**8. References**

286 New Advances in the Basic and Clinical Gastroenterology

liprotamase demonstrated that they maintained their nutritional status; and survival in people living with cystic fibrosis was maintained too (Borowitz & al., 2011). Subsequent to the completion of the stage III clinical study on liprotamase, the drug's manufacturer submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for approval. However, on January 13th of this year, the FDA panel stated that he was not convinced that Liprotamase was any better than the current pancreatic enzyme products available now. The manufacturer disclosed that another clinical trial must be conducted before the FDA will consider the approval of this drug (Eli Lilly, IN, USA, www. Lilly.com). In yet other approaches, plant acid-stable lipases were suggested as good alternatives to porcine preparations. Hence, considerable attention has focused in these enzymes and suitable techniques for isolating and purifying them have been well documented. A lipase sourced from *Carica papaya* latex has been recently proposed as suitable candidate for use as a therapeutic tool in patients with pancreatic exocrine insufficiency (Abdelkafi et al., 2009). The enzyme showed several biochemical properties enabling it to act in the gastro-intestinal tract like mammalian digestive lipases (Abdelkafi et al., 2009): (i) its activity on long-chain Triacylglycerols reaches an optimum at pH 6.0 in the presence of bile, (ii) it is only weakly inhibited by bile salts, (iii) it shows a similar pattern of regioselectivity to that of human pancreatic lipase, generating 2-Mono acylglycerol and free fatty acids (FFA), the lipolysis products absorbed at the intestinal level, and (iv) it shows significant levels of stability and activity at low pH values at a temperature of 37 °C. Therefore, *Carica papaya* lipase seems to be tailored to act optimally under the physiological conditions pertaining in the gastro-

intestinal tract. However, its sensitivity to digestive proteases still needs to be tested.

Development of non-porcine enzyme replacement therapies is currently extended to new research areas including design, by direct molecular evolution, of human pancreatic lipase variants that display lipolytic activity at acidic pH higher than that of the native enzyme. Colin et al. (2008) investigated, first, the feasibility of altering the pH optimum of pancreatic lipase to improve its performances in the intestinal conditions of cystic fibrosis by sitedirected mutagenesis. Later, they demonstrated that directed molecular evolution approach combined to a sensitive screening strategy could be useful to improve pancreatic lipase activity at acidic pH. The authors showed that a single round of random mutagenesis was successful in identifying lipase variant with approximately 1.5-fold increased activity at low

Future therapies may also include structuring food emulsions and creation of functional dietary lipids that are more effectively digested. This new area of research could substantially help patient suffering from pancreatic insufficiency with the design of specific more digestible or absorbable lipid sources. Hence, the addition of specific phospholipids able to enhance lipase activity in enzyme supplements or in formula would both increase

Pancreatic exocrine insufficiency is a condition commonly associated with diseases such as pancreatitis or cystic fibrosis. When pancreatic insufficiency is severe, impaired absorption

lipase activity and, in parallel, enhance lipid nutrient absorption (Fieker et al., 2011).

**6.4 Future therapies and new research areas** 

pH (Colin et al., 2010).

**7. Conclusion** 


Emerging Approaches for the Treatment of

pp. 673 – 681.

pp. 597–560.

pp. 411-419.

335.

*Gastroenterology*, Vol.105, pp. 876–888.

*Gastroenterology.* Vol. 28, pp. 443–454.

*Pancreatology*. Vol.1, No. 4, pp.320–335.

*Gastroenterology & Hepatology.*Vol. 3, No 1, pp. 28–38.

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 289

Carrière, F.; Barrowman, J.A. ; Verger, R. & Laugier, R. (1993a). Secretion and contribution to

Carriere, F.; Laugier, R.; Barrowman, J.A.; Douchet, I.; Priymenko, N. & Verger, R. (1993b)

Carrière, F.; Grandval, P.; Renou, C. ; Palomba, A. ; Priéri, F. ; Giallo, J. ; Henniges, F. ;

Camp, L.; Reina, M.; Llobera, M.; Vilaro, S. & Olivecrona, T. (1990). Lipoprotein lipase:

Chauhan, S. & Forsmark, C.E. (2010). Pain management in chronic pancreatitis: A treatment

Chey, W.Y. & Chang, T. (2001). Neural hormonal regulation of exocrine pancreatic secretion.

Choi, S.Y.; Hirata, K.; Ishida, T.; Quertermous, T. & Cooper, A.D. (2002). Endothelial lipase: a new lipase on the block. *Journal of Lipid Research*. Vol. 43, pp. 1763–1769. Czakó, L.; Takács, T.; Hegyi, P., Prónai, L.; Tulassay, Z.; Lakner, L.; Döbrönte, Z.; Boda, K. &

Crenon, I.; Foglizzo, E.; Kerfelec, B.; Vérine, A.; Pignol, D.; Hermoso, J.; Bonicel, J. & Chapus

Cohen, J.C. (2003). Endothelial lipase: direct evidence for a role in HDL metabolism. *Journal* 

Colin,D.Y. ; Deprez-Beauclair,P. ; Allouche,M. ; Brasseur,R. & Kerfelec,B. (2008). Exploring

Colin,D.Y. ; Deprez-Beauclair,P.; Silva, N.; Infantes, L. & Kerfelec, B. (2010). Modification of

De Caro, A.; Figarella, C.; Amic, J.; Michel, R. & Guy, O. (1977). Human pancreatic lipase: A

DeNigris, S.J.; Hamosh, M.; Kasbekar, D.K.; Fink, C.S.; Lee, T.C. & Hamosh, P. (1985).

*Biophysica Acta (BBA) -Lipids and Lipid Metabolism.* Vol. 836, No 1, pp. 67-72. DiMagno, EP. (1993). A short eclectic history of exocrine pancreatic insufficiency and chronic pancreatitis. *Gastroenterology*, Vol. 104, No. 5, pp. 1255 - 1262.

enzyme. *Protein Engineering*. Vol. 11, No. 2, pp.135–142.

*of Clinical Investigation.* Vol. 111, pp. 318–321

*Communication*, Vol. 370, No. 3, pp. 394–398.

*Design & Selection*, Vol. 23, No. 5, pp. 365–373.

lipolysis of gastric and pancreatic lipases during a test meal in humans,

Gastric and pancreatic lipase levels during a test meal in dogs. *Scandinave Journal of* 

Sander-Struckmeier, S. & Laugier, R. (2005). Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis. *Clinical* 

cellular origin and functional distribution, *American Journal of Physiology.* Vol. 258,

algorithm. *Best Practice Research in Clinical Gastroenterology*. Vol. 24, No. 3, pp. 323–

Lonovics, J. (2003). Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. *Canadian Journal of Gastroenterology*, Vol. 17, No. 10,

C. (1998). Pancreatic lipase-related protein type I: a specialized lipase or an inactive

the active site cavity of human pancreatic lipase. *Biochemical and Biophysical Research* 

pancreatic lipase properties by directed molecular evolution. *Protein Engineering*,

glycoprotein. *Biochimica and Biophysica Acta (BBA)-Protein Structure,* Vol. 490, No 2,

Secretion of human gastric lipase from dispersed gastric glands. *Biochimica &* 

gastric function and fat digestion in the premature infant. *Pediatric Research*. Vol. 40, No. 3, pp.429–437.


Armand, M. ; Pasquier, B.; Andre, M.; Borel, P. ; Senft, M.; Peyrot, J.; Salducci, J. ; Portugal,

Bang Jørgensen, B.; Thorsgaard Pedersen, N. & Worning, H. (1991). Short report: lipid and

Ben-Zeev, O.; Stahnke, G.; Liu, R.; Davis, C. & Doolittle, M. H. (1994). Lipoprotein lipase and

Berton, A.; Sebban-Kreuzer, C.; Rouvellac, S.; Lopez, C. & Crenon, I. (2009) Individual and

Breithaupt, D. E.; Alpmann, A. & Carrière, F. (2007). Xanthophyll esters are hydrolysed in

Bodmer, M.W.; Angal, S.; Yarranton, G.T.; Harris, T.J.R.; Lyons, A.; King, D.J.; Pieroni, G.;

Borgstrom, B. (1964). Influence of bile salt, pH, and time on the action of pancreatic lipase.

Borowitz, D.; Stevens, C.; Brettman, L.R.; Campion, M.; Chatfield, B. & Cipolli, M. & for the

Brady, M.S.; Garson, J.L.; Krug, S.K.; Kaul, A.; Rickard, K.A.; Caffrey, H.H.; Fineberg, N.,

study. *Journal of American Dietetic Association.* Vol. 106, No. 8, pp. 1181-1186. Braun, J.E. & Severson, D.L. (1992). Regulation of the synthesis, processing and translocation of lipoprotein lipase. *Biochemistry Journal*. Vol. 287, No 2, pp. 337–347. Brockman, H.L. (2000). Kinetic behaviour of the pancreatic lipase– colipase–lipid system.

Brown, A.; Hughes, M.; Tenner, S. & Banks, P.A. (1997). Does pancreatic enzyme

Case, C.L.; Henniges, F. & Barkin, J.S. (2005). Enzyme content and acid stability of entericcoated pancreatic enzyme products in vitro. *Pancreas*, Vol. 30, No. 2, pp.180–183.

*American Journal of Gastroenterology*, Vol.92, pp. 2032–2035.

functional enzyme. *Journal of Lipid Research*. Vol. 35, pp. 1511–1523.

*Clinical Nutrition*. Vol. 70, No. 6, pp.1096–1106.

*Therapeutics*, Vol*.* 5, No. 2, pp. 207-210.

*Research.* Vol.53, No.12. pp.1592–1602.

*Journal of Lipid Research.* Vol. 5, pp.522–531.

*Fibrosis,* In press doi:10.1016/j.jcf.2011.07.001 |

*Biochimie*, Vol. 82, pp. 987–995.

Bai, J. (1998).Malabsorption syndromes. *Digestion*, Vol. 59, No.5, pp 530–546.

No. 3, pp.429–437.

237–244.

gastric function and fat digestion in the premature infant. *Pediatric Research*. Vol. 40,

H. ; Jaussan, V. & Lauron, D. (1999). Digestion and absorption of 2 fat emulsions with different droplet sizes in the human digestive tract. *The American Journal of* 

vitamin B12 malassimilation in pancreatic insufficiency. *Alimentary Pharmacology &* 

hepatic lipase: the role of asparagine linked glycosylation in the expression of a

combined action of pancreatic lipase and pancreatic lipase-related proteins 1 and 2 on native versus homogenized milk fat globules. *Molecular Nutrition & Food* 

the presence of recombinant human pancreatic lipase. *Food Chemistry*, 103, 651–656.

Riviere, C.; Verger R. & Lowe P.A. (1987).Molecular cloning of human gastric lipase and expression of the enzyme in yeast, *Biochimica and Biophysica Acta*, Vol. 909, pp.

Liprotamase 726 Study Group (2011).. International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients. *Journal of Cystic* 

Balistreri, W.F.; Stevens, J.C. (2006). An enteric-coated high-buffered pancrelipase reduces steatorrhea in patients with cystic fibrosis: a prospective, randomized

supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis.


Emerging Approaches for the Treatment of

No. 1, pp. 89-103.

pp. 1012-1015

4, pp. 759-761.

274, pp.14170 -14175.

*Investigation,* Vol.30, No. 6, pp. 351- 364.

*Symposium,* Vol. 16-18, No. 70, pp. 69-98.

*Research.* Vol. 43, No. 12, pp.2017-2030.

*Acta.* Vol.1594, No. 4, pp. 255–265.

pancreatic insufficiency. *Gut,* Vol. 34, pp. 708–712.

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 291

Graff, G.R.; McNamara, J.; Royall, J.; Caras, S.; Forssmann, K. (2010b). Safety and tolerability

Griffin, S. M.; Alderson, D.; Farndon, J.R. (1989). Acid resistant lipase as replacement

Guarner, L. ; Rodriguez, R. ; Guarner, F. ; Malagelada, J. R. (1993). Fate of oral enzymes in

Gullo, L.; Tassoni, U.; Mazzoni, G. ; Stefanini F. (1996). Increased prevalence of aortic

Halm, U.; Löser, C.; Löhr, M.; Katschinski, M. & Mössner, J. (1999). A double-blind,

Hamosh, M. & Scow, R.O. (1973). Lingual lipase and its role in the digestion of dietary lipid.

Hirata, K.-I.; Dichek, H.L.; Cioffi, J.A.; Choi, S.Y.; Leeper, N.J.; Quintana, L.; Kronmal, G.S.;

Hui, D.Y. & Howles, P.N. (2002). Carboxyl ester lipase: structure-function relationship and

Iliano, L.O. & Lodewijk, J.S. (1990). A composition for the treatment of exocrine insufficiency of the pancreas, and the use of said composition. European Pat. ES 2059986 (T3). Isaksson, G.; Ihse, I. (1983). Pain reduction by an oral pancreatic enzyme preparation in

Jaye, M.; Lynch, K.J.; Krawiec, J.; Marchadier, D.; Maugeais, C.; Doan, K.; South, V.; Amin,

Jayne, S.; Kerfelec, B.; Foglizzo, E.; Chapus, C. & Crenon, I. (2002). High expression in adult

Kalnins, D., Ellis, L.; Corey, M.; Pencharz, P.B., Stewart, C., Tullis, E., Durie, P.R. (2006).

chronic pancreatitis. *Digestive Disease Science*, Vol. 28, pp. 97–102.

modulates HDL metabolism. *Nature Genetics*. Vol. 21, pp. 424–428.

Cooper, A.D. & Quertermous, T. (1999). Cloning of a unique lipase from endothelial cells extends the lipase gene family. *Journal of Biological Chemistry*. Vol.

physiological role in lipoprotein metabolism and artherosclerosis. *Journal of Lipid* 

D.; Perrone, M. & Rader, D.J. (1999). A novel endothelial-derived lipase that

horse of PLRP2 displaying a low phospholipase activity. *Biochimica & Biophysica* 

Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-

*Alimentary Pharmacology and Therapeutics.* Vol. 13, No. 7, pp. 951-957. Hamosh, M. (1979). The role of lingual lipase in neonatal fat digestion. *Ciba Foundation* 

Hamosh, M. (1990). Lingual and gastric lipase. *Nutrition,* Vol. 6, pp. 421–428.

*Journal of Clinical Investigation.* Vol. 52, No. 1, pp. 88–95.

controlled, two-period crossover, superiority study. *Clinical Therapeutics,* Vol. 32,

of a new formulation of pancrelipase delayed-release capsules (CREON) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an open-label, multicentre, single-treatment-arm study. *Clinical Drug* 

therapy in chronic pancreatic exocrine insufficiency: a study in dogs. *Gut,* Vol. 30,

calcification in chronic pancreatitis. *American Journal of Gastroenterology*, Vol. 91, No.

randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency.


DiMagno, E.P.; Go, V.L. & Summerskill, W.H (1973). Relations between pancreatic enzyme

Dominguez-Munoz, J.E., Hieronymus, C., Sauerbruch, T., & Malfertheiner, P. (1995). Fecal

Domínguez-Muñoz, J.E.; Iglesias-García, J.; Iglesias-Rey, M.; Figueiras, A. & Vilariño-Insua,

Dominguez-Munoz, J.E.; Iglesias-Garcia, J.; Vilarino-Insua, M. & Iglesias-Rey M. (2007). 13C-

Dutta, S.K.; Bustin, M.P., Russell, R.M. & Costa, B.S. (1982). Deficiency of fat-soluble

Duttan, S.K.; Anand, K. & Gadacz, T.R. (1986). Bile salt malabsorption in pancreatic

Eli Lilly, IN, USA, Liprotamase Liprotamase Regulatory Review Bus (Liprotamase) is a

Emmerich, J.; Beg, O.U.; Peterson, J.; Previato, L.; Brunzell, J.D.; Brewer, J.r.H.B. &

Ferrone, M., Raimondo, M., Scolapio, J.S.(2007). Pancreatic enzyme pharmacotherapy.

Fickers, P.; Marty, A. & Nicaud, J.M (2011). The lipases from *Yarrowia lipolytica:* Genetics,

applications, *Biotechnology Advances*, doi: 10.1016/j.biotechadv.2011.04.005 Fieker, A.; Philpott, J. & Armand, M. (2011). Enzyme replacement therapy for pancreatic

Galle, M.; Gregory, P.C.; Potthoff, A. & Henniges, F. (2004). Microbial enzyme mixtures

Graff, G.R.; Maguiness, K.; McNamara, J.; Morton, R.; Boyd, D.; Beckmann, K. & Bennett, D.

useful to treat digestive disorders. US Patent 20040057944

*Journal of Gastroenterology,* Vol. 90, No. 10, pp.1834–1837.

*of Medecine,* Vol. 288, pp. 813–815.

Vol. 21, pp. 993-1000.

*Medcine*, Vol. 97, pp. 549–552.

*Chemistry*, Vol. 267, pp. 4161–4165

*Pharmacotherapy*, Vol. 27, No.6, pp. 910-920.

488.

1249.

*Pipeline/14.html.* 

pp. 55-73.

outputs and malabsorption in severe pancreatic insufficiency. *New England Journal* 

elastase test: evaluation of a new noninvasive pancreatic function test. *American* 

M. (2005). Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. *Alimentary Pharmacology and Therapeutics.*

mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. *Clinical Gastroenterology and Hepatology*, Vol. 5, pp. 484–

vitamins in treated patients with pancreatic insufficiency. *Annals of Internal* 

insufficiency secondary to alcoholic pancreatitis. *Gastroenterology*, Vol. 91, pp.1243–

biologic entity that combines three biotechnology-produced enzymes. *http://www.lilly.com/SiteCollectionDocuments/FlashFiles/PipeLine/Clinical Development* 

Santamarina-Fojo, S. (1992). Human lipoprotein lipase. Analysis of catalytic triad by site-directed mutagenesis of Ser-132, Asp-156 and His-241, *Journal of Biological* 

production, regulation, biochemical characterization and biotechnological

insufficiency: present and future. *Clinical and Experimental Gastroenterology*. Vol. 4,

(2010a). Efficacy and tolerability of a new formulation of pancrelipase delayedrelease capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebocontrolled, two-period crossover, superiority study. *Clinical Therapeutics,* Vol. 32, No. 1, pp. 89-103.


Emerging Approaches for the Treatment of

753– 769.

pp. 1315–1325.

48, No. 6, pp. 735-740

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 293

Lowe, M.E , Rosemblum, J.L. & Strauss, A.W. (1989). Cloning and characterization of human pancreatic lipase cDNA. *Journal of Biological Chemistry*. Vol. 264, pp. 20042-20048. Lindquist, S. & Hernell, O. (2010). Lipid digestion and absorption in early life: an update. *Current Opinion of Clinical Nutrition Metabolism Care.* Vol. 13, No. 3, pp. 314-320. Maggio, L.; Bellagamba, M.; Costa, S.; Romagnoli, C.; Rodriguez, M.; Timdahl, K.; Vågerö,

Mead, J.R.; Irvine, S.A. & Ramji, D.P. (2002). Lipoprotein lipase: structure, function,

Meyer, J.H.; Elashoff, J.; Porter-Fink, V., Dressman, J. & Amidon, G.L. (1988). Human

Meyer, J.H. & Lake, R. (1997). Mismatch of duodenal deliveries of dietary fat and pancreatin from enterically coated microspheres. *Pancreas*, Vol. 15, pp. 226–235. Miled, N.; Canaan, S.; Dupuis, L.; Roussel, A.; Rivière, M.; Carrière, A.; Caro, A.; Cambillau,

Moreau, H.; Laugier, R.; Gargouri, Y.; Ferrato, F. & Verger, R. (1988). Human pre-duodenal lipase is entirely of gastric fundic origin. *Gastroenterology,*Vol. 95, pp.1221–1226. Mukherjee, M. (2003).Human digestive and metabolic lipases—a brief review. *Journal of* 

Mizushima, M.; Ochi, K.; Ichimura, M.; Kiura K.; Harada, H. & Koide, N. (2004). Pancreatic

Nouri-Sorkhabi, M.H.; Chapman, B.E.; Kuchel, P.W.; Gruca, M.A. & Gaskin, K.J. (2000).

Nustede, R.; Köhler, H.; Fölsch, U.R. & Schafmayer, A. (1991). Plasma concentrations of

O'Keefe, S.J.; Cariem, A.K. & Levy, M. (2001).The exacerbation of pancreatic endocrine

Pasquali, C.; Fogar, P.; Sperti, C.; Bassob, D.; De Paolib, M.; Plebanib, M. & Pedrazzoli, S.

Perret, B.; Mabile, L.; Martinez, L.; Tercé, F.; Barbaras, R. & Collet, X. (2002). Hepatic lipase:

pancreatitis. *Journal of Clinical Gastroenterology,* Vol. 32, pp. 319–323.

before 32 weeks of gestational age. Abstract EAPS meeting.

physiology. *Biochimie*, Vol. 82, pp. 973−986.

*Molecular Catalysis B: Enzymatic*. Vol. 22, pp. 369–376.

*of Gastroenterology and Hepatology*, Vol. 19, No. 9, pp. 1005–1009.

enzyme substitution. *Pancreas.* Vol. 6, No. 3, pp. 260-265.

*Experimentation*, Vol. 57, No. 5, pp. 358-365.

Vol. 43, No. 8, pp. 1163-1169.

M.; Carnielli, V.P. A prospective, randomized, double-blind crossover study comparing rhBSSL (recombinant human Bile Salt Stimulated Lipase) and placebo added to infant formula during one week of treatment in preterm infants born

regulation, and role in disease. *Journal of Molecular Medecine.* Vol. 80, No. 12, pp.

postprandial gastric emptying of 1-3-millimeter spheres. *Gastroenterology*, Vol. 94,

C. & Verger, R. (2000). Digestive lipases: From three-dimensional structure to

enzyme supplement improves dysmotility in chronic pancreatitis patients. *Journal* 

Parallel Secretion of Pancreatic Phospholipase A2, Phospholipase A1, Lipase, and Colipase in Children with Exocrine Pancreatic Dysfunction. *Pediatric Research*. Vol.

neurotensin and CCK in patients with chronic pancreatitis with and without

dysfunction by potent pancreatic exocrine supplements in patients with chronic

(1996). Efficacy of a pancreatic enzyme formulation in the treatment of steatorrhea in patients with chronic pancreatitis. *Current Therapeutic Research & Clinical* 

structure/function relationship, synthesis, and regulation. *Journal of Lipid Research*.

coated enzyme in treating malabsorption in cystic fibrosis. *Journal of Pediatric Gastroenterology and Nutrition.* Vol. 42, No. 3, pp. 256-261.


Keller, J. & Layer P. (2005). Human pancreatic exocrine response to nutrients in health and

Keller, J.; Aghdassi, A.A.; Lerch, M.M.; Mayerle, J.V. & Layer, P. (2009). Tests of pancreatic

*Best Practice & Research Clinical Gastroenterology*, Vol. 23, pp. 425–439. Krishnamurty, D. M.; Rabiee, A.; Jagannath, S. B. & Andersen, D.K. (2009) Delayed release

*Gastroenterology and Nutrition.* Vol. 42, No. 3, pp. 256-261.

disease. *Gut.* Vol. 54, No. 6, pp.1–28.

Vol. 34, No. 2, pp.158–166.

pp. 475- 480.

880–891

coated enzyme in treating malabsorption in cystic fibrosis. *Journal of Pediatric* 

exocrine function – Clinical significance in pancreatic and non-pancreatic disorders.

pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis. *Therapeutics and clinical risk management*, Vol. 5, pp. 507-520. Kraisinger, M.; Hochhaus, G.; Stecenko, A.; Bowser, E. & Hendeles, L. (1994). Clinical

pharmacology of pancreatic enzymes in patients with cystic fibrosis and *in vitro* performance of microencapsulated formulations. *Journal of Clinical Pharmacology*,

intestinal aboral transit in humans.*American Journal of Physiology*. Vol. 251, No. 4,

(1997). Altered postprandial motility in chronic pancreatitis: role of malabsorption

*Integrated Textbook of Basic Science, Medicine, and Surgery, Second Edition,* (eds H. G. Beger, A. L. Warshaw, M. W. Büchler, R. A. Kozarek, M. M. Lerch, J. P. Neoptolemos, K. Shiratori, D. C. Whitcomb and B. M. Rau), pp.78-90, Blackwell

fibrosis: Robust challenges for preventing the development of co-morbidities.

different pancreatin preparations used in pancreatic exocrine insufficiency. *European Journal of Gastroenterology and Hepatology.* Vol. 21, No. 9, pp. 1024-1031. Lohse, P.; Chahrokh-Zadeh, S. & Seidel, D. (1997). The acid lipase gene family: three

enzymes, one highly conserved gene structure. *Journal of Lipid Research*. Vol. 38, pp.

Lankisch, P.G.; Lembcke, B.; Wemken, G. & Creutzfeldt, W. (1986). Functional reserve capacity of the exocrine pancreas. *Digestion*, Vol. 35, No. 3, pp. 175 - 181. Layer, P.; Go, V.L. & DiMagno, E.P. (1986) Fate of pancreatic enzymes during small

Layer, P.; vonderOhe, M.R.; Holst, J.J.; Jansen, J.B.; Grandt, D.; Holtmann, J. & Goebell, H.

Layer, P. & Keller J. (2003). Lipase Supplementation Therapy: Standards, Alternatives, and

Lee, M.G. & Muallem, S. (2009). Physiology of duct cell secretion, *In : The Pancreas: An* 

Levy, E. (2011). Nutrition-related derangements and managements in patients with cystic

Löhr, JM, Hummel FM, Pirilis KT, Steinkamp G, Körner A, Henniges F. (2009). Properties of

Lowe, M.E. (1997). Molecular mechanisms of rat and human pancreatic triglyceride lipases.

Lowe, M.E. (2000). Properties and function of pancreatic lipase related protein 2. *Biochimie,*

Lowe, M.E. (2002). The triglyceride lipases of the pancreas. *Journal of Lipid Research*, Vol. 43,

.*Gastroenterology*, Vol. 112, No.5, pp. 1624- 1634.

Perspectives. *Pancreas*, Vol. 26, No. 1, pp. 1-7.

Publishing Ltd., 9781444300123, Oxford, UK.

*Clinical Biochemistry*, Vol. 44, pp. 489–490

*Journal of Nutrition*. Vol. 127, pp.549–557.

Vol. 82, No 11, pp. 997-1004.

No. 12, pp. 2007–2016.


Emerging Approaches for the Treatment of

*gastroenterology,*Vol. 24, No. 3, pp. 337-347.

Vol. 343, No. 8889, pp. 85- 86.

Swedish Orphan Biovitrum website www. sobi.com

doi:10.1016/j.jcf.2009.08.008.

No. 2, pp. 84 - 87.

August 2008

No. 8985, pp.1247-1251.

pp. 1932-1938.

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 295

Sikkens, E.C.M.; Cahen, D.L.; Kuipers, E.J. & Bruno, M.J. (2010). Pancreatic enzyme

Slaff, J.; Jacobson, D.; Tillman, C.R.; Curington, C. & Toskes, P. (1984). Protease-specific suppression of pancreatic exocrine secretion. *Gastroenterology,* Vol. 87, pp. 44–52. Smyth, R.L.; Smyth, A.R.; Lloyd, D.A.; vanVelzen, D. & Heaf D.P. (1994). Strictures of a

Smyth, R.L.; O'Hea, U.; Burrows, E.; Ashby, D.; Lewis, P. & Dodge, J.A. (1995). Fibrosing

Stein, J.; Jung, M.; Sziegoleit, A.; Zeuzem, S.; Caspary, W.F. & Lembcke, B. (1996).

Stern, R.C.; Eisenberg, J.D.; Wagener, J.S.; Ahrens, R.; Rock, M.; doPico, G.; Orenstein, D.M.

Swan, J.S.; Hoffman, M.M.; Lord, M.K. & Poechmann, J.L. (1992).Two forms of human milk bile-salt-stimulated lipase. *Biochemistry Journal*, Vol. 283, No. 1, pp. 119 –122.

Taylor, C.J. (2002). Fibrosing colonopathy unrelated to pancreatic enzyme supplementation. *Journal of Pediatric Gastroenterology and Nutrition*, Vol. 35, No. 3, pp. 268-269. Thirstrup, K.; Verger, R. & Carrière, F. (1994). Evidence for a pancreatic lipase subfamily with new kinetic properties. *Biochemistry,* Vol. 33, No. 10, pp. 2748–2756. Trapnell, B.C.; Maguiness, K.; Graff, G.R., Boyd, D.; Beckmann, K. & Caras, S. (2009).

Trolli, P.A.; Conwell, D.L.; Zuccaro, G. Jr (2001). Pancreatic enzyme therapy and nutritional

Turki, S.; Mrabet, G.; Jabloun Z.; Destain, J.; Thonart, P. & Kallel, H. (2010a). A highly stable

Turki, S.; Jabloun, Z.; Mrabet, G.; Marouani, A.; Thonart, P.; Diouani, M.F.; Ben Abdallah, F.;

toxicity studies in rats. *Food and Chemical Toxicology*, Vol. 48, pp. 2393-2400. U.S. Food and Drug Administration. (2004). FDA requires pancreatic extract manufacturers

*Biotechnology and Applied Biochemistry,* Vol. 57, No. 4, 134 -149.

pancreatic function. *Clinical Chemistry,* Vol. 42, pp. 222–226.

replacement therapy in chronic pancreatitis. *Best practice research Clinical* 

scending colon in cystic fibrosis and high-strength pancreatic enzymes. *The Lancet,*

colonopathy in cystic fibrosis: results of a case-control study. *The Lancet,* Vol. 346,

Immunoreactive elastase I: clinical evaluation of a new noninvasive test of

(2000). A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. *The American Journal of Gastroenterology.* Vol. 95, No. 8,

Efficacy and safety of Creon® 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. *Journal of Cystic Fibrosis,*

status of outpatients with chronic pancreatitis. Gastroenterology Nursing, Vol. 24,

*Yarrowia lipolytica* lipase formulation for the treatment of pancreatic insufficiency.

Amra A.; Rejeb, A. & Kallel, H. (2010 b). Preliminary safety assessment of Yarrowia lipolytica extracellular lipase: Results of acute and 28-day repeated dose oral

to submit marketing applications. FDA News. *http://www. fda.gov/bbs/topics/news/2004/NEW01058.html.* Published April 27, 2004. Accessed 8


Reboul, E.; Berton, A.; Moussa, M.; Kreuzer, C.; Crenon, I. & Borel, P. (2006). Pancreatic

Richmond, G.S. & Smith, T.K. (2011). Phospholipases A1. *International Journal of Molecular* 

Rogalska, E.; Ransac, S. &Verger, R. (1990). Stereoselectivity of lipases. II. Stereoselective

Rosenlund, M.L.; Kim, H.K. & Kritchevsky, D. (1974). Essential fatty acids in cystic fibrosis.

Roussel, A.; Canaan, S.; Egloff, M.P.; Rivière, M.; Dupuis, L.; Verger, R. & Cambillau, C.

Russell, R.M.; Dutta, S.K.; Oaks, E.V.; Rosenberg, I.H. & Giovetti, A.C. (1980). Impairment of

Sahasrabudhe, A.V.; Solapure, S.M.; Khurana, R.; Suryanarayan, V.; Ravishankar, S.;

Safdi, M.; Bekal, P.K.; Martin, S.; Saeed, Z.A.; Burton, F.; Toskes, P.P. (2006). The effects of

Santamarina-Fojo, S. & Dugi, K.A. (1994). Structure, function and role of lipoprotein lipase in lipoprotein metabolism. *Current Opinion in Lipidology*. Vol. 5, pp. 117–125. Santamarina-Fojo, S.; Gonza´lez-Navarro, H.; Freeman, L.; Wagner, E. & Nong, Z. (2004).

Schuler, C. & Schuler, E.F. (2008). Composition With a Fungal (Yeast) Lipase and Method

Shama, L.M. & Peterson, R.K.D. (2008).Assessing risk of plant-based pharmaceuticals: I.

Sias, B.; Ferrato, F.; Grandval, P.; Lafont, D.; Boullanger, P.; De Caro, A.; Leboeuf, B.; Verger,

Sims, H.F.; Jennens, M.L. & Lowe, M.E. (1993). The human pancreatic lipase-encoding gene:

*Biophysica Acta*. Vol. 1761, No. 1, pp. 4–10.

*Sciences.*Vol. 12, pp. 588- 612.

*Chemistry.*Vol. 265, pp. 20271–20276

*Nature.* Vol. 25, pp. 251(5477):719.

Vol. 274, No. 24, pp. 16995–7002

*purification,*Vol. 14, pp. 425–433.

*Thrombosis Vascular Biology*. Vol. 24, pp.1750-1754

galactolipase. *Biochemistry,* Vol. 43, pp. 10138–10148.

From Pancreatic Lipase Insufficiency. *US Patent 20080279839.*

25, No. 5, pp. 369-373.

33, pp.156–162.

131, pp. 281–285.

lipase and pancreatic lipase-related protein 2, but not pancreatic lipase-related protein 1, hydrolyze retinyl palmitate in physiological conditions. *Biochimica &* 

hydrolysis of triglycerides by gastric and pancreatic lipases. *Journal of Biology &.* 

(1999). Crystal structure of human gastric lipase and model of lysosomal acid lipase, two lipolytic enzymes of medical interest. *Journal of Biology and Chemistry*,

folic acid absorption by oral pancreatic extracts. *Digestive Diseases and Sciences,*Vol.

deSousa, S.M. & Das, G. (1998) Production of Recombinant Human Bile Salt Stimulated Lipase and Its Variant in *Pichia pastoris*. *Protein expression and* 

oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: a multicenter, placebo controlled, parallel group trial in subjects with chronic pancreatitis. *Pancreas*, Vol.

Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis. *Arteriosclerosis* 

For Treating Lipid Malabsorption in Cystic Fibrous as Well as People Suffering

human dietary exposure. *Human and Ecological Risk Assessment*, Vol. 14, pp. 179-193.

R. & Carriere, F. (2004). Human pancreatic lipase-related protein 2 is a

structure and conservation of an Alu sequence in the lipase gene family. *Gene,* Vol.


**14** 

*1University of Sydney 2Ferngrove Pharmaceuticals* 

*Australia* 

**Pharmacology of Traditional Herbal** 

**Medicines and Their Active Principles Used in the Treatment of Peptic Ulcer,** 

**Diarrhoea and Inflammatory Bowel Disease** 

The endocrine, exocrine and paracrine secretions of the gastrointestinal (GI) tract play a pivotal role in the digestion and absorption of food and orally administered drugs. The secretion of mucus by mucus-secreting cells protects the erosion of the gastric mucosa from the highly acidic gastric juice. The secretion of hydrochloric acid from parietal cells is regulated by acetylcholine, histamine and gastrin. Disturbances in secretory functions of the gastrointestinal tract can lead to several GI complications. Conventional therapies employ a range of drugs that have been pharmacologically well characterised. While these drug molecules are proven to be beneficial, the adverse effects and drug-drug interactions

Since ancient times, herbal medicines have been traditionally used to treat several diseases. The gastroprotective properties of these herbs and their active constituents have been experimentally demonstrated (Al Mofleh, 2010). Asian traditional medicine systems have identified several herbs and spices to treat GI tract disorders (Langmead & Rampton, 2006; Sengupta et al., 2004). In support of these traditional claims, several preclinical and clinical studies have provided the scientific basis for the effectiveness of herbal extracts (e.g. *Glycyrrhiza glabra*) and their active constituents (e.g. flavonoids) in treating GI tract disorders (Borrelli & Izzo, 2000). The discovery and development of anti-ulcer agents such as carbenoxolone from *Glycyrrhiza glabra* and gefarnate from cabbage further highlight the presence of pharmacologically active components in herbal extracts and suggests their use

The effectiveness and the mechanisms of action of crude herbal extracts vary according the composition of their chemical constituents. Herbal medicine seems to fill this gap, especially when employing high manufacturing standardised forms of herbal medicine with regard to the quality and quantity of ingredients (Suzuki et al., 2009). In addition, well characterised herbal formulations may lead to the production of reliable clinical data on efficacy and safety. As several studies have shown that herbal medicines may produce adverse reactions and herb-

highlight the need for better treatment modalities for GI tract disorders.

as an alternative therapy to treat GI tract disorders.

**1. Introduction** 

Bhavani Prasad Kota1, Aik Wei Teoh2 and Basil D. Roufogalis1

