Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study.

OBJECTIVE: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. DESIGN: GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection. METHODS: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. RESULTS: IGF-I levels decreased from 1.75+/-0.91-fold the upper limit of normal at baseline to 1.05+/- 0.62 at the 6-month visit, 0.96+/-0.60 at the 12-month visit, and to 0.89+/-0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8+/-35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4+/-45.9 to 101.5+/- 42.8 mg/dl after 6 months (P<0.01) and to 100.6+/-33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. CONCLUSIONS: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

The renal urodilatin system: clinical implications.

A renal natriuretic peptide and the 'renal urodilatin system' were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na(+) and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na(+) and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.

Bronchodilation using combined urodilatin - albuterol administration in asthma: a randomized, double-blind, placebo-controlled trial.

Urodilatin, the renal form of natriuretic peptide type A, induces bronchodilation, increasing intracellular cyclic guanosine monophosphate (cGMP), whereas the bronchorelaxant effect by b2-agonists is triggered by cyclic adenosine monophosphate (cAMP). The objective of this investigation is to demonstrate the efficacy of urodilatin in inducing bronchodilation, and to show this activity alone or in combination with albuterol. Therefore, a randomized, double-blind, placebo-controlled, dose-finding study with cross-over design was carried out including 12 stable, mild to severe (step 2 to 4, definition by NIH/NHLBI guideline 1997) asthmatics. 96 treatments were thus performed. The intervention was comprised of an intravenous infusion of urodilatin (0, 10, 30, or 60 ng/kg/min) combined with inhaled albuterol (0 or 200 microg). As primary objective, the increase in forced expiratory volume in one second (FEV subset1) was measured. - The trial shows that urodilatin at all applied doses or 200 microg albuterol significantly increases FEV subset1 (p < 0.05). Combination of urodilatin and albuterol treament significantly improves FEV subset1 (p < 0.05) compared to either monotherapy and results in maximum bronchodilation. - From the results, the following conclusions can be drawn. In stable asthmatics, the combined activation of cGMP- and cAMP-mediated pathways results in a significantly improved, maximal bronchodilation in comparison to either type of monotherapy. This shows that urodilatin combined with albuterol improves lung function and ameliorates the therapy in asthmatics.

The Whipple partial duodenopancreatectomy for the treatment of chronic pancreatitis.

BACKGROUND/AIMS: Operations for chronic pancreatitis can be divided into drainage and resection procedures. The standard Whipple pancreatoduodenectomy is the preferred resection procedure for most cases of painful complicated pancreatitis centred in the pancreatic head. METHODOLOGY: The medical records of 134 patients who underwent standard Whipple pancreatoduodenectomy for complicated chronic pancreatitis were analyzed. Exocrine and endocrine pancreatic function was assessed. Pain intensity was estimated using a pain scoring system. Mean follow-up was 8.3 years and the follow-up rate was 62%. RESULTS: All patients underwent a standard Whipple pancreatoduodenectomy. Operative mortality was 0.7%. No postoperative complications were seen in 112 patients (83.6%). Re-laparotomy for adhesions, major septic complications, bleeding and pancreatic anastomotic leak were noted in 13 patients (9.7%). Delayed gastric emptying occurred in 1 patient (0.7%). Complete pain relief was noted in 66%. An increase in body weight was observed in 65% and 60% of the patients were able to return to work postoperatively. Postoperative exocrine insufficiency developed in 24% and postoperative diabetes in 12%. CONCLUSIONS: The Whipple standard procedure proves to be a safe and effective technique for the treatment of chronic pancreatitis. More important than any particular operative technique is the selection of an appropriate method of management for each individual patient.

[Non-surgical therapy of pancreatitis complications (pseudocyst, abscesses, stenoses)]. / Nichtchirurgische Therapie von Pankreatitiskomplikationen (Pseudozysten, Abszessen, Stenosen).

Acute and chronic pseudocysts differ. Chronic pseudocysts develop during the evolution of chronic pancreatitis unrelated to a specific bout of clinically recognizable acute pancreatitis. Acute pseudocysts arise in conjunction with an episode of acute pancreatitis. Whereas until recently surgical therapy has been the standard treatment for acute (or chronic) pancreatic pseudocysts, a range of nonsurgical options has been developed. The most important nonsurgical treatment of all is to watch and wait. Pseudocysts following acute pancreatitis should be observed when they are truly asymptomatic and less than or equal to 6 cm in diameter and left alone if not increasing in size. Only if after a six-week observation period pancreatic pseudocysts increase in diameter and become symptomatic, percutaneous needle aspiration, catheter drainage or an endoscopic drainage procedure (cystogastrostomy/cystoduodenostomy) or ultimately operative drainage procedure should be considered. Antibiotic therapy should be considered for all patients presenting with pancreatic necrosis. They should be treated with drugs administered intravenously at the maximum recommended dose as early as possible after onset of symptoms, continued throughout at least the first two weeks of the disease. Moreover, they should be treated alone and/or in combination with antibiotics that are active against gram-negative organisms of intestinal origin, commonly isolated in necrotic tissue, pseudocysts and infected pancreatic abscesses, and that are capable of penetrating into the pancreatic juice and necrotic tissue (e.g. mezlocillin, cephalosporin, metronidazole). Removal of pancreatic stones and pancreatic stenosis by endoscopic procedures in the treatment of pain in patients with chronic pancreatitis is still not an established and generally accepted treatment. Controlled trials to validate stenting and ESWL in chronic pancreatitis are needed.

[Acute cholecystitis--conservative therapy]. / Akute Cholezystitis--konservative Therapie.

In about 95% of patients with acute cholecystitis the cystic duct is obstructed by a gall stone. The imprisoned bile salts have a toxic action on the gall bladder wall. Acute cholecystitis is liable to be confused with other causes of sudden pain and tenderness in the right hypochondrium. Below the diaphragm, acute retrocecal appendicitis, intestinal obstruction, a perforated peptic ulcer or acute pancreatitis may be confusing factors; however, the gall bladder remains shrunken, fibrotic, full of stones and nonfunctioning. Recurrent acute cholecystitis may follow, but there may be surprisingly long clinically silent periods. The treatment of choice is elective cholecystectomy. General measures include bed rest, intravenous fluids, a light diet and relief of pain with pethidine and buscopan. Antibiotics are given to treat septicemia and prevent peritonitis and empyema. During the first 24 h., 30% of the gall bladder cultures are positive. This rises to 80% after 72 h. Common infecting organisms are Escherichia coli, Streptococcus faecalis and Klebsiella, often in combination. Anaerobes are present, if sought, and are usually found with aerobes. They include Bacteroides and Clostridia. Antibiotic(s) should have a spectrum to cover the colonic type micro-organisms which are usually found with infection of the biliary tree. The choice depends upon the clinical picture. A broad-spectrum penicillin or a cephalosporin is usually adequate for the stable patient with pain and mild fever. The severely septicemic patient is better treated with a combination of ureidopenicillin (mezlocillin or piperacillin) and metronidazole.

[How to proceed? ERCP in acute pancreatitis?]. / Was tun? ERCP bei akuter Pankreatitis?

The standard treatment of acute pancreatitis is primarily supportive, including a well standardized conservative therapy and additionally specific interventions in complicated disease. The role of early endoscopic retrograde cholangiopancreatography in acute pancreatitis has been discussed for about 20 years. The etiology of pancreatitis plays an important role in making the decision for early interventional treatment. The results of clinical trials about early interventional treatment of acute biliary pancreatitis demonstrate that the outcome of patients without signs of biliary stone impaction or acute cholangitis is burdened by more severe complications than in patients treated conservatively. Urgent endoscopic retrograde cholangiopancreatography, endoscopic sphincterotomy and stone extraction within 72 hours of admission reduces the frequency of major complications only in patients with acute biliary pancreatitis with obstructive jaundice or biliary sepsis.

[Therapy of Crohn disease in internal medicine: short bowel syndrome and toxic megacolon]. / Internistische Therapie bei M. Crohn: Kurzdarmsyndrom und toxisches Megakolon.

In most cases a short-bowel syndrome is the consequence of extensive bowel resection for Crohn's disease with loss of gastrointestinal function. After operation the patients should be adapted to enteral feeding as soon as possible. The nutritional management is determined by the type of intestinal resection and length of remaining small and large bowel. Total parenteral nutrition for life-time is necessary in patients with less than 50 cm of small bowel. Toxic megacolon is a rare complication seen in Crohn's disease. Conservative therapy includes high doses of intravenous steroids, electrolyte replacement and hydration, antibiotics, decompression of the bowel as well as vigorous surveillance for potential complications. About 50% of the patients with toxic megacolon recover with conservative treatment alone. Surgical intervention should be performed not later than 48 hours after unsuccessful conservative therapy.

Isolation and structural analysis of "urodilatin", a new peptide of the cardiodilatin-(ANP)-family, extracted from human urine.

Two major forms of cardiac peptides have been established in the last few years: (a) a prohormone of 126 amino acids (CDD/ANP-1-126) in the endocrine heart and (b) the circulating CDD/ANP-99-126 (= alpha ANP) in blood plasma. The method we applied earlier to isolate the circulating form of cardiodilatin from human blood was used to detect and analyze the biologically active, predominant form of the same polypeptide family excreted by the kidneys. Each step of the isolation procedure was followed up by a bioassay using an in vitro vascular smooth muscle relaxation test and a highly specific RIA against cardiodilatin (CDD-99-126) for the initial purification steps. The polypeptides excreted in 1000 l of normal human urine were adsorbed to 2.5 kg of alginic acid, and after elution and lyophilization processed on a G-25 Sephadex column. The obtained crude polypeptide fractions were applied to ion-exchange chromatography. Thereafter four steps of HPLC were carried out to purify the polypeptide which was the suggested form of cardiodilatin (CDD) in human urine. The amino acid analysis and gas phase sequence analysis showed that the main form of urinary cardiodilatin is a 32 amino acid residue containing molecule, cardiodilatin-95-126. The molecule is N-terminally extended compared to the circulating CDD-99-126. This suggests that the analyzed urinary peptide is not the residual plasma form, filtrated and renally cleared from blood, but probably a polypeptide produced and processed in the kidney tubules and cleaved by a different postranslational process. Therefore, this vasorelaxant polypeptide is called urodilatin.

[Vasoconstrictive Therapies for Bleeding Esophageal Varices and their Mechanisms of Action]. / Wirkmechanismen der vasokonstriktiven Therapie der Osophagusvarizenblutung.

Variceal bleeding is one of the most dramatic complications in gastroenterology and has a high mortality rate. Early treatment with vasoactive drugs can save lives when skilled endoscopists are not immediately available. Vasoactive drugs like terlipressin, somatostatin or octreotide are not only indicated as first-choice emergency treatment, but they also increase the success rate of endoscopic treatments. Whereas the efficacy and mechanisms of action of terlipressin to arrest haemorrhage and to improve the disturbed cardiovascular situation of cirrhotic patients, including those with hepatorenal syndrome, are well documented, the efficacy and mechanisms of action of somatostatin and octreotide remain unclear and uncertain. On account of its vasoconstrictive effects on the dilated splanchnic blood vessels, terlipressin reduces blood flow into the portal vein and, thus, reduces portal venous pressure and blood flow through porto-systemic shunts. As a consequence, variceal bleeding is arrested, central and arterial hypovolaemia is corrected, and activation of the renin-angiotensin-aldosterone system as well as the sympathetic nervous system is reduced, leading to lower intrahepatic and intrarenal resistance. The result is an improvement of organ perfusion - including perfusion of the kidneys and the liver - as well as an improvement of the hyperdynamic cardiovascular situation and a better survival rate. Whereas terlipressin has been shown to stimulate kidney function and to prolong survival time in patients with bleeding esophageal varices as well as those with hepatorenal syndrome, no such promising effects were observed with somatostatin or octreotide.

Fecal elastase-1 determination: 'gold standard' of indirect pancreatic function tests?

BACKGROUND: Tubeless pancreatic function tests measuring the content of elastase-1 and the activity of chymotrypsin in stool are used with different cut-off levels and with varying success in diagnosing functional impairment of the pancreas. The aim of our study was to re-evaluate the sensitivity and specificity of elastase-1 and chymotrypsin in stool in the assessment of exocrine pancreatic insufficiency. METHODS: In 127 patients displaying clinical signs of malassimilation, the secretin-caerulein test ('gold standard'), fecal fat analysis, fecal chymotrypsin activity and fecal elastase-1 concentration were performed. Exocrine pancreatic insufficiency was graded, according to the results of the secretin-caerulein test, into mild, moderate and severe. Chymotrypsin and elastase-1 in stool were estimated using two commercially available test kits. Fecal elastase-1 concentration of 200 and 100 microg/g stool and chymotrypsin activity of 6 and 3 U/g stool were used separately as cut-off levels for calculation. RESULTS: 1) In 65 patients, a normal pancreatic function was found using the secretin-caerulein test. In 62 patients, an exocrine pancreatic insufficiency was found and classified into severe (n = 25), moderate (n = 14) and mild (n = 23). 2) The correlation between fecal elastase-1 and chymotrypsin with duodenal enzyme outputs of amylase, lipase, trypsin, chymotrypsin and elastase-1 ranged between 33% and 55% and 25% and 38%, respectively. 3) Using a cut-off of 200 microg elastase-1/g, stool sensitivities of fecal elastase-1 and fecal chymotrypsin (cut-off: 6 U/g) were 100% and 76%, respectively (P < 0.0001 and P < 0.001 respectively) in severe exocrine pancreatic insufficiency, 89% and 47% respectively (P < 0.001; P = 0.34, respectively) in moderate and 65% for both in mild pancreatic insufficiency. Specificities of elastase-1 and chymotrypsin in stool were 55% and 47%, respectively. 4) Elastase-1 based diagnostic provided a positive predictive value of 50% using a cut-off' 200 microg/g stool in a representative group of consecutively recruited patients with gastroenterological disorders. CONCLUSION: Determination of fecal elastase-1 is highly sensitive in the diagnosis of severe and moderate exocrine pancreatic insufficiency and is of significantly higher sensitivity than fecal chymotrypsin estimation. Specificity for both stool tests is low. Correlation between elastase-1 and chymotrypsin in stool and duodenal enzyme outputs is moderate. Neither test is suitable for screening, as they provide a pathologic result in roughly half of 'non-pancreas' patients.

Isolation and structural analysis of the circulating human cardiodilatin (alpha ANP).

A new method was applied to isolate a polypeptide hormone from human blood. The polypeptides from 1,000 1 of hemofiltrate with a molecular weight lower than 20 kDaltons were adsorbed to 2.5 kg alginic acid, then eluted, precipitated, and desalted on a G-25 Sephadex column, thus obtaining a crude lyophilised plasma polypeptide extract. These polypeptides were further submitted to ion-exchange chromatography. Thereafter, two steps of HPLC were carried out to purify a distinct polypeptide which was the circulating form of cardiodilatin (CDD) in this case. The amino acid analysis, C-terminal enzymatic cleavage by carboxypeptidase A, and sequence analysis showed that the only form of circulating cardiodilatin is the 28 amino acid residue containing molecule, cardiodilatin-99-126 cleaved from the C-terminus of cardiodilatin-126 and identical with alpha-ANP (alpha atrial natriuretic polypeptide). Other bioactive molecular forms of the polypeptide hormones of the cardiodilatin family were not detected in the hemofiltrate. The isolation procedure was followed up by a bioassay using in vitro vascular smooth muscle relaxation.

[Postoperative follow-up in patients with partial Whipple duodenopancreatectomy for chronic pancreatitis]. / Postoperative Verlaufskontrolle bei Patienten mit partieller Duodenopankreatektomie nach Whipple wegen chronischer Pankreatitis.

BACKGROUND AND AIM: Physicians and surgeons essentially agree today that chronic pancreatitis must primarily be treated conservatively. The aim of surgery in chronic pancreatitis is the treatment of symptoms. Surgical treatment cannot be a causal therapy for chronic pancreatitis. If surgery is indicated at all. Whipple's operation is considered to be the gold standard. PATIENTS AND METHODS: Between 1973 and 1992, out of a total of 700 patients referred to the surgery University Department in Mannheim with the express purpose of having an operation for chronic pancreatitis, duodenopancreatectomy (Whipple's operation) was performed in 110 cases. 58 of these patients were followed up postoperatively and the results have been compared with preoperative findings. RESULTS: All patients returned to full or only slightly impaired activity. 60% took up work again, 40% retired after the operation with a mean age of 49 years. 38 patients (66%) were totally free of pain, 13 patients (22%) had less pain than preoperatively and only seven (12%) often need analgesics postoperatively because of abdominal pain. Preoperatively there has been a history of long-standing excessive alcohol use in 32 (55%) patients, in the postoperative period there was a significant reduction to only three (5%) patients. 40 patients clinically examined were in a sufficient nutritional condition. Exocrine function of the pancreas (stool chymotrypsin and fluorescein dilaurate test) showed an insufficiency in 20 (71%) of 28 cases. The preoperative exocrine function of the pancreas was not examined in most cases. Examination of endocrine function showed diabetes mellitus treated with insulin occurring preoperatively in six (10%) patients and in 21 (36%) patients postoperatively. CONCLUSION: As chronic pancreatitis very often is concentrated in the head of the pancreas, Whipple's operation seems to be a good procedure for pain relief and concerning late results of life quality and socioeconomic situation.