Salivary Amylase-Responsive Buccal Tablets Wipe Out Chemotherapy-Rooted Refractory Oral Mucositis.

Oral mucositis (OM) is the most common and refractory complication of cancer chemotherapy and radiotherapy, severely affecting patients' life quality, lowering treatment tolerance, and discouraging patient compliance. Current OM delivery systems mostly affect the comfort of patient use and lead to poor compliance and unsatisfactory effects. Herein, salivary amylases (SAs)-responsive buccal tablets consisting of porous manganese-substituted Prussian blue (PMPB) nanocubes (NCs), anti-inflammatory apremilast (Apr) and starch controller have been engineered. PMPB NCs with large surface area can serve as carriers to load Apr, and their multienzyme-mimicking activity enables them to scavenge reactive oxygen species (ROS), which thus synergize with Apr to mitigate inflammation. More significantly, the starch controller can respond to abundant SAs in the oral cavity and realize the cascade, continuous, and complete drug release after enzymatic decomposition, which not only aids with high tissue affinity to prolong the resistance time but also improves the comfort of use. The preclinical study reveals that contributed by the above actions, such buccal tablets mitigate inflammation, promote endothelium proliferation and migration, and accelerate wound healing for repressing chemotherapy-originated intractable OM with positive oral microenvironment and shorter recovery time, thus holding high potentials in clinical translation.

[A case of lung adenocarcinoma with markedly elevated amylase in airway secretions].

A 45-year-old male patient was admitted to the hospital because of intermittent cough and expectoration for more than 1 year, worsened by dyspnea for 2 months, and was finally diagnosed with lung adenocarcinoma. The CT scan of the chest revealed lesions of diversity with fibrosis, mass and effusion, but his severe cough limited biopsy of the lesions. The difficult process of diagnosis was aided by the further analysis of the sputum, which showed significantly elevated amylase without any evidence of pancreatic disease. The cough was relieved by intravenous pumping octreotide acetate, and both CT-guided lung biopsy and transbronchial biopsy revealed the lung adenocarcinoma. The diagnostic process of this case provided a helpful diagnostic thinking and demonstrated the rare clinical features of lung adenocarcinoma.

[Diffuse large B-cell lymphoma complicated with pancreatic fistula and peritonitis following initial chemotherapy].

A 59-year-old-woman complained of weight loss and abdominal pain. A CT scan revealed a 20 cm large retroperitoneal mass, and she was diagnosed with diffuse large B-cell lymphoma via biopsy of the mass. After 75% CHP therapy, she developed an acute abdomen and CT revealed generalized peritonitis. Amylase in the ascites fluid was elevated, and infiltration into the pancreas was suspected on CT before treatment, suggesting a pancreatic fistula caused by tumor shrinkage. Enterobacteria were found in ascites fluid culture, suggesting a gastrointestinal perforation complication. The patient was refractory to treatment, and death was confirmed due to progression of the primary disease. The pathological autopsy revealed diffuse pancreatic infiltration, suggesting that the pancreatic fistula was caused by pancreatic injury. Pancreatic fistula is a known complication of surgical procedures but is rarely caused by tumor shrinkage due to chemotherapy. Since there is no preventive method for pancreatic injury caused by tumor shrinkage, early diagnosis and early treatment of pancreatic fistula are critical, and ascites fluid analysis, including amylase, was thought to be useful for the diagnosis.

Therapeutic role of kaempferol and myricetin in streptozotocin-induced diabetes synergistically via modulation in pancreatic amylase, glycogen storage and insulin secretion.

Kaempferol and Myricetin alone have promising benefits on diabetes and related complications, yet the effectiveness of cotreating the two compounds on diabetes have not been studied. The existing investigation was to study the combined anti-diabetic effect of kaempferol and myricetin in Streptozotocin (STZ)-activated diabetes in rats. To evaluate the anti-diabetic activity, 36 Wistar rats were segregated into six groups; Normal, 50 mg/kg STZ-induced diabetes, and four (50 mg/kg kaempferol, 50 mg/kg myricetin, 25 mg/kg kaempferol + myricetin, and 5 mg/kg glibenclamide) compound-treated diabetic groups. The effects of co-treatment on parameters, glucose, insulin, lipid profile, liver enzymes, antioxidant biomarkers, and inflammatory cytokines were measured. The study revealed that combined treatment restored the assessed parameters including glucose levels, inflammatory cytokines, oxidative markers, and lipid and liver enzymes in diabetic rats. The results indicate that cotreatment of kaempferol and myricetin has a beneficial role against diabetes suggesting that cotreatment of these compounds can be used therapeutically in treating diabetes.

Bifidobacterium spp. and their metabolite lactate protect against acute pancreatitis via inhibition of pancreatic and systemic inflammatory responses.

Severe acute pancreatitis (SAP) is a critical illness characterized by a severe systemic inflammatory response resulting in persistent multiple organ failure and sepsis. The intestinal microbiome is increasingly appreciated to play a crucial role in modulation of AP disease outcome, but limited information is available about the identity and mechanism of action for specific commensal bacteria involved in AP-associated inflammation. Here we show that Bifidobacteria, particularly B. animalis, can protect against AP by regulating pancreatic and systemic inflammation in germ-free (GF) and oral antibiotic-treated (Abx) mouse models. Colonization by B. animalis and administration of its metabolite lactate protected Abx and GF mice from AP by reducing serum amylase concentration, ameliorating pancreatic lesions and improving survival rate after retrograde injection of sodium taurocholate. B. animalis relieved macrophage-associated local and systemic inflammation of AP in a TLR4/MyD88- and NLRP3/Caspase1-dependent manner through its metabolite lactate. Supporting our findings from the mouse study, clinical AP patients exhibited a decreased fecal abundance of Bifidobacteria that was inversely correlated with the severity of systemic inflammatory responses. These results may shed light on the heterogeneity of clinical outcomes and drive the development of more efficacious therapeutic interventions for AP, and potentially for other inflammatory disorders.

Identification of novel immune-related targets mediating disease progression in acute pancreatitis.

Introduction: Acute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear. Methods: An integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo. Results: The numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10-3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10-8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation. Discussion: In summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression.

Improvement in serum amylase and glucose levels in diabetic rats on oral administration of bisdemethoxycurcumin from Curcuma longa and limonoids from Azadirachta indica.

Curcuma longa and Azadirachta indica are traditionally used in Indian cuisine and Ayurvedic medicine as nutraceuticals against diabetes. The crude C. longa isopropanol extract, bisdemethoxycurcumin (BDMC), the purified bioactive component from C. longa, and limonoids azadiradione, gedunin from A. indica, are able to inhibit in vitro the antidiabetic target human pancreatic α-amylase independently. However, no reports on their in vivo efficacy in animal models exist. Thus, the antidiabetic effect of these orally administered human pancreatic α-amylase inhibitors was performed on streptozotocin-induced Sprague-Dawley rats. Initially, the normal rats were treated with test compounds (10-100 mg/kg of body weight) in corn oil (5 ml/kg), and as no lethality was observed in these doses, further studies were carried out with lowest concentration of 10 mg/kg of body weight. A reduction in area under curve (AUC) suggested glucose-lowering effect of these compounds in starch fed diabetic rats. The efficacy study showed a significant improvement in body weight, blood glucose levels, serum amylase, and fructosamine levels as well in other serum parameters associated with diabetes with respect to liver and renal functions. Hence, under in vivo conditions, inhibition of α-amylase activity by BDMC and limonoids affirms it as one of the mechanisms of action resulting in reduction of blood glucose levels. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin from C. longa and limonoids, namely, azadiradione and gedunin, from A. indica are potent inhibitors of the antidiabetic target human pancreatic α-amylase. Oral Starch Tolerance Test (OSTT) and 28-day efficacy study to check the effect of these orally administered inhibitors in diabetic rat models showed significant improvements in serum blood glucose and amylase levels as well as in other diabetes related serum parameters, namely, bilirubin, lipids, lactate dehydrogenase, alkaline phosphatase, and urea. The study contributes to understanding the action and efficacy of these pancreatic α-amylase inhibitors and suggests a potential role for them as nutraceuticals/therapeutics in management of post-prandial hyperglycemia.

Study of the gastrointestinal bioavailability of a pancreatic extract product (Zenpep) in chronic pancreatitis patients with exocrine pancreatic insufficiency.

INTRODUCTION: The Food and Drug Administration in 2006 required that all pancreatic enzyme products demonstrate bioavailability of lipase, amylase, and protease in the proximal small intestine. METHODS: In this phase I open-label, randomized, crossover trial, 17 adult chronic pancreatitis (CP) patients with severe exocrine pancreatic insufficiency (EPI) underwent two separate gastroduodenal perfusion procedures (Dreiling tube suctioning and [14C]-PEG instillation by an attached Dobhoff tube in the duodenal bulb). Patients received Ensure Plus® alone and Ensure Plus with Zenpep (75,000 USP lipase units) in random order. The bioavailability of Zenpep was estimated by comparing the recovery of lipase, amylase, chymotrypsin activity in two treatment conditions. 14C-PEG was used to correct duodenal aspirates volume. The primary efficacy endpoint was lipase delivery in the duodenum after Zenpep administration under fed conditions. Secondary efficacy endpoints included chymotrypsin and amylase delivery, serum CCK levels, and measuring duodenal and gastric pH. RESULTS: Zenpep administration with a test meal was associated with significant increase in duodenal aspiration of lipase (p = 0.046), chymotrypsin (p = 0.008), and amylase (p = 0.001), compared to the test meal alone, indicating release of enzymes to the duodenum. Lipase delivery was higher in the pH subpopulation (the efficacy population with acid hypersecretors excluded) (p = 0.01). Recovery of [14C]-PEG was 61%. Zenpep was generally well tolerated. All adverse events were mild and transient. CONCLUSIONS: In CP patients with severe EPI, lipase, chymotrypsin and amylase were released rapidly into the duodenum after ingestion of Zenpep plus meal compared to meals alone. Results also reflected the known pH threshold for enzyme release from enteric coated products.

Continuous absorbable suture versus interrupted permanent suture in the treatment of diastasis of the rectus abdominis muscle / Sutura contínua com fio absorvível versus interrompida com fio permanente no tratamento da diástase do músculo reto abdominal

Introduction: Plication of the rectus abdominis muscle is an important step in remodeling the abdomen in abdominoplasties. It can be performed using several types of threads with interrupted or continuous sutures, according to the surgeon's preferences. Few studies in the literature compared the different plication techniques in abdominoplasties. The present study aimed to compare continuous anchored suture with polydioxanone (PDS) with interrupted nylon suture regarding surgical time, relapse, and costs and discuss the advantages and disadvantages of each method. Methods: A randomized clinical trial in which 30 patients were enrolled for each of the two groups, 15 with continuous suture and 15 with interrupted suture, was conducted. The plication time was compared between the groups using the Student's t-test. Between 10 and 12 months postoperatively, all patients underwent ultrasonography for investigating diastasis recurrence. Results: Continuous suture decreased the plication time by almost 40% when compared to the interrupted suture (p < 0.001), without affecting the esthetic outcome. The PDS used in the continuous suture implied higher costs than those with the nylon threads used in the interrupted suture. No recurrence was found on the postoperative control ultrasonography results. Conclusion: Continuous suture reduced the plication time by almost 40% (p < 0.001) when compared to interrupted suture. Despite being associated with higher costs, PDS seems to be a good alternative to non-absorbable sutures, such as nylon threads, in plications of the rectus abdominis, since it is a more biocompatible material.

Introdução: A plicatura do músculo reto abdominal é um passo importante no remodelamento do abdômen nas abdominoplastias. Ela pode ser realizada com vários tipos de fios e com suturas interrompidas ou contínuas, de acordo com as preferências do cirurgião. Poucos estudos na literatura compararam diferentes técnicas de plicatura nas abdominoplastias. O objetivo do estudo é comparar a sutura contínua ancorada com polidioxanona (PDS) com a sutura interrompida com náilon quanto ao tempo cirúrgico, recidiva, custos e discutir vantagens de desvantagens de cada método. Métodos: Ensaio clínico randomizado no qual 30 pacientes foram arroladas para cada um dos grupos, 15 sutura contínua e 15 sutura interrompida. O tempo de plicatura foi comparado entre os grupos utilizando-se o teste t de Student. Entre 10 a 12 meses de pós-operatório, todas as pacientes foram submetidas à ecografia em busca de recidivas da diástase. Resultados: A sutura contínua diminuiu em quase 40% o tempo de plicatura quando comparada à sutura interrompida (p < 0,001), sem prejuízo no resultado estético. O PDS utilizado na sutura contínua implicou maiores custos que os fios de náilon utilizados na sutura interrompida. Nenhuma recidiva foi encontrada na ecografia de controle no pós-operatório. Conclusão: A sutura contínua quando comparada à sutura interrompida foi capaz de reduzir o tempo de plicatura em quase 40% (p < 0,001). A utilização do PDS, apesar dos maiores custos, parece ser uma boa alternativa às suturas com fios não absorvíveis como o náilon nas plicaturas do músculo reto abdominal, uma vez que se trata de um fio de maior biocompatibilidade.

[DELAYED RESULTS OF ENZYME REPLACEMENT THERAPY, PRESCRIBED BY RESULTS OF 13C-TRIGLYCERIDE BREATH TEST].

Maldigestion persists in most patients with chronic pancreatitis (CP). The objective lipase and amylase insufficiency diagnosis is needed to achieve an adequate clinical response to oral pancreatic enzyme substitution therapy. The novel data is presented in the article about the role of 13C-mixed triglyceride breath test as a tool for exocrine pancreatic insufficiency diagnosis, for evaluating fat malabsorbtion in CP patients. 135 patients were included in the investigation. Delayed results of enzyme replacement therapy were estimated after 1 and 2 year of surveillance. It has been shown, that partial recovery of exocrine pancreatic function is possible, and replacement therapy leads to patients nutritional status improving. Thus 13C-triglyceride breath test could be useful tool in clinical practice for CP diagnosis. The test make it possible to choose the initial pancreatic enzyme dosage and are beneficial during the treatment for pancreatic enzyme dose correction.

Plicatura dos retos do abdome em dois planos versus plano único contínuo / Plication of the rectus abdominis muscles in one continuous and two planes

Introdução: A correção da diástase dos músculos retos do abdome é realizada principalmente pela sua plicatura, procedimento que consome muito tempo cirúrgico. O objetivo deste estudo é avaliar a eficácia e o tempo necessário para a correção da diástase dos retos do abdome comparando a plicatura com sutura contínua em plano único à plicatura em dois planos. Método: Foram incluídas 20 mulheres com história de pelo menos uma gestação. Foram randomizadas em dois grupos, um submetido à plicatura dos retos do abdome em dois planos (controle) e outro à sutura em plano único contínuo (estudo) com mononylon 2-0. Mediu-se o tempo necessário para a realização de cada uma das técnicas. Para análise estatística, foram usados os testes não paramétricos de Mann-Whitney, Friedman e Wilcoxon, considerando estatisticamente significante p < 0,05. Todas as pacientes foram submetidas à ultrassonografia previamente à cirurgia, 3 semanas e 6 meses de pós-operatório. Resultados: A plicatura do grupo estudo mostrou-se tão eficaz quanto à do grupo controle, mantendo seu resultado em longo prazo, apresentando diferença estatisticamente significante (p = 0,018) na comparação das medidas pré e pós-operatórias. No grupo estudo, porém, a plicatura consumiu menor tempo cirúrgico para ser realizada, também com diferença estatisticamente significante (p = 0,002). Conclusão: Com este estudo, pode ser concluído que tanto a sutura em dois planos como a em plano único contínuo são eficazes na correção da diástase dos retos do abdome e mantêm o resultado por longo tempo. Concluiu-se também que a técnica de sutura contínua demanda menor tempo para ser realizada.

Introduction: The correction of diastasis of the rectus abdominis muscles is primarily performed using the plication technique, which involves a surgical procedure. To evaluate the efficacy and the surgical time necessary to correct diastasis of the rectus abdominis muscles using plication and sutures in one continuous or two planes. Method: Twenty women with at least one pregnancy were included in the study. The study participants were randomized into two groups: the control group was subjected to plication in two planes, and the experimental group was subjected to plication using suture in one continuous plane with mono-nylon 2-0. The time required to perform each of these techniques was measured. For statistical analysis, the nonparametric Mann-Whitney test, Friedman test, and Wilcoxon test were used, and p-values of < 0.05 were considered statistically significant. All patients underwent ultrasonography before surgery, and at 3 weeks and 6 months postoperatively. Results: The plication technique was similarly effective in the two groups, achieving a long-term surgical outcome; however, the differences in the ultrasound measurements in the pre- and postoperative periods were statistically significant (p = 0.018). In addition, plication was performed in a significantly shorter time in the experimental group (p = 0.002). Conclusion: Sutures in one continuous plane and in two planes were effective in correcting diastasis of the rectus abdominis muscles, with the maintenance of a long-term surgical outcome. In addition, the continuous suture technique can be performed in a shorter time.

[The clinical application of 13C-breath tests in pancreatic diseases].

Maldigestion persists in most patients with chronic pancreatitis (GP). The objective lipase and amylase insufficiency diagnosis is needed to achieve an adequate clinical response to oral pancreatic enzyme substitution therapy. The novel data is presented in the article about the role of 13C-mixed triglyceride and 13C-corn starch breath tests as a tools for exocrine pancreatic insufficiency diagnosis, for evaluating fat and starch malabsorbtion in CP patients. 135 patients were included in the investigation. It has been shown, that 13C-breath tests could be useful tools in clinical practice for CP diagnosis. They are well correlate with fecal elastase-1 level, has high sensitivity and specificity for diagnosis of lipase and amylase deficiency. Tests make it possible to choose the initial pancreatic enzyme dosage and are beneficial during the treatment for pancreatic enzyme dose correction.

The effect of oral pancreatic enzyme supplementation on the course and outcome of acute pancreatitis: a randomized, double-blind parallel-group study.

CONTEXT: Pancreatic exocrine insufficiency is a significant problem after acute pancreatitis. OBJECTIVE: To evaluate whether oral pancreatic enzyme supplementation improves the recovery of pancreatic exocrine function and to explore the efficacy, safety and tolerability of pancreatic enzyme supplementation in patients during the refeeding period after acute pancreatitis. DESIGN: Prospective double-blind, placebo controlled, randomized study. PATIENTS: The sudy included 56 patients with acute pancreatitis. MAIN OUTCOME MEASURES: Primary efficacy variable was recovery from pancreatic exocrine insufficiency. Secondary objectives were body weight, abdominal pain, course of APACHE II score, patient's symptoms and quality of life. RESULTS: Twenty of the 56 patients showed low fecal elastase values indicating pancreatic exocrine insufficiency after acute pancreatitis. Median time to recovery from exocrine pancreatic insufficiency was 14 days in the enzyme supplementation group and 23 days in the placebo group but overall differences for primary and all but one secondary endpoint did not reach statistical significance. However, a positive tendency in favour of enzyme supplementation was found for quality of life parameters (FACT-Pa) in all subscores. There were no relevant differences between placebo and oral pancreatic enzyme supplementation detected with respect to safety and tolerability. CONCLUSION: Enzyme supplementation positively effects the course of acute pancreatitis if administered during the early refeeding phase after acute pancreatitis. There is evidence that oral pancreatic enzyme supplementation has a positive impact on the course of the disease and the global health status (less weight loss, less flatulence, improved quality of life). Oral pancreatic enzyme supplementation was safely administered and can be added to the treatment regimen of patients in a refeeding status after severe acute pancreatitis.

Pancreatitis aguda: nuestra experiencia / Acute pancreatitis: our experience

Introducción: La pancreatitis aguda es un cuadro de dolor abdominal poco frecuente en la infancia. Nuestro objetivo es describir las características de los pacientes ingresados entre1988 y 2008 en un hospital terciario con este diagnóstico. Métodos: Estudio observacional retrospectivo por revisión de historias clínicas. Se recogen datos epidemiológicos, etiológicos, clínicos, de laboratorio, radiológicos, de manejo terapéutico y evolución clínica. Resultados: Incluimos 27 pacientes (un 66% varones), con una media de edad de 7,2 años (rango: 6 meses-16 años). El52% presenta enfermedades crónicas relevantes. El mecanismo etiológico más frecuente fue el estructural (37%), aunque hubo otros agentes causales, como ingesta de fármacos, infecciones, shock e inmunodeficiencias. Un 26% de los casos fueron catalogados como idiopáticos. El síntoma guía en todos los pacientes estables fue el dolor abdominal, de localización y características variables, acompañado de vómitos (55%), fiebre(33%), anorexia (19%) y otros síntomas relacionados con el agente causal. En todos se observó un aumento de las enzimas pancreáticas. La prueba de imagen más realizada fue la ecografía (patológica en un 74% de los casos), y el aumento del tamaño de la glándula fue el hallazgo más común. En el 89%de los pacientes el tratamiento fue médico, con dieta absoluta durante una mediana de 48 horas. Dos pacientes precisaron la realización de una colangiopancreatografía retrógrada endoscópica para el tratamiento de una coledocolitiasis. La duración media del ingreso fue de 9 días, y el 40% de los casos evolucionó favorablemente. Tres pacientes evolucionaron hacia pancreatitis crónica y 6 fallecieron por causas extradigestivas. Conclusiones: La pancreatitis aguda es una entidad poco frecuente en la edad pediátrica, con una amplia variedad de factores etiológicos que condicionan un pronóstico muy heterogéneo(AU)

Introduction: Acute pancreatitis is an unusual disorder in childhood that commonly onsets with sudden abdominal pain. Our goal is to describe the features of the patients diagnosed of acute pancreatitis between 1988 and 2008 who were admitted to our hospital. Methods: Retrospective observational study by review of medical records. We collected data referred to epidemiology, aetiology, clinical symptoms, analytical (amylase, lipase) and radiological findings, medical treatment administered and outcome. Results: We included 27 patients (66% males), with a mean age of 7.2 years (range: 6 months-16 years). 52% of them suffered from chronic diseases. The most common cause was a structural anomaly (37%). Other aetiologies included: drugs, infections, shock and immunodeficiencies. 26% of cases were catalogued as idiopatic. The presenting symptom in non-critical patients was abdominal pain, in different areas and with diverse features, associated with vomiting (55%), fever (33%),anorexia (19%) and other symptoms related to the a etiological agent. Pancreatic enzyme levels were elevated in all patients. The most widely used radiological test was ecography (abnormalin 74%), being the most common image the enlargement of the gland. 89% of patients were managed conservatively with complete bowel rest during a median of 48 hours. ERCP was indicated in 2 patients to treat coledocolitiasis. Median hospital stay was 9 days, with favourable outcome in 40% of patients. Recurrence was described in 3 patients and 6 died because of non-digestive causes. Conclusions: Acute pancreatitis is an unusual disease in childhood with a great variety of aetiological factors that determine different prognosis(AU)

Liprotamase long-term safety and support of nutritional status in pancreatic-insufficient cystic fibrosis.

OBJECTIVES: Patients with cystic fibrosis (CF) who have exocrine pancreatic insufficiency (EPI) require treatment with pancreatic enzyme replacement therapy (PERT) to maintain adequate nutrition and age-appropriate growth and weight gain. Liprotamase, a nonporcine, highly purified biotechnology-derived PERT, has demonstrated significant efficacy in fat and protein malabsorption in patients with EPI compared to placebo. This study of liprotamase is the first ever long-term trial of a PERT to evaluate safety and nutritional parameters. METHODS: This phase III 12-month open-label trial assessed the safety, tolerability, and long-term nutritional effects of liprotamase treatment in patients with CF and EPI 7 years and older. All of the patients were required to discontinue their long-term use of porcine PERTs at the time of enrollment. Dosing started at 1 capsule of liprotamase (32,500 US Pharmacopoeia (USP) units crystallized cross-linked lipase, 25,000 USP units crystallized protease, and 3,750 USP units amorphous amylase) per meal or snack; dose could be increased based on protocol-defined parameters. RESULTS: A total of 215 subjects were enrolled and 214 received at least 1 dose of liprotamase (mean 5.5 capsules per day). During the study period, height, weight, and body mass index z scores and lung function as measured by forced expiratory volume in 1 second were stable. There were no clinically meaningful changes in laboratory tests, including levels of fat-soluble vitamins. Liprotamase was well tolerated without any significant safety concerns. Adverse events, primarily gastrointestinal, led to treatment discontinuation for 36 subjects (16.8%), most within the first 3 months. CONCLUSIONS: Treatment with a mean of 5.5 capsules of liprotamase per day, during meals and snacks, for up to 12 months was safe, well tolerated, and associated with age-appropriate growth and weight gain or weight maintenance in subjects with CF-related EPI.

International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients.

BACKGROUND: Most cystic fibrosis (CF) patients have exocrine pancreatic insufficiency (EPI) and need supplementation with pancreatic enzyme replacement therapy (PERT). Liprotamase, a novel non-porcine PERT containing highly purified biotechnology-derived lipase, protease, and amylase, has successfully undergone initial efficacy and safety testing. METHODS: In this international phase III parallel-group, randomized-withdrawal, double-blind placebo-controlled trial, CF patients with EPI 7 years and older, including nutritionally and functionally compromised individuals, underwent baseline testing for coefficients of fat and nitrogen absorption (CFA and CNA) and stool weight and frequency while off PERT. After an open-label treatment period with liprotamase, subjects were randomized 1:1 to one liprotamase or placebo capsule taken with 3 meals and 2 snacks per day. The dose was fixed and increases were not allowed. The same measurements were obtained again after treatment with double-blind study drug or placebo. RESULTS: 138 subjects were randomized. The adjusted least squares mean (LSM) difference between the treatment and placebo groups for change in CFA was 15.1% (p=0.001) for the subgroup with baseline CFA <40%, 8.6% (p=0.006) for subjects with baseline CFA ≥40%, and 10.6% (p<0.001) for the overall intent-to-treat population. Similar results were seen for change in CNA. Stool weight was significantly decreased although not stool frequency. Liprotamase was well tolerated with no safety concerns identified. CONCLUSIONS: In a CF patient population reflective of that encountered in clinical practice, this trial demonstrated that liprotamase at a fixed dose of one capsule per meal or snack (5 capsules per day) was well tolerated and significantly increased fat absorption as measured by improvement in CFA, significantly increased protein absorption as measured by improvement in CNA, and significantly decreased stool weight.

Pancreatic enzyme supplementation.

PURPOSE OF REVIEW: In 2010, the Food and Drug Administration required manufacturers of pancreatic enzymes replacement therapy (PERT) to have approval for marketing, rescinding the distribution of PERT that had been available for decades without definitive studies of efficacy and safety. Therefore, many patients on PERT had to change preparation in the last year and be placed on new formulations of PERT or switched to a new branded product altogether. This review summarizes the clinical data on these new products and reviews their general use. RECENT FINDINGS: The three new commercially available PERTs all demonstrated similar (as good as or slightly improved) abilities to increase the absorption of fat and nitrogen compared with previous PERT preparations. All preparations tests demonstrated superiority over placebo-controlled portions of the clinical trials. Side-effects seem to be no different compared with placebo. Additional PERTs are being evaluated including a nonporcine preparation which may be available in the future. SUMMARY: These new preparations, Creon, Zenpep, and Pancreaze, demonstrated improvement in the absorption of fat and nitrogen in patients with pancreatic insufficiency related to cystic fibrosis. Some patient variability to response continues, so clinicians need to continue to titrate dose and preparations based on weight gain and patient response.

Properties of different pancreatin preparations used in pancreatic exocrine insufficiency.

BACKGROUND: Pancreatic enzyme preparations are a life-saving substitution for a pivotal physiological function of the entire organism that is impaired in chronic pancreatitis, cystic fibrosis and other diseases with exocrine pancreatic insufficiency. Pancreatic enzyme preparations, generically called pancreatin, are not alike. Rather, they present a broad variety of pancreatin composition. AIM: The properties of a set of commercially available pancreatin preparations were investigated in light of the physiological tasks such enzymes must fulfill during the normal digestive process. METHODS: Measurements of size, surface, acid resistance, release of enzymes, pharmacokinetics and batch consistency were undertaken. RESULTS: Although all pancreatin preparations contain the declared lipase units and are acid-stable, a wide variation was observed in the particle size (pyloric passage), specific surface area and release kinetics of lipase activity at pH 6 (duodenum). CONCLUSION: At present, available pancreatin preparations vary widely with respect to investigated parameters, which may have consequences for facilitating optimal digestion.

Systematic review: pancreatic enzyme treatment of malabsorption associated with chronic pancreatitis.

BACKGROUND: Pancreatic enzyme supplementation is standard treatment for malabsorption caused by chronic pancreatitis. The FDA recently required all manufacturers to submit New Drug Applications to continue to market these agents because published data demonstrated variation in formulation, bioavailability and shelf-life while providing limited data about efficacy and safety. AIM: To review systematically the design and results of randomized, parallel-design trials of pancreatic enzyme supplements in chronic pancreatitis patients with steatorrhea. METHODS: A computer-assisted search of MEDLINE and EMBASE was performed to identify relevant studies. Two authors performed duplicate data extraction on study design, improvement in coefficient of fat absorption (CFA), diarrhoea and adverse events using pre-specified forms. Agreement between investigators for data extraction was greater than 95%. RESULTS: Of 619 articles found through literature searching, 20 potentially relevant articles were identified and four manuscripts met inclusion criteria. No studies performed head-to-head comparisons of different supplements. Enzyme supplementation is more likely to improve CFA compared with placebo, but fat malabsorption remained abnormal. Important differences in patient population, study endpoint, study design, pancreatic enzyme dosage and measurement of CFA were present across trials, which precluded comparison of different agents. CONCLUSIONS: Enzyme supplementation improves CFA compared to placebo, but may not abolish steatorrhoea.