Pancreatitis treatment

Sandilands, D., Jeffrey, I.J.M., Haboubi, N.Y., MacLennan, I.A.M. and Braganza, J.M. (1990). Abnormal drug metabolism in chronic pancreatitis. Treatment with antioxidants. Gastroenterology 98, 766-772. 

A high fatality rate associated with this disease suggests that the effectiveness of conservative and surgical treatment is not sufficient in the case of acute pancreatitis. New methods of extracorporeal detoxification using hemoperfusion over carbon sorbents has made it possible to improve the outcome of pancreatitis treatment. However, hemosorption leads to only a transient decrease in blood proteolytic activity and does not correct the imbalance in the protease-inhibitor system, and the carbon hemosorbents are nonspecific. The development and application of antiprotease hemosorbents with specific bioligands therefore has potential in pancreatitis treatment. 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

The usual dose consists of 1000 mg/m2 i.v. It is the most active single agent for treating pancreatic cancer, and it is used as a fust-line treatment for both pancreatic and small cell lung cancers. The dose-limiting toxicity is bone marrow suppression. 

Cancer treatment is a multimodality treatment, i.e., surgery is combined with radiotherapy and antineoplastic chemotherapy. The latter treatment mode is used mainly for cancers which have disseminated. Different forms of cancer differ in their sensitivity to chemotherapy with antineoplastic agents. The most responsive include lymphomas, leukemias, choriocarcinoma and testicular carcinoma, while solid tumors such as colorectal, pancreatic and squamous cell bronchial carcinomas generally show a poor response. The clinical use of antineoplastic agents is characterized by the following principles. 

SLTR1/Kir6.2 Glibenclamide and glipizide that block pancreatic KAXP channels have been used for the treatment of type II diabetes. New class of insulin secretagogues includes repaglinide and nateglinide, which improve insulin secretion, action and reduce carbohydrate absorption. 

While the fibric acid derivatives have antihyperlipidemic effects, their use varies depending on the drug. For example, Clofibrate (Atromid-S) and gemfibrozil (Lopid) are used to treat individuals with very high serum triglyceride levels who present a risk of abdominal pain and pancreatitis and who do not experience a response to diet modifications. Clofibrate is not used for the treatment of other types of hyperlipidemia and is not thought to be effective for prevention of coronary heart disease. Fenofibrate (Tricor) is used as adjunctive treatment for the reduction of LDL, total cholesterol, and triglycerides in patients with hyperlipidemia. 

Niacin is used as adjunctive therapy for the treatment of very high serum triglyceride levels in patients who present a risk of pancreatitis (inflammation of the pancreas) and who do not experience an adequate response to dietary control. 

This lactamization process can be promoted by enzymes such as pancreatic porcine lipase. Reduction of co-azido carboxylic acids leads to macrocyclic lactams. Although treatment of carboxylic acids with amines does not directly give amides, the reaction can be made to proceed in good yield at room temperature or... 

Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

Only one study to date has been conducted on the treatment of acute pancreatitis with antioxidants. Clemens et al. (1991) were unable to show any difference in the incidence or severity of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in a prospective, randomized, double-blind, placebo-controlled trial of allopurinol. However, Salim (1991) performed a similar trial of the effect of allopurinol and DMSO in patients with pain from recurrent pancreatitis, and found significant benefit. On the basis that depletion of antioxidants is important in the pathogenesis of chronic pancreatitis, the administration of a cocktail of antioxidants was assessed for its effect on pain in this disease. Treatment with a combination of organic selenium, d-carotene, vitamins C and E, and methionine was of benefit in the initial pilot study, and in a placebo-controlled trial (San-dilands etal., 1990 Uden et al., 1990). 

Studies of both acute and chronic pancreatitis in humans and in animals support the hypothesis that free radicals are involved in the pathogenesis of pancreatitis. There is some conflicting data from the animal work, which may in part be due to differences in the models used. It does also indicate that free radicals are not the only factors involved and su ests that activation of pancreatic enzymes are also imprortant, particularly in the development of haemorrhagic pancreatitis (Sanfey, 1991). The findings of decreased antioxidant defences and the success of treatment reported in chronic pancreatitis with a cocktail of antioxidants and with allopurinol surest further studies are required to establish the role of antioxidants in pancreatic disease and its prevention. 

Salim, A.S. (1991). Role of oxygen-derived free radical scavengers in the treatment of recurrent pain produced by chronic pancreatitis. A new approach. Arch. Surg. 126, 1109-1114. 

Laboratory testing confirms the diagnosis of CF, and Jessica has been referred to her regional CF center for treatment. Additional stool studies indicate the presence of severe fat maldigestion. The pulmonologist indicates that she would like to start Jessica (weight 8.2 kg) on pancreatic enzyme replacement therapy. 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

Medications aimed at decreasing pancreatic enzyme release (e.g., somatostatin), nasogastric suction, and anticholinergic medications have all failed to show benefit in the treatment of acute pancreatitis. 

Treatment of chronic pancreatitis is aimed at removing the cause (ethanol abuse or biliary stones), providing analgesia, supplementing with pancreatic enzyme preparations, and implementing dietary restrictions. 

The goals of treatment for acute pancreatitis include (1) resolution of nausea, vomiting, abdominal pain, and fever (2) ability to tolerate oral intake (3) normalization of serum amylase, lipase, and white blood cell count and (4) resolution of abscess, pseudocyst, or fluid collection as measured by CT scan. 

FIGURE 20-2. Algorithm for evaluation and treatment of acute pancreatitis. ERCP, endoscopic retrograde cholangiopancreatography. (From Berardi RR, Montgomery PA. Pancreatitis. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 726, with permission.)... 

Patient Encounter 1, Part 3 Treatment and Monitoring for Acute Pancreatitis... 

Mayerle J, Simon P, Lerch MM. Medical treatment of acute pancreatitis. Gastroenterol Clin North Am 2004 33 855-869. 

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