Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study. STUDY DESIGN: We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. RESULTS: A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P < .001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. CONCLUSIONS: Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01710644.

Prolonged course of eravacycline leading to acute pancreatitis.

Eravacycline is the newest member of the broad-spectrum class of tetracycline antimicrobials. Pancreatitis has been previously associated with the tetracycline class of antibiotics, but, to our knowledge, we believe that this is the first reported case of eravacycline-induced pancreatitis. We describe a 46-year-old male who received eravacycline for treatment of a perirectal abscess. While the patient had slightly elevated lipase levels at baseline post-cardiopulmonary arrest, he developed abdominal pain and a further increase in lipase levels following 10 days of eravacycline, consistent with pancreatitis. Based on the Naranjo adverse drug reaction probability scale, eravacycline was the probable etiology of acute pancreatitis given improvement immediately after discontinuation. Clinicians should be aware of this potential adverse effect of eravacycline and should not initiate eravacycline in those with risk factors for acute pancreatic injury. However, acute pancreatitis should be suspected in all patients complaining of symptoms followed by immediate discontinuation of eravacycline.

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.

A novel protocol for the preparation of active recombinant human pancreatic lipase from Escherichia coli.

An active recombinant human pancreatic lipase (recHPL) was successfully prepared for the first time from the Escherichia coli expression system using short Strep-tag II (ST II). The recHPL-ST II was solubilized using 8 M urea from E.coli lysate and purified on a Strep-Tactin-Sepharose column. After refolding by stepwise dialyses in the presence of glycerol and Ca2+ for 2 days followed by gel filtration, 1.8-6 mg of active recHPL-ST II was obtained from 1 L of culture. The recHPL was non-glycosylated, but showed almost equal specific activity, pH-dependency and time-dependent stability compared to those of native porcine pancreatic lipase (PPL) at 37°C. However, the recHPL lost its lipolytic activity above 50°C, showing a lower heat-stability than that of native PPL, which retained half its activity at this temperature.

Gastrointestinal symptoms before and after total pancreatectomy with islet autotransplantation: the role of pancreatic enzyme dosing and adherence.

OBJECTIVES: In a large cohort of subjects undergoing total pancreatectomy with islet autotransplantation (TPIAT), we assessed the prevalence and duration of gastrointestinal (GI) symptoms before and after the procedure to determine the impact of enzyme adherence on GI symptoms. METHODS: Three hundred fifty-six preoperative and postoperative questionnaires were collected from 184 subjects between ages of 5 and 66 years who underwent TPIAT between 2008 and 2011 at the University of Minnesota. Questionnaires were analyzed for self-reported frequency and severity of GI symptoms, pancreatic enzyme usage, and glycemic variability index (GVI). RESULTS: After surgery, patient-reported steatorrhea increased whereas constipation decreased. Gastrointestinal symptoms interfered with daily activity in 44% to 69% of subjects, before and after surgery, despite high reported enzyme adherence. Postoperatively, more than 79% of subjects reported consistent use of enzymes at all meals. Presence of GI symptoms did not vary with adherence. The GVI of 2 had a 2.8-fold increased odds of steatorrhea (95% confidence interval, 1.1-7.0) compared with GVI of 0. CONCLUSIONS: Gastrointestinal symptoms were common after TPIAT; ongoing management is needed. Enzyme nonadherence was not a major contributor to diarrhea/steatorrhea in this cohort. Glycemic variability was closely associated with steatorrhea; poor response to enzyme replacement may complicate diabetes management.

Human asthma due to a dog's drugs.

A woman had a recurrence of asthma due to sensitization to her dog's pancreatic enzyme powder. The cause of her asthma was confirmed by bronchial inhalation challenge, and specific IgE antibodies against the enzymes were found in her serum but not in that of control subjects.

Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

The pathology of fibrosing colonopathy of cystic fibrosis: a study of 12 cases and review of the literature.

The authors studied eight colectomy and eight biopsy specimens from 12 patients with cystic fibrosis who had developed fibrosing colonopathy, a complication observed in patients receiving high-strength enzyme replacement. The colectomies originated from five male and three female patients ranging in age from 18 months to 6 years. Five individuals had localized strictures of the right colon and three had stenosing fibrosis of the entire colon. The affected colon had a cobblestone appearance, submucosal fibrosis, thickening of the muscularis propria and chronic mucosal inflammation in all patients, with active cryptitis in four. Moderate to severe infiltration by eosinophils, with increase in the number of mast cells, and widespread interruption of the muscularis mucosa were present in every case. Four colectomies were preceded by endoscopic biopsies; four patients who have not undergone surgery also underwent biopsy. All the biopsies showed evidence of active or chronic inflammation, and all had increased mucosal eosinophils. Prolonged colonic mucosal contact with either the enzymes and/or the enteric coating itself may lead to mucosal colonic ulceration and inflammation. Topical allergy may then promote the stenosing fibroplasia.

Acute lipase-induced panniculitis in rats with ligated veins of the hindlimb: a contribution to the role of acute panniculitis as a precursor of lipodermatosclerosis of venous disease.

The authors studied the effect of ligation of the femoral and saphenous veins on the evolution of lipase injection-induced subcutaneous fibrosis and inflammation in the rats' hindlimbs. The superficial muscular fascia was thickened and the number of veins was increased 3 days and 3 weeks after vein ligation; both abnormalities disappeared 6 weeks postoperatively. Vein ligation did not quantitatively affect fascial thickening or fibrosing panniculitis in hindlimbs injected with lipase 6 weeks prior to sacrifice. The results contradict the proposition that lipase-induced injury of rats' subcutaneous tissues compromised by venous stasis may lead to a persistent chronic inflammation and fibrosis of the subcutaneous-fascial complex duplicating lipodermatosclerosis in man.

IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis.

BACKGROUND/AIM: Insulin-like growth factor-1 (IGF-1) and other growth factors overexpression was reported in acute pancreatitis. Previous studies have shown the protective effect of epidermal growth factor (EGF), Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor (FGF) in the course of experimental acute pancreatitis. The aim of our studies was to determine the effect of IGF-1 administration on the development of caerulein-induced pancreatitis. METHODS: Acute pancreatitis was induced by infusion of caerulein (10 micro/kg/h) for 5 h. IGF-1 was administrated twice at the doses: 2, 10, 50, or 100 micro/kg s.c. RESULTS: Administration of IGF-1 without induction of pancreatitis increased plasma interleukin-10 (IL-10). Infusion of caerulein led to development of acute edematous pancreatitis. Histological examination showed pancreatic edema, leukocyte infiltration and vacuolization of acinar cells. Also, acute pancreatitis led to an increase in plasma lipase and interleukin 1beta (IL-1beta) level, whereas pancreatic DNA synthesis and pancreatic blood flow were decreased. Treatment with IGF-1, during induction of pancreatitis, increased plasma IL-10 and attenuated the pancreatic damage, what was manifested by histological improvement of pancreatic integrity, the partial reversion of the drop in pancreatic DNA synthesis and pancreatic blood flow, and the reduction in pancreatitis-evoked increase in plasma amylase, lipase and IL-1beta level. Protective effect of IGF-1 administration was dose-dependent. Similar strong protective effect was observed after IGF-1 at the dose 2 x 50 and 2 x 100 microg/kg. CONCLUSIONS: (1) Administration of IGF-1 attenuates pancreatic damage in caerulein-induced pancreatitis; (2) This effect is related, at least in part, to the increase in IL-10 production, the reduction in liberation of IL-1beta and the improvement of pancreatic blood flow.

Fibrosing colonopathy in children with cystic fibrosis.

PURPOSE: Fibrosing colonopathy is a newly described entity seen in children with cystic fibrosis. The radiological hallmarks are foreshortening of the right colon with varying degrees of stricture formation. High-dose enzyme therapy has been implicated as the cause of this process. The purpose of this study is to review the author's experience with evaluation and treatment of these patients. METHODS: There are currently 380 patients being treated at our CF center. Fifty-five of these patients have been treated with high-dose enzyme therapy (> 5,000 units of lipase/kg). The medical records of these patients, who are at risk for developing fibrosing colonopathy, were reviewed for the presence of recurrent abdominal complaints, and the work-up and treatment of these symptoms. RESULTS: Chronic complaints of abdominal pain, distension, change in bowel habits, or failure to thrive were present in 24 of the 55 patients treated with high-dose enzymes. So far, 18 of these 24 patients have been evaluated by contrast enema. Thirteen of eighteen have been found to have fibrosing colonopathy characterized by foreshortening and strictures of the colon. Additional findings included focal strictures of the right colon (7 of 13), long segment strictures (5 of 13), and total colonic involvement (1 of 13). Nine patients with the most severe symptoms have undergone colon resection, including five segmental right colectomies, three extended colectomies (ileo-sigmoid anastomosis), and one subtotal colectomy with end-ileostomy. Pathological evaluation has shown submucosal fibrosis, destruction of the muscularis mucosa, and eosinophilia. No postoperative complications or deaths occurred. All nine postoperative patients have noted marked symptomatic improvement. Contrast enema follow-up results are available for six patients, and have documented no recurrent strictures to date. Three of four nonoperative patients have less severe symptoms and are currently being treated conservatively. The other family has refused surgery and the patient is being treated symptomatically. CONCLUSION: High-dose lipase replacement has been implicated as the etiology for FC and was present in all of our patients. Our cystic fibrosis center now routinely limits lipase to 2,500 U/kg per dose. We recommend the use of the contrast enemas to evaluate at-risk patients who have chronic abdominal complaints or who present with recurrent bowel obstruction. Colon resection should be performed in those with clinically and radiographically significant strictures with the expectation of a good outcome.

[Occupational respiratory risks in workers exposed to enzymes in detergents]. / Risque professionnel respiratoire chez les ouvriers exposés aux enzymes des détergents.

The addition of encapsulated enzymes (proteases and lipases) to detergents in Morocco dates from 1993. We have carried out a retrospective survey which has enabled us to evaluate the prevalence of the clinical symptoms and respiratory function problems in two groups, one exposed and the other non-exposed. This enquiry which concerns 32 exposed workers and 42 non-exposed consisted of a questionnaire (CECA OMS), a chest x-ray and some respiratory function tests. The medical study involves a question in the workplace with an evaluation of dust levels (weight of dust and enzyme activity). Fifty seven per cent of those exposed had clinical respiratory symptomatology against only 7 per cent of those who were not exposed. Rhinitis, asthma, cough, chronic bronchitis, eczema and conjunctivitis were significantly more frequent in those exposed than in the non-exposed. Respiratory function was altered in 65.5 per cent of the exposed against only 38.6 per cent of those who were not exposed. The overall lung function was of an obstructive type. The peak flow (VEMS) were more frequently reduced in those exposed (25 per cent) than in the non-exposed (7.14 per cent). These anomalies were worst at the end of a day's work. Atopy seems to be a potentiating factor. Tobacco interferes significantly in the alteration of respiratory function parameters. The enquiry in the work place revealed evidence of insufficient means of protection for the work force and elevated levels of dust which pass the mean recommended atmospheric values (500 mcg per cubic mm). On the other hand, enzymatic activity of the dust collected remained within normal limits (< 0.5 GU/m3). It is thus imperative to develop means for collective prevention (a more effective encapsulation of the enzymes, work in closed areas, ventilation with more effective dust extraction) and individuals (protective clothing and specific respiratory masks for the enzymes) to maximally reduce the risk.

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.

Self injection of lipase--an extreme case for regulation in non-surgical cosmetic procedures.

Mesotherapy or subcutaneous fat dissolution for cosmetic purposes has been described using phosphatidylcholine. A literature search found no reports of the use of lipase for mesotherapy. Substances for cosmetic mesotherapy are not licensed for use in the United Kingdom. We report a case of self injection using lipase obtained from the internet.

Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients.

OBJECTIVES: Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. METHODS: We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. RESULTS: There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% +/- 24.9% and 17.8% +/- 13.6%, respectively, whereas the mean stool weight decreased by 517 +/- 362 g. CONCLUSIONS: TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.