vivo in the rat. In conclusion, exogenous leptin can modulate exocrine pancreatic secretion through mechanisms involving CCK(1) receptors and capsaicin-sensitive afferent fibres in the rat. Whether this may have a physiological relevance in the postprandial regulation of exocrine pancreatic secretion and thus in nutrient digestion will require further investigations.     

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy,Advocacy, and Development (LEAD) faculty

ABSTRACT

Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes.

Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when ≥50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey.

Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug–drug interactions.

Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.     

Identification,diagnosis, and management of anemia in adult ambulatory patients treated by primary care physicians: evidence-based and consensus recommendations

ABSTRACT

Objective: Provide recommendations for the identification, diagnosis, and management of ambulatory patients with anemia.

Materials and methods: The RAND/UCLA Appropriateness Method was used to develop the recommendations. A literature review of anemia prevalence (based on a search of PubMed for the period 1990 to 2003), etiology, and treatment outcomes was reviewed by a panel comprised of nine physicians (six primary care, three specialists) who then rated 336 clinical scenarios and grouped them into three categories: ‘appropriate’, ‘uncertain’, or ‘inappropriate’.

Results: Performing a complete blood count on a yearly basis was rated ‘appropriate’ for patients with an underlying chronic condition, for men ≥ 50 years old, and for all women with no chronic condition on an every-5‐years basis. Specific recommendations were made for five anemia management options (observation, referral, empiric trial of iron, transfusion, and erythropoietic growth factors). Recommendations for observation alone were based on age, gender, and hemoglobin level. Immediate referral to a gastroenterologist or hematologist for a work-up was rated ‘inappropriate’ in all cases. An empiric trial of iron was rated ‘inappropriate’ for women over age 40 and for all men. Recommendations on the use of erythropoietic growth factors were based on hemoglobin level and anemia symptoms (‘appropriate’ if Hb < 9.5?g/dL, or if Hb = 9.5–11.0?g/dL and anemia symptoms were present). Finally, recommendations about transfusion were based on the severity of anemia and the presence of cardiovascular disease (‘appropriate’ in patients ≥ 70 years old and in those presenting with either symptoms of anemia or underlying cardiovascular disease). The recommendations did not address anemia related to nutritional deficiencies, cancer/chemotherapy, or chronic renal failure.

Conclusion: Primary care physicians should obtain screening blood counts, perform diagnoses, and manage anemia in patient groups known to be at risk. These recommendations on the identification, diagnosis, and management of anemia represent an opportunity to improve outcomes in ambulatory patients with anemia.     

北京地区基层医疗机构中成药处方点评共识报告(2018版)

基层医疗机构的中成药品种数和临床使用日益增长,合理用药问题日趋突出,但目前缺少适用于基层医疗机构中成药处方合理性评价的技术规范和指导。针对这一亟须解决的问题,北京市卫计委基层医疗机构处方点评工作组中成药学组会同北京市10余家二、三级医院的一线临床中药师,在前期工作和现有认识基础上,编写了本共识。本共识的编写遵循中华医学会、中华中医药学会关于指南编写的建议,参考国内外权威、常用的Delphi专家咨询法和GRADE证据评价系统,采取最新的共识报告形式完成。最终形成的共识涉及点评工作的组织管理、适应证和遴选药品点评、用法用量和疗程点评、联合用药点评4部分共27条"陈述",为基层医疗机构的中成药处方点评提供技术参考和学术指导。     

Novel action of the chalcone isoliquiritigenin as a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor: potential therapy for cholera and polycystic kidney disease

Overstimulation of cAMP-activated Cl(-) secretion can cause secretory diarrhea. Isoliquiritigenin (ISLQ) is a plant-derived chalcone that has a wide range of biological activities. The present study thus aimed to investigate the effect of ISLQ on cAMP-activated Cl(-) secretion in human intestinal epithelium, especially the underlying mechanism and therapeutic application. Short-circuit current analysis of human intestinal epithelial (T84) cell monolayers revealed that ISLQ dose-dependently inhibited cAMP-activated Cl(-) secretion with an IC(50) of approximately 20 μM. ISLQ had no effect on either basal short-circuit current or Ca(2+)-activated Cl(-) secretion. Apical Cl(-) current analysis of T84 cell monolayers indicated that ISLQ blocked mainly the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels, but not other unidentified cAMP-dependent Cl(-) channels. ISLQ did not affect intracellular cAMP levels or cell viability. ISLQ completely abolished the cholera toxin-induced transepithelial Cl(-) secretion in T84 cells and reduced the cholera toxin-induced intestinal fluid secretion in mouse closed loop models by 90%. Similarly, ISLQ completely inhibited the cAMP-activated apical Cl(-) current across monolayers of Madin-Darby Canine Kidney (MDCK) cells and retarded cyst growth in MDCK cyst models by 90%. This study reveals a novel action of ISLQ as a potent CFTR inhibitor with therapeutic potential for treatment of cholera and polycystic kidney disease.     

Pilot cluster randomized controlled trial of a complex intervention to improve management of vertigo in primary care (PRIMA-Vertigo): study protocol

Objectives: Vertigo and dizziness are highly prevalent symptoms in primary care, frequently misdiagnosed. Based on a thorough need assessment, INDICORE (INform, DIagnose, COmmunicate, REfer), an evidence-based complex intervention has been developed to transfer knowledge of specialized tertiary clinics to primary care providers (PCPs), improve the referral process and, ultimately, improve the functioning and quality of life of patients with vertigo/dizziness. The main objective of the PRIMA-Vertigo pilot study is to examine whether the INDICORE intervention is feasible and sufficiently promising to warrant a larger trial.

Methods: We plan to perform a single-blind, pragmatic cluster-randomized controlled pilot study with an accompanying process evaluation. PCPs will be the cluster units of randomization. Patients who consult these PCPs because of vertigo/dizziness symptoms will be included consecutively and considered the units of analysis. The intervention will be multi-faceted training on diagnostics targeted at the PCPs, supported by patient education material and a newly developed tool to structure the referral process. To balance the influence of non-specific effects, all clusters will receive generic communication training.

Expected results: The process evaluation aims to provide results on the acceptability and feasibility of the INDICORE intervention components to PCPs and patients. Additionally, this study will provide a first estimate of the likely effectiveness of the intervention on patients’ quality of life, functioning and participation.

Conclusions: The PRIMA-Vertigo pilot study will allow further tailoring of the INDICORE intervention to stakeholder needs before its effectiveness is evaluated in a large-scale main study.     

Micronized purified flavonoid fraction (MPFF): a review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency

Initially, the progression of chronic venous insufficiency is related to venous hypertension. The earliest complaints or symptoms, as well as vessel wall deterioration, valve restructuring, and, eventually, varicose veins, result not only from elevation of pressure, but also from a cascade of biochemical events related to both the macro- and the microcirculation. Thickening and remodelling of the venous wall are influenced by two parameters: abnormal shear stress and hypoxia that activate the endothelium first at the level of valve cusps and then in large veins. Hypoxia leads to activation of the endothelium and leukocyte accumulation. By inhibiting endothelial activation, micronized purified flavonoid fraction (MPFF) (Daflon 500 mg), an edema-protective agent, can prevent the inflammatory cascade resulting from the leukocyte-endothelium interaction. This subsequently delays the appearance of reflux and inhibits the initiation of the vicious circle ending in enhanced venous pressure. This is how Daflon 500 mg relieves patients from symptoms and edema and possibly also prevents the appearance of varicose veins. Rheological disturbances also play a major role in the appearance of these disorders. Furthermore, venous hypertension provokes leakage from the vessels and capillaries exhibiting increased permeability, leading to increases in hydrostatic load, and overloading of the lymphatic network, which subsequently results fluid exudation causing edema. Microcirculatory dysfunction leads to capillary damage, skin changes and venous leg ulcers. The clinical efficacy of Daflon 500 mg in venous leg ulcers has been demonstrated by several randomised controlled studies, in which the rate of ulcer healing was significantly shortened. An explanation for the ability to speed ulcer healing comes from the protection Daflon 500 mg exerts on the microcirculation.     

Comparison of a fixed combination of domperidone and paracetamol (Domperamol) with sumatriptan 50 mg in moderate to severe migraine: a randomised UK primary care study

Migraine is a common and debilitating condition routinely managed in primary care. A number of treatment options--both acute and prophylactic--are currently available but may differ in terms of efficacy, tolerability and cost. The aim of this study was to compare the effectiveness and tolerability of a fixed combination of domperidone and paracetamol (Domperamol; Servier), which has anti-nauseant and anti-emetic activity, with sumatriptan 50 mg in moderate to severe migraine. To do this, 120 patients were recruited from 23 primary care practices throughout the UK and were enrolled into the six-month trial. Patients were randomised at entry to one of the comparator regimens (used to treat their first migraine attack) and then crossed over to the alternative treatment for their second attack. Detailed diary cards were completed for each attack using a scale of pain severity. At two hours and four hours post-dose, the two treatments showed comparable efficacy (< or = 15% difference) in relieving headache and reducing nausea and vomiting. Both were well tolerated and there were no serious adverse effects. In the management of migraine patients typically seen in routine general practice, this trial showed that the effects of Domperamol and sumatriptan 50 mg were broadly comparable. Since Domperamol is considerably less expensive than sumatriptan (and other triptans), a first-line role for this agent appears appropriate.     

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part I): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD), involving a triad of laboratory and bone abnormalities, and tissue calcifications, are associated with dismal hard-outcomes.

Areas covered: In two comprehensive articles, we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (this part 1) and hyperparathyroidism (part 2), taking into account CKD-accelerated atheromatosis/atherosclerosis and/or cardiovascular calcification (CVC) processes.

Expert opinion: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Individualization of treatment with P-binders and combinations of anti-parathyroid agents may improve biochemical control with lower incidence of undesirable effects. Isolated biochemical parameters do not accurately reflect calcium or P load or bone activity and do not stratify high cardiovascular risk patients with CKD. Initial guidance is provided on reasonable therapeutic strategies which consider the presence of CVC. This part reflects that although there is not an absolute evidence, many studies point to the need to improve P imbalance while trying to, at least, avoid progression of CVC by restriction of Ca-based P-binders if economically feasible. The availability of new drugs (i.e. inhibitors of intestinal transporters), and studies including early CKD should ultimately lead to clearer and more cost/effective clinical targets for CKD-MBD.     

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes.

Areas covered: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes.

Expert opinion: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.     

Oxidative biotransformation in primary cultures of chick embryo hepatocytes: induction of cytochrome P-450 and the metabolism of benzo(a)pyrene

Primary cultures of chick embryo hepatocytes are known to maintain their initial level of cytochrome P-450 for a number of days. To explore the possibilities of chick embryo hepatocyte cultures as a tool in drug metabolism, induction profiles of cytochrome P-450 were determined and the metabolism of benzo(a)pyrene as a model substrate was studied.Maximum induction by phenobarbitone and Aroclor 1254 is reached after 21 h and 18 h, respectively, both in the presence and absence of serum. For -naphthoflavone induction is maximal after 31 h in the presence and 43 h in the absence of serum. The levels of P-450 after induction are comparable to those found in vivo in rats: increases of 200% for phenobarbitone, 200% for -naphthoflavone and 210% for Aroclor 1254. Ethoxyresorufin-0-deethylase activities are induced by -naphthoflavone and Aroclor 1254, but as expected only slightly by phenobarbitone. In the absence of serum in the culture medium, for the control as well as the induced cells a plateau of activity is maintained for at least 24 h. In the presence of serum a decline in P-450 levels is observed. Especially in the case of Aroclor, an increase in porphyrin content of 320% of control values is seen at the same time.A number of representative metabolites of benzo(a)pyrene were quantitated during a 4-h incubation. Relative amounts are comparable to those observed with rat liver microsomes. As expected, -naphthoflavone and Aroclor induce the rate of metabolism (by 500% and 400%, respectively, in the absence of serum), but phenobarbitone has no or very little effect.Interestingly, when benzo(a)pyrene is incubated with control or phenobarbitone-induced cells an increase in rate of metabolite formation with time is observed: benzo (a)pyrene seems to induce its own metabolism. The chick embryo hepatocytes thus offer the possibility of studying induction and biotransformation in the same system at the same time, in vitro.     

Exenatide BID Observational Study (ExOS): results for primary and secondary endpoints of a prospective research study to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes in a real-world setting

Abstract

Objective:

The Exenatide BID Observational Study (ExOS) was designed to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes (T2D) in a real-world clinical practice setting in the United States.     

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies,statistical optimization,ex vivo,and in vivo studies

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor^® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.