In vitro Comparison of Pancreatic Enzyme Preparations Available in the Indian Market.

PURPOSE: Pancreatic enzyme replacement therapy (PERT) involves exogenous enzyme supplementation and is used in the treatment of pancreatic exocrine insufficiency. Clinical efficacy of PERT preparations is a function of physical properties and release kinetics that vary between commercially available products. In this study, we evaluated the physical properties, in vitro dissolution, and release kinetics of commercially available pancreatic enzyme preparations available in the Indian market. METHODS: Physical properties such as particle size distribution and water content of the capsules were measured by dynamic light scattering and Karl-Fischer titration method, respectively. An analytical procedure based on the European pharmacopoeia (EP) method was used to determine lipase activity, and a modified United States pharmacopoeia (USP)-based method was used for dissolution studies. Enzyme release was ascertained under gastroduodenal conditions in buffered media. RESULTS: Considerable variations in physical properties such as particle size and water content were observed between pancreatic enzyme preparations. Some preparations failed to meet the labeled lipase content as per USP standards (>90% label claim) and showed inconsistent release behavior (>5% relative standard deviation). CONCLUSION: Differences exist between pancreatic enzyme preparations in terms of physical properties, dissolution, and release behavior that can affect their clinical efficacy. The present study suggests, therefore, that these preparations should not be used interchangeably.

Does rifaximin offer any promise in Crohn's disease in remission and concurrent irritable bowel syndrome-like symptoms?

ABSTRACT: Microbiota plays an important role in many diseases including inflammatory bowel diseases. Inflammatory bowel disease patients can have concurrent irritable bowel syndrome symptoms similar to those associated with a flare. The potential role of gut dysbiosis in the pathogenesis of inflammatory bowel disease provides a rationale for treating such patients with rifaximin. This study aimed to assess the efficacy of rifaximin in the management of irritable bowel syndrome-like symptoms (bloating, abdominal pain, stool consistency) and quality of life in patients with Crohn's disease in remission.The present study included 86 patients with Crohn's disease in remission (fecal calprotectin <50 µg/g, C-reactive protein <0.5 mg/dL, simple endoscopic score for Crohn's disease <2) and associated irritable bowel syndrome-like symptoms (bloating, abdominal pain, diarrhea). These patients were randomly assigned to rifaximin treatment group (44 patients) and the control group (42 patients). Besides the baseline inflammatory bowel disease treatment and antispasmodics (as needed), patients in the rifaximin treatment group received 3 repeated courses of treatment, each course being represented by 1200 mg/d of rifaximin for 10 days and 20 days free of treatment (3 months consecutively); patients in the control group also received antispamodics as needed and were observed for 3 months.Monthly analyses of bloating score, abdominal pain score, stool consistency score, and quality of life score showed significant improvement after treatment in the rifaximin group in contrast with control group. Significantly more patients in the rifaximin group than in the control group met the criteria for adequate improvement of bloating score after 3 months of treatment (59.09% vs 19.04%, P = .01), adequate improvement of abdominal pain score (54.5% vs 21.4%, P = .04), stool consistency score (34.09% vs 14.2%, P = .03), and quality of life score (70.4% vs 21.4%, P < .001).Rifaximin in a dose of 1200 mg/d, 10 d/mo, 3 months consecutively is an effective medication for concurrent irritable bowel syndrome-like symptoms in patients with Crohn's disease in remission.

Anoperineal lesions in Crohn's disease: French recommendations for clinical practice.

BACKGROUND: Anoperineal lesion (APL) occurrence is a significant event in the evolution of Crohn's disease (CD). Management should involve a multidisciplinary approach combining the knowledge of the gastroenterologist, the colorectal surgeon and the radiologist who have appropriate experience in this area. Given the low level of evidence of available medical and surgical strategies, the aim of this work was to establish a French expert consensus on management of anal Crohn's disease. These recommendations were led under the aegis of the Société Nationale Française de Colo-Proctologie (SNFCP). They report a consensus on the management of perianal Crohn's disease lesions, including fistulas, ulceration and anorectal stenosis and propose an appropriate treatment strategy, as well as sphincter-preserving and multidisciplinary management. METHODOLOGY: A panel of French gastroenterologists and colorectal surgeons with expertise in inflammatory bowel diseases reviewed the literature in order to provide practical management pathways for perianal CD. Analysis of the literature was made according to the recommendations of the Haute Autorité de Santé (HAS) to establish a level of proof for each publication and then to propose a rank of recommendation. When lack of factual data precluded ranking according to the HAS, proposals based on expert opinion were written. Therefore, once all the authors agreed on a consensual statement, it was then submitted to all the members of the SNFCP. As initial literature review stopped in December 2014, more recent European or international guidelines have been published since and were included in the analysis. RESULTS: MRI is recommended for complex secondary lesions, particularly after failure of previous medical and/or surgical treatments. For severe anal ulceration in Crohn's disease, maximal medical treatment with anti-TNF agent is recommended. After prolonged drainage of simple anal fistula by a flexible elastic loop or loosely tied seton, and after obtaining luminal and perineal remission by immunosuppressive therapy and/or anti-TNF agents, the surgical treatment options to be discussed are simple seton removal or injection of the fistula tract with biological glue. After prolonged loose-seton drainage of the complex anal fistula in Crohn's disease, and after obtaining luminal and perineal remission with anti-TNF ± immunosuppressive therapy, surgical treatment options are simple removal of seton and rectal advancement flap. Colostomy is indicated as a last option for severe APL, possibly associated with a proctectomy if there is refractory rectal involvement after failure of other medical and surgical treatments. The evaluation of anorectal stenosis of Crohn's disease (ARSCD) requires a physical examination, sometimes under anesthesia, plus endoscopy with biopsies and MRI to describe the stenosis itself, to identify associated inflammatory, infectious or dysplastic lesions, and to search for injury or fibrosis of the sphincter. Therapeutic strategy for ARSCD requires medical-surgical cooperation.

Biosimilar monoclonal antibodies: preclinical and clinical development aspects.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

QbD-enabled systematic development of gastroretentive multiple-unit microballoons of itopride hydrochloride.

The objectives of present studies were to develop the systematically optimized multiple-unit gastroretentive microballoons, i.e. hollow microspheres of itopride hydrochloride (ITH) employing quality by design (QbD)-based approach. Initially, the patient-centric QTPP and CQAs were earmarked, and preliminary studies were conducted to screen the suitable polymer, solvent, solvent ratio, pH and temperature conditions. Microspheres were prepared by non-aqueous solvent evaporation method employing Eudragit S-100. Risk assessment studies carried out by constructing Ishikawa cause-effect fish-bone diagram, and techniques like risk estimation matrix (REM) and failure mode effect analysis (FMEA) facilitated the selection of plausible factors affecting the drug product CQAs, i.e. percent yield, entrapment efficiency (EE) and percent buoyancy. A 3(3) Box-Behnken design (BBD) was employed for optimizing CMAs and CPPs selected during factor screening studies employing Taguchi design, i.e. drug-polymer ratio (X1), stirring temperature (X2) and stirring speed (X3). The hollow microspheres, as per BBD, were evaluated for EE, particle size and drug release characteristics. The optimum formulation was embarked upon using numerical desirability function yielding excellent floatation characteristics along with adequate drug release control. Drug-excipient compatibility studies employing FT-IR, DSC and powder XRD revealed absence of significant interaction among the formulation excipients. The SEM studies on the optimized formulation showed hollow and spherical nature of the prepared microspheres. In vivo X-ray imaging studies in rabbits confirmed the buoyant nature of the hollow microspheres for 8 h in the upper GI tract. In a nutshell, the current investigations report the successful development of gastroretentive floating microspheres for once-a-day administration of ITH.

Evaluation of Coptidis Rhizoma-Euodiae Fructus couple and Zuojin products based on HPLC fingerprint chromatogram and simultaneous determination of main bioactive constituents.

CONTEXT: Coptidis Rhizoma-Euodiae Fructus couple (CEC) is a classic traditional Chinese medicine preparation consisting of Coptidis Rhizoma and Euodiae Fructus at the ratio of 6:1, and used to treat gastro-intestinal disorders. Alkaloids are the main bioactive component. This research provides comprehensive analysis information for the quality control of CEC. OBJECTIVE: To develop a high-performance liquid chromatography-diode array detection fingerprint for chemical composition characteristics of CEC and its products. MATERIALS AND METHODS: The samples were separated with a Gemini C18 column by using gradient elution with water-formic acid (100:0.03) and acetonitrile as mobile phase. Flow rate was 1.0 mL/min and detection wavelength was 250 nm. Similarity analysis and principal component analysis (PCA) were employed to evaluate quality consistencies of analytes. Mean chromatograms and correlation coefficients of analytes were calculated by the software "Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine". RESULTS: Fingerprint chromatogram comparison determined 20 representative general fingerprint peaks, and the fingerprint chromatogram resemblances are all better than 0.988. Consistent results were obtained to show that CEC and its related samples could be successfully divided into three groups. Contribution plots generated by PCA were performed to interpret differences among the sample groups while peaks which significantly contributed to classification were identified. Seven bioactive constituents in the samples were verified by quantitative analysis. DISCUSSION AND CONCLUSION: The chromatographic fingerprint with similarity evaluation and PCA assay combined with quantification of seven compounds could be utilized as a quality control method for the herbal couple.

Stability-indicating methods for the determination of mosapride citrate in the presence of its degradation products according to ICH guidelines.

In the present work, different spectrophotometric methods and one spectrofluorimetric method have been developed and validated for the determination of mosapride citrate in the presence of its acid-induced degradation products. The drug was subjected to stress stability study including acid, alkali, oxidative, photolytic, and thermal stress degradation. The developed spectrophotometric methods included the use of first order derivative ((1)D), derivative of ratio spectra ((1)DD), mean centring of ratio spectra (MC) and H-point standard additions (HPSAM) spectrophotometric methods. For (1)D method, the peaks amplitudes at 282.8 and 319.6 nm were measured, while for (1)DD method those at 308 nm and 323 nm were measured. Mean centring of ratio spectra method used the values at 317 nm for calibration, while for HPSAM the absorbance at 273 and 288.6 nm were used. These methods were successfully applied for determination of mosapride in the concentration range of 5-70 µg.ml(-1). The spectrofluorimetric method was based on measuring the native fluorescence of mosapride in 0.1 M NaOH using λ(excitation) 276 nm and λ(emission) 344 nm and 684 nm with linearity ranges of 50-3000 ng.ml(-1) and 50-9000 ng.ml(-1), respectively. All the developed methods were validated according to the International Conference on Harmonization (ICH) guidelines and were applied for bulk powder and dosage form. The results obtained were statistically compared to each other using one-way ANOVA testing.

Accuracy of drug advertisements in medical journals under new law regulating the marketing of pharmaceutical products in Switzerland.

BACKGROUND: New legal regulations for the marketing of pharmaceutical products were introduced in 2002 in Switzerland. We investigated whether claims in drug advertisements citing published scientific studies were justified by these studies after the introduction of these new regulations. METHODS: In this cross-sectional study, two independent reviewers screened all issues of six major Swiss medical journals published in the year 2005 to identify all drug advertisements for analgesic, gastrointestinal and psychopharmacologic drugs and evaluated all drug advertisements referring to at least one publication. The pharmaceutical claim was rated as being supported, being based on a potentially biased study or not to be supported by the cited study according to pre-specified criteria. We also explored factors likely to be associated with supported advertisement claims. RESULTS: Of 2068 advertisements 577 (28%) promoted analgesic, psychopharmacologic or gastrointestinal drugs. Among them were 323 (56%) advertisements citing at least one reference. After excluding multiple publications of the same drug advertisement and advertisements with non-informative references, there remained 29 unique advertisements with at least one reference to a scientific study. These 29 advertisements contained 78 distinct pairs of claims of analgesic, gastrointestinal and psychopharmacologic drugs and referenced studies. Thirty-seven (47%) claims were supported, 16 (21%) claims were not supported by the corresponding reference, and 25 (32%) claims were based on potentially biased evidence, with no relevant differences between drug groups. Studies with conflict of interest and studies stating industry funding were more likely to support the corresponding claim (RR 1.52, 95% CI 1.07-2.17 and RR 1.50, 95% CI 0.98-2.28) than studies without identified conflict of interest and studies without information on type of funding. CONCLUSION: Following the introduction of new regulations for drug advertisement in Switzerland, 53% of all assessed pharmaceutical claims published in major medical journals are not supported by the cited referenced studies or based on potentially biased study information. In light of the discrepancy between the new legislation and the endorsement of these regulations, physicians should not trust drug advertisement claims even when they seem to refer to scientific studies.

Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs.

This perspective is the second in a series discussing drugs dropped from development in 2006, with a focus on pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. A survey of discontinued drugs from 2006 is provided, based on data from the Pharmaprojects database, along with an analysis of biology, mechanisms of action and economic considerations in developing new drugs.

Clinical practice and evidence in endoscopic treatment of bleeding peptic gastroduodenal ulcer.

OBJECTIVE: To investigate treatment practice in non-variceal upper gastrointestinal bleeding (NVUGIB) caused by gastroduodenal ulcer and how it adheres to the best evidence as documented in randomized studies and meta-analyses. MATERIAL AND METHODS: The literature was surveyed to identify appropriate practices, and a structured multiple choice questionnaire developed and mailed to all departments in Denmark treating UGIB. RESULTS: All 42 departments responded. All had therapeutic gastroscopes and equipment necessary for endoscopic haemostasis; 90% of departments had written guidelines. Adjuvant pharmacologic treatment included tranexamic acid in 38%. Proton-pump inhibitors (PPIs) were used by all departments, with 29% starting prior to endoscopic treatment. Eight departments (19%) used continuous PPI infusion, three of them starting with a bolus dose. In 50% of departments an anaesthesiologist was always present regardless of whether endotracheal intubation (routinely used by 10%) was used or not. Ten percent did not treat Forrest IIa and IIb ulcers, while IIc ulcers were treated by 36%. In 10% of departments clots were never removed, while in 2/3 attempts were made to remove resistant clots by mechanic means. Seven departments (17%) used monotherapy with epinephrine, while 59% always used dual therapy; 19% injected less than 10 ml. In rebleeding, 92% attempted endoscopic treatment before surgery, and used epinephrine in 79% of cases, while the remainder used epinephrine or polidocanol at the discretion of the endoscopist. Two out of three departments used high-dependency or intensive-care units for surveillance. Seventeen percent applied scheduled second-look gastroscopy. CONCLUSIONS: Practice is variable, even in areas with established evidence based on randomized controlled studies, such as dosage and way of administration and duration of PPI treatment, injection treatment used as monotherapy and the volume used, including ulcers with clots for treatment, and the use of scheduled second-look endoscopy. Since the rebleeding rate has remained unchanged for decades, and rebleeding implies increased surgery and mortality rates, appropriate practices must be promoted in order to improve results. Development and implementation of national guidelines may facilitate the process.

Comparison of inulin and lactulose as reference standards in the breath hydrogen test assessment of carbohydrate malabsorption in patients with chronic pancreatic exocrine insufficiency.

Although often used as a reference standard in the breath hydrogen test (BHT), lactulose fermentation produces more hydrogen, compared to starch, and may therefore not be ideal. This study compares inulin with lactulose as reference standard in the study of carbohydrate malabsorption. Seventeen patients with malabsorption due to chronic pancreatitis and 15 normal controls were studied. Following overnight fasts, BHTs were performed after ingesting 10 g lactulose, 10 g inulin, and 200 g (16 g highly resistant starch) maize meal. Lactulose fermentation produced significantly more hydrogen than inulin in patients with malabsorption (97 +/- 20 vs 45 +/- 22 ppm x hr; P < 0.05) and controls (43 +/- 18 vs 21 +/- 10 ppm x hr; P < 0.05). Patients produced more hydrogen than controls with both standards (lactulose, 97 +/- 20 vs 43 +/- 18 ppm x hr, P < 0.05; inulin 45 +/- 22 vs 21 +/- 10 ppm x hrs; P < 0.05), suggesting adaptation of the colonic flora. Calculated CHO malabsorption was 2.5 +/- 0.8 vs 5.2 +/- 3.8 g with lactulose and 5.2 +/- 3.1 vs 11.2 +/- 9.6 g with inulin as standards in controls and patients, respectively (P < 0.05). Lactulose produces more breath hydrogen than inulin. Calculation of CHO malabsorption using these standards is therefore not comparable.

[New preparation method for barium enema: efficacy and administration of oral intestinal lavage solution with gastrointestinal prokinetic agent].

The modified Brown's method is commonly used in Japan as preparation for barium enema; however, in a few cases, its cleansing effect is not satisfactory even with the use of adequate diet. To develop a new method of preparation for barium enema, we examined the use of an oral intestinal lavage solution (PEG-ELS) with mosapride and compared it with the modified Brown's method. We administered mosapride and PEG-ELS by four different methods. These methods were assessed by the amount of remaining feces and the adequacy of barium coating. Methods in which mosapride was taken separately before and after the intake of PEG-ELS were more effective than the method using mosapride and the modified Brown's method. Lesion detection was almost the same as that with the modified Brown's method. In conclusion, preparation for barium enema using mosapride before and after PEG-ELS intake is more effective than the modified Brown's method.

Lipase supplementation therapy: standards, alternatives, and perspectives.

Treatment of steatorrhea by lipase supplementation therapy has become more successful in the last decade due to better understanding of the physiology and pathophysiology of the digestive process. Porcine lipase has been the therapeutic standard for several decades and will continue to be the treatment of choice in pancreatic exocrine insufficiency. Modern therapeutic concepts recommend administration of 25,000-40,000 units of porcine lipase per meal using pH-sensitive pancreatin microspheres. In case of treatment failure, the dose should be increased, compliance should be checked, and other reasons for malabsorption should be excluded. Still, in most patients, lipid digestion cannot be completely normalized by current standard therapy, and future developments are needed for optimizing treatment. In this article, pathophysiologic characteristics of pancreatic exocrine insufficiency, prerequisites for use of alternative lipase sources as well as currently available lipases of nonporcine origin, and new developments are discussed. Current literature suggests that bovine lipase products present a theoretical alternative but play no major role in the western world. Fungal lipase has inferior properties compared with conventional products. Bacterial lipase products show promising potential and offer future therapeutic alternatives. Moreover, human pancreatic lipase gene transfer and application of bioengineered human gastric lipase appear on the horizon.