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1.  Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region 
Gut  1998;42(1):92-96.
Background—Impeded flow of pancreatic juice due to mechanical obstruction of the pancreatic duct in patients with cancer of the pancreatic head region causes exocrine pancreatic insufficiency with steatorrhoea and creatorrhoea. This may contribute to the profound weight loss that often occurs in these patients. 
Aims—To investigate whether pancreatic enzyme replacement therapy prevents this weight loss. 
Patients—Twenty one patients with unresectable cancer of the pancreatic head region with suspected pancreatic duct obstruction, a biliary endoprosthesis in situ, and a Karnofsky performance status greater than 60. 
Methods—Randomised double blind trial of eight weeks with either placebo or high dose enteric coated pancreatin enzyme supplementation. All patients received dietary counselling. 
Results—The mean difference in the percentage change of body weight was 4.9% (p=0.02, 95% confidence interval for the difference: 0.9 to 8.9). Patients on pancreatic enzymes gained 1.2% (0.7 kg) body weight whereas patients on placebo lost 3.7% (2.2 kg). The fat absorption coefficient in patients on pancreatic enzymes improved by 12% whereas in placebo patients it dropped by 8% (p=0.13, 95% confidence interval for the difference: -6 to 45). The daily total energy intake was 8.42 MJ in patients on pancreatic enzymes and 6.66 MJ in placebo patients (p=0.04, 95% confidence interval for the difference: 0.08 to 3.44). 
Conclusions—Weight loss in patients with unresectable cancer of the pancreatic head region and occlusion of the pancreatic duct can be prevented, at least for the period immediately after insertion of a biliary endoprosthesis, by high dose enteric coated pancreatin enzyme supplementation in combination with dietary counselling. 


Keywords: pancreatic cancer; weight loss; pancreatic enzyme therapy; enteric coated enzyme therapy; palliation; dietary counselling
PMCID: PMC1726970  PMID: 9505892
2.  Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis 
Pancreatic enzyme supplements (PES) are used in chronic pancreatitis (CP) for correction of pancreatic exocrine insufficiency (PEI) as well as pain and malnutrition. The use of porcine pancreatic enzymes for the correction of exocrine insufficiency is governed by the pathophysiology of the disease as well as pharmacologic properties of PES. Variability in bioequivalence of PES has been noted on in vitro and in vivo testing and has been attributed to the differences in enteric coating and the degree of micro-encapsulation. As a step towards standardizing pancreatic enzyme preparations, the Food and Drug Administration now requires the manufacturers of PES to obtain approval of marketed formulations by April 2010. In patients with treatment failure, apart from evaluating drug and dietary interactions and compliance, physicians should keep in mind that patients may benefit from switching to a different formulation. The choice of PES (enteric coated versus non-enteric coated) and the need for acid suppression should be individualized. There is no current standard test for evaluating adequacy of therapy in CP patients and studies have shown that optimization of therapy based on symptoms may be inadequate. Goals of therapy based on overall patient presentation and specific laboratory tests rather than mere correction of steatorrhea are needed.
PMCID: PMC2710383  PMID: 19707261
pancreatic exocrine insufficiency; chronic pancreatitis; pancreatic enzyme supplement
3.  Liver biochemical and histopathological findings in dogs with experimentally induced exocrine pancreatic insufficiency 
Abstract
Routine liver biochemical parameters were evaluated in 8 dogs with exocrine pancreatic insufficiency (EPI) induced by surgical ligation of the pancreatic duct and the pancreatic branch of the pancreaticoduodenal artery and confirmed with the trypsin-like immunoreactivity test. Eight additional dogs were used as healthy controls. Data collection began at the 4th week postoperatively and continued weekly to the 21st week. In the dogs with EPI, the serum activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were consistently elevated. The serum total and conjugated bilirubin concentrations remained within normal limits throughout the experimental period. Histopathological study revealed hepatic lipidosis in the dogs with EPI. Therefore, since this condition seems to be an additional consequence of EPI in dogs, laboratory evaluation of dogs with EPI must include assessment of liver function, to determine if additional or different therapeutic measures are indicated.
PMCID: PMC1142130  PMID: 14979436
4.  Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test. 
Gut  1990;31(11):1324-1328.
The cholesteryl-14C-octanoate breath test was used to monitor the intraluminal enzymatic activity of pancreatin preparations in six patients with severe pancreatic insufficiency. Conventional enzyme replacement, with cimetidine as an adjunct, was compared to supplementation with enteric coated microspheres. In healthy control subjects, 14CO2 excretion rose rapidly and peaked at 90-120 minutes; mean (SD) cumulative recovery at four hours was 51 (8)%. In patients with pancreatic insufficiency on no treatment mean (SD) cumulative recovery was only 6 (4)%. After pancreatin, with previous administration of cimetidine, it increased to 27 (11)% with a time course resembling that in controls. With 2 mm enteric coated microspheres, 14CO2 excretion did not rise significantly before 120 minutes and cumulative recovery after four hours was 15 (11)%. In a control study, 2 mm radio-opaque microspheres did not empty from the stomach until two hours after ingestion. The results suggest that the cholesteryl octanoate breath test can be successfully used to monitor the intraluminal enzymatic activity after treatment with different forms of enzyme replacement in pancreatic insufficiency. In contrast to treatment with conventional pancreatin and cimetidine as an adjunct, 2 mm enteric coated microspheres did not show in vivo enzymatic activity until two hours after administration.
PMCID: PMC1378708  PMID: 2253920
5.  Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs 
Immunogenetics  2013;65(7):10.1007/s00251-013-0704-y.
Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA- DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR>17; P=0.000125), while two haplotypes were found to confer protection from EPI (P=0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.
doi:10.1007/s00251-013-0704-y
PMCID: PMC3857963  PMID: 23604463
Autoimmune; Canine; Exocrine pancreatic insufficiency; Pancreatic acinar atrophy; Major histocompatibility complex
6.  Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis 
Background
Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication.
Results
Acute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P ≤ 0.01) and tramadol (P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (SR ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied.
Conclusion
Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs.
doi:10.1186/1746-6148-8-185
PMCID: PMC3527270  PMID: 23035739
Dog; Hip; Osteoarthritis; Outcome measures; Clinical trial; Carprofen; Tramadol; ABT-116
7.  Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition 
Critical Care  2013;17(4):R171.
Introduction
Malnutrition is a frequent problem associated with detrimental clinical outcomes in critically ill patients. To avoid malnutrition, most studies focus on the prevention of inadequate nutrition delivery, whereas little attention is paid to the potential role of exocrine pancreatic insufficiency (EPI). In this trial, we aim to evaluate the prevalence of EPI and identify its potential risk factors in critically ill adult patients without preexisting pancreatic diseases.
Methods
In this prospective cross-sectional study, we recruited 563 adult patients with critical illnesses. All details of the patients were documented, stool samples were collected three to five days following the initiation of enteral nutrition, and faecal elastase 1 (FE-1) concentrations were assayed using an enzyme-linked immunosorbent assay kit. Blood samples were also taken to determine serum amylase and lipase activity.
Results
The percentages of recruited patients with EPI (FE-1 concentration <200 μg/g) and severe EPI (FE-1 concentration <100 μg/g) were 52.2% and 18.3%, respectively. The incidences of steatorrhea were significantly different (P < 0.05) among the patients without EPI, with moderate EPI (FE-1 concentration = 100 to 200 μg/g) and severe EPI (FE-1 concentration < 100 μg/g). Both multivariate logistic regression analysis and z-tests indicated that the occurrence of EPI was closely associated with shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis.
Conclusions
More than 50% of critically ill adult patients without primary pancreatic diseases had EPI, and nearly one-fifth of them had severe EPI. The risk factors for EPI included shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis.
Trial registration
NCT01753024
doi:10.1186/cc12850
PMCID: PMC4057406  PMID: 23924602
8.  Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension 
Background
Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery.
Aim
To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9–15 capsules/day) over placebo in treating PEI after pancreatic resection.
Methods
A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9–15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova).
Results
All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. −4.2% (−12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE.
Conclusions
This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).
doi:10.1111/apt.12236
PMCID: PMC3601428  PMID: 23383603
9.  Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study 
Summary
Background
Pancreatic exocrine insufficiency (PEI) results in maldigestion, leading to abdominal pain, steatorrhoea, malnutrition and weight loss.
Aim
To assess the efficacy and safety of pancreatin (Creon 40000 MMS) in treating PEI due to chronic pancreatitis (CP).
Methods
This was a 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study in India. Men and women ≥18 years of age with proven CP and PEI [defined as a coefficient of fat absorption (CFA) ≤80% during run-in phase] were randomised 1:1 to pancreatin or placebo (two capsules orally per main meal, one with snacks). The primary outcome measure was change in CFA from baseline to end of double-blind treatment (analysis of covariance).
Results
Of 62 patients randomised (34 pancreatin, 28 placebo), 61 completed treatment; one patient in the placebo arm withdrew consent before completion. Patient characteristics were similar in both groups except for the proportion of men (pancreatin 82% vs. placebo 68%). Patients receiving pancreatin had a statistically significant greater improvement in fat absorption from baseline to the end of double-blind treatment compared with those receiving placebo, with a least squares mean change (95% CI) in CFA of 18.5% (15.8–21.2) vs. 4.1% (1.0–7.2), respectively. This resulted in a treatment difference of 14.4% (10.3–18.5); P = 0.001. Patients receiving pancreatin also had a statistically significant greater improvement in nitrogen absorption and greater reductions in mean stool fat, stool frequency and stool weight compared with those receiving placebo. Treatment-emergent adverse events occurred in 12 patients on pancreatin and in seven on placebo; none led to study discontinuation.
Conclusions
The results provide evidence for the efficacy of pancreatin (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis, and confirm that this formulation is well tolerated, with a good safety profile, at the dose administered.
doi:10.1111/j.1365-2036.2012.05202.x
PMCID: PMC3528066  PMID: 22762290
10.  OA01.24. A study of effect of neem oil on clinical signs of canine atopy 
Ancient Science of Life  2012;32(Suppl 1):S24.
Purpose:
Due to growing nuclear nature of urban families, pets like dogs are becoming popular companions. A skin disorder is common in dogs and is a concern for human coming in contact. Natural remedies need to be assessed for long term safety of dogs and humans. There is evidence that in dogs, Neem oil can help with fleas, ticks, intestinal parasites and mange mites. According to Ayurvedic medicine. Neem oil improves the clinical signs of skin disorders. To study its action in canines, further work was required on the efficacy of Neem oil in the treatment of canine atopy.
Method:
Effect of a preparation of Neem oil on canine atopy was assessed in a open, placebo-controlled trial. Privately owned dogs were used and the clinical signs of atopic dermatitis were evaluated by the owners. For a period of 3 weeks, the dogs daily received application with Neem oil (n = 9) or vehicle (n = 8). During the trial, all dogs were cleaned with the use of regular bathing shampoo in order to maintain hygiene. To assess the severity of atopic dermatitis, the clinical signs scored were itching, redness, scaling, thickening and stripping of skin. The severity of the signs of atopic dermatitis was scored by the owners by marking with a cross a 10cm, horizontal line.
Result:
For all five clinical signs, the group-mean improvement, expressed as change of severity score over time, was greater in the test group than in the controls. Within each group, the changes for the five clinical signs were added up to arrive at an overall index of improvement of atopic dermatitis. The extra improvement caused by the application of Neem oil was significant.
Conclusion:
Neem oil can be considered as effective and is beneficial for dogs with atopic dermatitis.
PMCID: PMC3800901
11.  Markers for faecal fat estimation in monitoring steatorrhoea in cystic fibrosis. 
Gut  1988;29(9):1286-1288.
Polyethylene glycol (PEG) 4000 is one of numerous substances used as non-absorbable markers to correct for variable faecal output when assessing daily faecal losses of nutrients. The introduction of enteric coated micro-encapsulated pancreatic enzyme (EMPE) preparations has greatly improved the control of fat malabsorption in cystic fibrosis and chronic pancreatitis patients. Unfortunately, these enzyme preparations contain significant quantities of PEG 4000 or polyvinyl pyrrolidine (PVP) as components of the enteric coating and thus PEG 4000 cannot be used either as a faecal marker, or in intubation studies, if these enzyme preparations are being used.
PMCID: PMC1434378  PMID: 3198006
12.  Fate of oral enzymes in pancreatic insufficiency. 
Gut  1993;34(5):708-712.
Oral pancreatic enzyme supplements, including those protected from gastric acidity by enteric coating, often achieve only partial correction of pancreatic steatorrhoea. To characterise the mechanisms involved in vivo, eight patients with steatorrhoea due to advanced pancreatic insufficiency and nine healthy controls were studied. Two sets of studies (small bowel intubation and five day faecal fat quantification) were randomly performed while patients were either on enteric coated pancreatin or equivalent placebo. A 260 cm long multilumen tube was used for double marker perfusion of two 20 cm segments located in the duodenum and in the ileum respectively. Luminal pH, flow, and trypsin and lipase activity outputs were measured at each segment for four hours postcibally. Placebo treated patients with pancreatic steatorrhoea had low enzyme outputs in the duodenal test segment and even lower outputs in the ileal segment. Pancreatin treatment significantly decreased steatorrhoea (p < 0.05) and increased luminal enzyme outputs (p < 0.05). The increase was much greater in the ileal than in the duodenal segment. Thus enteric coated pancreatin treatment abolished the normal gradient between postcibal duodenal and ileal lipase output. The results suggest that enteric coated pancreatin nearly corrects severe pancreatic steatorrhoea. The ingested lipase was utilised inefficiently, however, as luminal enzyme activity in the ileum was enhanced to a greater extent than in the duodenum, and consequently the absorptive potential of the small bowel was only partially utilised.
PMCID: PMC1374195  PMID: 8504976
13.  Comparative Trial of Nutrizym in Chronic Pancreatic Insufficiency 
British Medical Journal  1970;4(5726):21-24.
A cross-over trial of pancreatic replacement therapy was carried out in 12 adults with chronic pancreatic insufficiency. The standard enteric-coated preparation, Pancrex V forte, was compared with Nutrizym, which has an enteric-coated core of pancreatic extract and a shell of bromelains—a mixture of proteolytic enzymes derived from the stem of the pineapple.
Nutrizym was significantly more effective than Pancrex V forte in improving fat absorption, and reduced faecal weight. Protein digestion was assessed by measuring the urinary excretion of hydroxyproline after a gelatin meal. Nutrizym produced an earlier and significantly higher peak in hydroxyproline excretion than Pancrex V forte, but the cumulative effect was similar. The value of bromelains was investigated by including a period on the Nutrizym core alone. This was similar to Pancrex V forte in improving fat absorption but had less effect on protein digestion, suggesting that the beneficial effect of Nutrizym compared with Pancrex V forte was due to the added bromelains, and not to differences in enzyme content or enteric coating.
PMCID: PMC1820532  PMID: 4919118
14.  Isolated co-lipase deficiency in two brothers. 
Gut  1982;23(3):243-246.
Two normally developed Assyrian brothers with isolated pancreatic co-lipase deficiency are described. They presented at the age of 5-6 years with loose stools. They had steatorrhoea, and analysis of exocrine pancreatic enzymes in the small intestine showed co-lipase deficiency, while amylase, chymotrypsin, trypsin and lipase were normal. Intraduodenal infusion of purified co-lipase improved fat digestion measured by the triolein breath test. Their steatorrhoea diminished on treatment with enteric-coated pancreatic enzymes.
PMCID: PMC1419644  PMID: 7068048
15.  Two enteric coated microspheres in cystic fibrosis. 
Archives of Disease in Childhood  1990;65(6):594-597.
In a randomised single blind crossover study in children with cystic fibrosis and pancreatic insufficiency, two enteric coated microsphere preparations of pancreatin were compared on a capsule for capsule basis, by measuring the coefficient of fat absorption, nitrogen excretion, weight change, and symptom scores after four weeks' treatment with each preparation. Thirty nine subjects were randomly allocated to receive Pancrease followed by Creon or vice versa. Each individual subject received the same number of capsules per day in each study period. Data from 27 children (Pancrease/Creon, n = 13 and Creon/Pancrease, n = 14) wer suitable for analysis. Results showed no significant differences between the two preparations in any variable studied. We conclude that there is no significant difference between Pancrease and Creon when compared on a capsule for capsule basis.
PMCID: PMC1792062  PMID: 2198848
16.  Role of somatostatin and somatostatin analogues in the treatment of gastrointestinal diseases: prevention of complications after pancreatic surgery. 
Gut  1994;35(3 Suppl):S20-S22.
Morbidity and mortality related to pancreatic surgery are still high: 30-40% and 3-10% respectively. As most complications are probably related to exocrine pancreatic secretion, its inhibition could improve the postoperative course. In 1979, Klempa saw a low complication rate after Whipple resection in a small number of patients treated with somatostatin, a powerful inhibitor of pancreatic exocrine secretion. The long acting somatostatin analogue, octreotide, also inhibits pancreatic exocrine secretion and can be given by subcutaneous injections. Two double blind, placebo controlled, multicentre studies with randomisation into parallel groups were recently performed to find out if peri and postoperative administration of octreotide (100 micrograms thrice daily subcutaneously) reduces the rate of complications specifically related to pancreatic surgery. Both trials consistently showed that octreotide can reduce substantially (over 40%) the risk of complications in these patients; the treatment acceptability was good.
PMCID: PMC1374391  PMID: 7911443
17.  Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation. 
Thorax  1987;42(7):533-537.
In an open, randomised crossover study enteric coated microspheres of pancreatin were compared with a standard preparation of enteric coated pancreatin over two consecutive 28 day treatment periods in 23 adults with steatorrhoea due to cystic fibrosis. Lipase intake was equal to the patients' previous requirements and was the same during the two months. Patients performed 72 hour faecal collections at the end of each month and completed diary cards daily throughout. Comparison of the month of treatment with enteric coated microspheres with the month of standard enteric coated tablets showed a significant increase in body weight on microsphere capsules (p less than 0.02). There was also a reduced frequency of bowel actions (p less than 0.001) and abdominal pain (p less than 0.05), and improvement in stool character (p less than 0.001) on microsphere capsules. Faecal fat excretion was reduced by 44% with the microsphere capsules (p less than 0.01), and 86% of patients showed an increased coefficient of fat absorption (mean increase 13%, 95% confidence limits 6.5-19.1%; p less than 0.001). Eighty one per cent of patients preferred microsphere capsules of the two treatments. Thus enteric coated microsphere capsules are more effective in treating steatorrhoea in cystic fibrosis than standard enteric coated tablets.
PMCID: PMC460823  PMID: 3326213
18.  Decreased Ratio of CD8+ T Cells to Regulatory T Cells Associated with Decreased Survival in Dogs with Osteosarcoma 
Background
Increased numbers of regulatory T cells (Treg) and decreased ratios of CD8+ T cells to Treg have been shown to correlate with decreased survival times (ST) in humans with certain malignancies. A possible connection between Treg and ST in dogs with cancer has not been investigated previously.
Hypothesis
The purpose of this study was to compare numbers of Treg and T lymphocyte subsets in dogs with osteosarcoma (OSA) to those of healthy dogs and to determine whether pretreatment values were associated with disease-free interval or with ST. We hypothesized that Treg numbers would be increased in dogs with cancer and that dogs with a high percentage of Treg would have a poorer prognosis.
Animals
Twelve client-owned dogs with appendicular OSA were entered into a prospective clinical trial. Twenty-two healthy dogs were used as controls.
Methods
The percentages and numbers of Treg and CD4+ and CD8+ T cells in blood, lymph nodes, and tumors were determined with flow cytometry and compared between dogs with OSA and control dogs.
Results
Dogs with OSA had significantly fewer circulating CD8+ T cells and significantly more Treg compared with healthy dogs. The CD8/Treg ratio also was significantly lower in dogs with OSA compared with control dogs. In dogs with OSA, a decreased CD8/Treg ratio was associated with significantly shorter STs.
Conclusions
These data support a role for Treg in the immune control of canine OSA and suggest that determination of the CD8/Treg ratio may be useful for assessing outcomes.
doi:10.1111/j.1939-1676.2010.0557.x
PMCID: PMC3557512  PMID: 20666983
Canine; Lymphocyte; Neoplasia; Prognosis
19.  Quantitative Measurement of C6 Antibody following Antibiotic Treatment of Borrelia burgdorferi Antibody-Positive Nonclinical Dogs▿  
The detection of antibody to the Borrelia burgdorferi C6 peptide by use of enzyme-linked immunoassays is a widely accepted method for the diagnosis of Lyme disease spirochete infection in dogs and in humans. Antibody to the C6 peptide is highly specific for B. burgdorferi and declines following treatment of dogs and humans exposed to B. burgdorferi. A quantitative assay for determining C6 antibody levels was developed and used to measure changes in antibody levels following antibiotic treatment of B. burgdorferi antibody-positive nonclinical dogs. One hundred thirty-two client-owned dogs were used in the study; 64 were negative, 53 of 68 positive animals received treatment, and 15 were untreated controls. Test sera were collected at 3, 6, and 12 months from seropositive dogs receiving treatment and untreated controls. Dogs in the treated group were assigned to moderate-to-high (≥29 U/ml)- and low (<29 U/ml)-C6-level groups because the change in the C6 level after treatment was dependent on the level prior to treatment. There were significant declines in the 30 dogs with moderate-to-high initial C6 levels that exceeded the maximal declines of the untreated control dogs in all cases at 6 months (16 data points) and 12 months (29 data points) posttreatment. There was little change in C6 level following antibiotic therapy in the 23 dogs with low initial C6 levels. The quantitative C6 antibody test can be used to measure changes in C6 antibody levels following treatment of antibody-positive nonclinical dogs.
doi:10.1128/CVI.00340-07
PMCID: PMC2223868  PMID: 18003819
20.  Diagnosis and treatment of pancreatic exocrine insufficiency 
Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the 13C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.
doi:10.3748/wjg.v19.i42.7258
PMCID: PMC3831207  PMID: 24259956
Chronic pancreatitis; Pancreatic exocrine insufficiency; Pancreatic enzyme replacement therapy
21.  Pancreatic Exocrine Function Testing 
Western Journal of Medicine  1981;135(5):368-374.
It is important to understand which pancreatic function tests are available and how to interpret them when evaluating patients with malabsorption. Available direct tests are the secretin stimulation test, the Lundh test meal, and measurement of serum or fecal enzymes. Indirect tests assess pancreatic exocrine function by measuring the effect of pancreatic secretion on various nutrients. These include triglycerides labeled with carbon 14, cobalamin labeled with cobalt 57 and cobalt 58, and para-aminobenzoic acid bound to a dipeptide. Of all these tests the secretin stimulation test is the most accurate and reliable if done by experienced personnel. However, the indirect tests are simpler to do and appear to be comparable to the secretin test at detecting pancreatic exocrine insufficiency. These indirect tests are becoming clinically available and clinicians should familiarize themselves with the strengths and weaknesses of each.
PMCID: PMC1273255  PMID: 6176075
22.  Effect of pancreatic atrophy and hypertrophy on the small intestine. 
Gut  1987;28(Suppl):193-195.
Intestinal enzyme activities were investigated in mice with spontaneously occurring exocrine pancreatic insufficiency (EPI), in rats after induction of pancreatic insufficiency by intraductal injection of oleic acid, and in rats after feeding a proteinase inhibitor (Camostate) which induced a marked pancreatic hypertrophy. An increase in saccharase activity and in vitro uptake of L-phenylalanine was found in EPI mice, while activities of alkaline phosphatase and lactase were not altered. In oleic acid induced pancreatic insufficiency and in pancreatic hypertrophy no alterations in enzyme activities were observed. Morphometric analysis revealed no alterations in mucosal surface of EPI mice. It was suggested that the small intestine adapts fuctionally to severe and long lasting pancreatic insufficiency, but not to pancreatic hypertrophy.
PMCID: PMC1434548  PMID: 3692308
23.  Efficacy and Safety of Deracoxib for the Control of Postoperative Pain and Inflammation Associated with Dental Surgery in Dogs 
ISRN Veterinary Science  2012;2011:593015.
The efficacy and safety of deracoxib administered at 1-2 mg/kg/day for 3 days was assessed for the control of postoperative pain and inflammation associated with dental surgery in dogs. Client-owned dogs scheduled for dental extractions were premedicated with butorphanol and randomly assigned to receive either deracoxib (n = 31) or placebo (n = 31) preoperatively and again once daily for 2 additional days. Dogs were evaluated prior to and after surgery using a modified Glasgow Composite Pain Scale (mGCPS). Dogs could be rescued at any time if they scored ≥4 on the mGCPS or in cases of obvious discomfort. Rescued dogs were considered treatment failures for determining treatment response and were removed from the study. Of the 62 dogs enrolled, 57 were usable for the efficacy analyses and all were assessed for safety. Four of 27 deracoxib-treated dogs (14.8%) were rescued compared to 20 of 30 placebo dogs (66.7%) (P = 0.0006). Deracoxib-treated dogs also had numerically lower mGCPS scores. Eight of 31 deracoxib dogs (26%) had adverse events reported compared to 6 of 31 placebo dogs (19%). Results indicate perioperative administration of deracoxib to dogs at 1-2 mg/kg/day for 3 days significantly improves analgesia after dental surgery.
doi:10.5402/2011/593015
PMCID: PMC3658545  PMID: 23738113
24.  Effect of tylosin on dogs with suspected tylosin-responsive diarrhea: a placebo-controlled, randomized, double-blinded, prospective clinical trial 
Background
The macrolid antibiotic tylosin has been widely used to treat canine chronic diarrhea, although its efficacy is based on anecdotal reports and experimental studies in dogs and not on strong scientific evidence. The term tylosin-responsive diarrhea (TRD) refers to diarrheal disorders responding to tylosin therapy within a few days. In TRD, the stool remains normal as long as tylosin treatment continues, but diarrhea reappears in many dogs within weeks after discontinuation. The aim of our trial was to assess the effect of tylosin on fecal consistency compared with a placebo treatment in dogs with suspected TRD and additionally to establish whether tylosin in dogs with recurrent diarrhea is as effective as empirical studies and anecdotal reports suggest.
Methods
Subjects comprised 71 client-owned dogs that, according to the owners, had previously been treated successfully with tylosin due to recurrent diarrhea of unknown etiology. At the initial examination, where there were no signs of diarrhea, the dogs were randomly assigned in a 2:1 ratio to a tylosin or placebo group. During a two-month follow-up the owners evaluated the fecal consistency according to previously published guidelines. When diarrhea recurred, either tylosin (25 mg/kg q 24 h, 7 days) or placebo treatment was initiated orally. Treatment outcome was evaluated as the mean of fecal consistency scores assigned during the last three days of the treatment period. To test for differences between the tylosin and placebo group in the proportion of responders, Pearson's Chi-squared test and Fisher's exact test were applied.
Results
Sixty-one dogs met the selection criteria and were followed for two months. During the follow-up 27 dogs developed diarrhea and either tylosin or placebo treatment was started. The proportion of dogs with normal fecal consistency at the end of treatment was 85% (17/20) in the tylosin group and 29% (2/7) in the placebo group (Pearson's Chi-squared test p = 0.0049 and Fisher's exact test two-sided, p = 0.0114).
Conclusions
Our findings indicate that tylosin is effective in treating recurrent diarrhea in dogs. The dose of 25 mg/kg once daily appears sufficient. No changes specific to TRD were detected in the examinations.
doi:10.1186/1751-0147-53-26
PMCID: PMC3084160  PMID: 21489311
25.  In vitro effect of duodenal juice on R binders cobalamin complexes in subjects with pancreatic insufficiency: correlation with cobalamin absorption. 
Gut  1987;28(1):70-74.
Absorption of cobalamin free or bound to chicken serum was assessed in nine patients with pancreatic insufficiency. Simultaneously the in vitro effect of duodenal juice collected from six patients and seven controls was tested on labelled cobalamin complexed to chicken serum or to R salivary binder. Malabsorption of free cobalamin was observed in one of nine patients and in four of nine patients when cobalamin was administered bound to chicken serum. The in vitro effect of duodenal juice on cobalamin complexed to chicken serum or to R salivary binder was studied: the percentage of free cobalamin released was significantly decreased in pancreatic insufficiency compared with controls whatever the binder used; the degradation of R salivary binder was different in pancreatic insufficiency and in controls. Despite the in vitro abnormalities observed in pancreatic insufficiency, these did not correlate with the in vivo absorption of cobalamin which was often normal in our patients.
PMCID: PMC1432734  PMID: 3817588

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