PANCREATITIS

Presenting by-:Omkar kapilM.S (pharm)Department of Pharmacology &ToxicologyNational Institute of Pharmaceutical Sciences and Research-AhmedabadSupervised By- Dr. Vinod Tiwari Asst. Prof (NIPER-A)

Ahmedabad

Discussion in seminar

Introduction Symptom of acute and chronic

pancreatitis. Causes of Pancreatitis. Diagnosis. Conventional Treatments. Novel targets. Novel therapy.

.

About Pancreas

Pancreas is the largest gland just behind the stomach and next to the duodenum.

it secrete digestive juice in to the small intestine through a tube called pancreatic duct.

Pancreas also release the hormone like insulin, somatostatin and glucagon into blood stream.

Picture comparison of Normal & Pancreatitis Panaceas.

Pancreatitis

It is an inflammation of pancreas. It happen when digestive enzyme start

digesting the pancreas itself.

Pancreatitis

Acute

Chronic

Clinical manifestation of Acute Pancreatitis Upper abdominal pain. Abdominal pain that radiates to your back. Abdominal pain that feels worse after eating. Nausea. Vomiting. Tenderness when touching the abdomen.

Cause of Acute Pancreatitis

Chronic pancreatitis

It does not heal or improve. It get worse over a time and lead to permanent damage.

Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the organ's normal structure and functions.

It can present as episodes of acute inflammation in a previously injured pancreas or as chronic damage with persistent pain.

It is a disease process characterized by irreversible damage to the pancreas as distinct from reversible changes in acute pancreatitis.

Image of chronic pancreatitis

Clinical manifestation of Chronic Pancreatitis Pain in your upper abdomen Diarrhea Steatorrhea Nausea and Vomiting Unexplained weight loss Excessive thirst and fatigue

• You may experience more severe symptoms as the disease progresses, such as:

• Pancreatic fluids in your abdomen.

• Jaundice.

• Internal bleeding.

• Intestinal blockage.

A number of causes have been Identified for acute Pancreatitis and chronic pancreatitis, including-:

Alcoholism

Gallstones

Abdominal surgery

Certain medications

Cigarette smoking

Cystic fibrosis

Diagnosis

Blood tests to look for elevated levels of pancreatic enzymes.Stool tests in chronic pancreatitis to measure levels of fat that could suggest your digestive system isn't absorbing nutrients adequately.Computerized tomography (CT) scan to look for gallstones and assess the extent of pancreas inflammation.Abdominal ultrasound to look for gallstones and pancreas inflammation.Endoscopic ultrasound to look for inflammation and blockages in the pancreatic duct or bile duct.Magnetic resonance imaging (MRI) to look for abnormalities in the gallbladder, pancreas and ducts.

Conventional

treatment

Analgesics Acetaminop

hen,Meperidine

AntibioticsImipenem , cilastatin

fasting Iv fluids

NOVEL TARGETS

&NOVEL

THERAPY

Signal transduc

er

Signaling pathway

Cell surfac

e protein

Receptor protein

Novel Targets

Non- coding RNA

Signal TransducerCTHRC1

Collagen Triple Helix Repeat Containing-1 is a secretory protein, which participates in vascular re modulation through limiting collagen matrix deposition, and also morphogenesis but most importantly enhancing cell migratory ability and adhesiveness in tumor cells.

CTHRC1 is found expressed in a wide spectrum of human cancer cells, and is in particular found highly expressed in pancreatic cells.

Over expression of CTHRC1 in pancreatic cancer has enhanced the tumour cells migration and have metastatic properties, CTHRC1 has increased the phosphorylation of Src and Erk, and vice versa, these indicating the CTHRC1 plays a critical role in controlling pancreatic tumour cell adhesiveness and metastasis & activating the kinases, CTHRC1 is reported to repress the production of collagen 1 into the stromal environment of pancreatic cancer, supporting of its role as a cancer metastasis enhancing gene.

Signaling PathwayNotch

• Important pathway in Pancreas development.

• Notch signaling pathway has been reported to maintain a pool of pancreatic progenitor cells at the early stage of pancreatic development, and governs pancreatic ductal cell differentiation which found to be triggered by the intensity of the Notch activation.

• In the pancreatic cancer, Notch signaling molecules are over-expressed and could produce oncogenic, anti-tumour, and drug resistance activities basing on the cellular context. Notch signaling is brought out by Notch2 receptor deletion in mutant KRAS carrier.

• Distribution of Notch1 and Notch2 in pancreatic cell may help to understand their roles in pancreatic cancer and the effectors downstream of this signaling pathway.

Metastatic suppressor-N-myc downstream-regulated gene-1

The N-myc downstream-regulated gene-1 (NDRG1) has recently been identified as a metastasis suppressor in several human cancer types, including human pancreatic cancer.

NDRG1 is found to increase the expression of tumor suppressor gene Smad4, which further inhibits the phosphatidylinositol-3 kinase (PI3K)/ phosphorylated protein kinase B signaling and extracellular signal-regulated kinase (ERK) pathway.

NDRG1 inhibits broad signaling molecules in nuclear factor - kappa B (NF-κB) signaling pathway, which resulted in reduced cancer metastasis.

As these three signaling pathways contribute to cancer cell proliferation and metastasis promotion, and cross-talk activities among them, therefore, NDRG1 is playing a role of modulator in orchestrating the signals in this triad networks.

Receptor protein The Protease-activated Receptor-2 (PAR2) is a member of the G-

protein coupled receptor family and is activated by trypsin.

PAR2 is able to promote angiogenesis through two distinct pathways. The first one is via the activation of the mitogen-activated protein

kinase (MAPK) to mediate VEGF release, another pathway involves the tissue factor to bind with integrin-linked kinase to up-regulate HIF-1α expression via AKT phophorylation and eventually enhanced VEGF expression.

PAR2 is essential for tumor survival under hypoxic condition in the micro environment, as PAR2 maintains a constitutive high level of HIF-1α for angiogenesis promotion and this also explains the high metastatic property of pancreatic cancer cell in hypoxia region. , PAR2 is found to mediate MAPK-epidermal growth factor receptor 1/2 (EGF1/2) signaling pathway with the utilization of extracellular ATP, blocking the cross talk between PAR2 and extracellular ATP can be a target in reducing pancreatic cancer metastasis.

HER-3 Protein Human Epidermal Growth Factor Receptor a

member of HER which is found over expressed 41% in pancreatic cancer.

Because of lacking tyrosine kinase activity in HER3, it requires phosphorylation by another HER receptor to activate PI3K/AKT signaling pathway to mediate cell angiogenesis and metastasis. The expression level of HER-3 has been correlated with tumor progression.

Reduces the activation of PI3K/AKT signaling pathway and its downstream effectors activation, resulting tumor growth suppression

Non- coding RNAmiR-34 

miR-34 is reported to be up-regulated by P53, inducing cell cycle arrest in primary and tumor derived cell lines.

A significant reduction of miR - 34 expression level in gastric cancer cells with p53 mutation has been observed and reconstituted miR - 34 expression by transfecting pancreatic cancer cells with virus carrying vector expressing miR - 34, and resulted in decreased Notch2 and Bcl-2 protein production, reduced tumour sphere formation from cancer stem cell (CSC).

Although the relationship between miR-34 and P53 is still unclear, the encouraging results generated by miR-4 in p53 deficient pancreatic cancer cells have make it a worthy therapeutic target.

Referance

Novel Therapies

FOLFIRINOX (A chemotherapy regimen)

FOLFIRINOX, a regimen composed of four drugs (Folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2 followed by 48 infusion 5-FU 2,400 mg, Irinotecan 180 mg, and oxaliplatin 85 mg) is currently considered a first-line treatment option for metastatic PDA (Pancreatic ductal adenocarcinoma).

S/E- Cytopenias, Neutropenic fever, Diarrhea, Vomiting.Study about drugA 2011 study published in the New England Journal of

Medicine found that FOLFIRINOX produced the longest improvement in survival ever seen in a phase III clinical trial of patients with advanced pancreatic cancer, with patients on the FOLFIRINOX treatment living approximately four months longer than patients receiving the standard gemcitabine treatment (11.1 months compared with 6.8 months).

(https://en.wikipedia.org/wiki/FOLFIRINOX)

Gemcitabine  Nucleoside analog  chemically the hydrogen atoms on the 2'

carbon of deoxycytidine are replaced by fluorine atoms.

Mechanism of action-: Target of this drug is inhibiting the enzyme  ribonucleotide reductase which catalyze the formation of deoxyribonucleotides from ribonucleotides.

The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly. Once RNR is inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced.

S/E-: Flu-like symptoms such as muscle pain, fever, headache, chills, and fatigue.

Fever (within 6–12 hours of first dose) Fatigue Nausea (mild),Vomiting ,Poor appetite, Skin rash ,Allergic reaction, Diarrhea ,Weakness, Hair loss, Mouth sores ,Difficulty sleeping , Shortness of breath.

Chemical structure of Gemcitabine

Matrix Metalloproteinase Inhibition

MMPs are zinc-dependent proteolytic enzymes that have different substrate specificities within the extracellular matrix and have been shown to be important in its degradation.

Vitronectin, fibronectin, Undulin, and laminin, along with their over expression of several MMPs, made pancreatic cancer an obvious choice for the testing of MMP inhibition as a clinical treatment strategy . Bramhall et al.

BAY 12-9566 is the drug which is in clinical trials Ph-III and the researchers of NCIC work on that and compare with the Gemcitabine ( marketed well established drug) .

The primary mechanism of action of MMP inhibitors is inhibition of invasion, but all past trials were conducted in patients with advanced pancreatic cancer in whom metastasis had already occurred.

Farnesyl Transferase Inhibition The farnesyl transferase inhibitors (FTIs) are a

class of experimental cancer drugs that target protein Farnesyl transferase with the downstream effect of preventing the proper functioning of the RAS (protein).

SCH66336 (Schering-Plough,Kenilworth, NJ) R115777 (Johnson & Johnson, Raritan,NJ), BMS-214662 (Bristol-Myers Squibb,Princeton,NJ). Thses are under clinical trials (Phase-III) Some are given in combination with Gemcitabine

for improve the activity of drug means it work as synergistic action.

Antiangiogeniesis therapy Angiogenesis- Growing mass of tumor cells must recruit its

own blood supply for the maintenance of oxygen and nutrients, termed tumor angiogenesis.

Anti angiogenic therapy offers several potential advantages as an approach to cancer treatment, including accessibility to tumor and independence of tumor cell resistance mechanism.

A number of agents that target multiple points along the angiogenic pathway have been developed of particular interest is the VEGF(vascular endothelial growth factor) . Several strategies have been used to inhibit VEGF-mediated signals, including anti-VEGF antibody, agents that inhibit the VEGF receptor tyrosine kinase, and soluble VEGFR-1, which traps VEGF. (Kindler et al)

PTK787 (Novartis), SU11248 (Sugen, South San Francisco, CA), and ZD6474 (AstraZeneca), which inhibit the kinase activity of VEGF receptor.

The VEGF (vascular endothelial growth factor) signaling pathway regulates vascular development in the embryo (vasculogenesis) and new blood vessel formation (angiogenesis). The VEGFR can induce several cellular processes which are common to many growth factor receptors, including cell migration, proliferation and survival.

.