Richard P. Rood

Effect of Octreotide on Refractory AIDS-associated Diarrhea: A Prospective, Multicenter Clinical Trial

OBJECTIVE To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN A prospective, open-label study. SETTING Inpatient metabolic units of four university medical centers. PATIENTS Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. INTERVENTION After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms. MAIN RESULTS Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01). CONCLUSION Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.

Carbachol- and elevated Ca(2+)-induced translocation of functionally active protein kinase C to the brush border of rabbit ileal Na+ absorbing cells.

Protein kinase C is involved in mediating the effects of elevated Ca2+ in ileal villus Na+ absorbing cells to inhibit NaCl absorption. The present studies were undertaken to understand the mechanism by which this occurs. The effects of carbachol and the calcium ionophore A23187, agents which elevate intracellular Ca2+ and inhibit NaCl absorption in ileal villus cells, were studied. Carbachol treatment of villus cells caused a rapid decrease in protein kinase C activity in cytosol, with an accompanying increase in microvillus membrane C kinase. Exposure of the villus cells to calcium ionophore also caused a quantitatively similar decrease in cytosol C kinase and increase in C kinase activity in the microvillus membrane. This increase caused by carbachol and Ca2+ ionophore was specific for the microvillus membrane. In fact, 30 s and 10 min after exposure of the cells to carbachol, basolateral membrane protein kinase C decreased, in a time-dependent manner; whereas 10 min of Ca2+ ionophore exposure did not alter basolateral C kinase. Exposure of villus cells to Ca2+ ionophore or carbachol caused similar increases in microvillus membrane diacylglycerol content. As judged by the ability to inhibit Na+/H+ exchange measured in ileal villus cell brush border membrane vesicles, the protein kinase C which translocated to the microvillus membrane was functionally significant. Inhibition of Na+/H+ exchange required ATP and was reversed by the protein kinase C antagonist H-7. In conclusion, the effect of carbachol and Ca2+ ionophore in regulation of ileal NaCl absorption is associated with an increase in microvillus membrane diacylglycerol content and functionally active protein kinase C. The effects of both carbachol and Ca2+ ionophore are different on brush border and basolateral membrane distribution of protein kinase C.

Role of calcium and calmodulin in the regulation of the rabbit ileal brush-border membrane Na+/H+ antiporter

SummaryIn rabbit ileum, Ca2+/calmodulin (CaM) appears to be involved in physiologically inhibiting the linked NaCl absorptive process, since inhibitors of Ca2+/CaM stimulate linked Na+ and Cl− absorption. The role of Ca2+/CaM-dependent phosphorylation in regulation of the brush-border Na+/H+ antiporter, which is believed to be part of the neutral linked NaCl absorptive process, was studied using purified brush-border membrane vesicles, which contain both the Na+/H+ antiporter and Ca2+/CaM-dependent protein kinase(s) and its phosphoprotein substrates. Rabbit ileal villus cell brush-border membrane vesicles were prepared by Mg precipitation and depleted of ATP. Using a freezethaw technique, the ATP-depleted vesicles were loaded with Ca2+, CaM, ATP and an ATP-regenerating system consisting of creatine kinase and creatine phosphate. The combination of Ca2+/CaM and ATP inhibited Na+/H+ exchange by 45±13%. This effect was specific since Ca2+/CaM and ATP did not alter diffusive Na+ uptake, Na+-dependent glucose entry, or Na+ or glucose equilibrium volumes. The inhibition of the Na+/H+ exchanger by Ca2+/CaM/ATP was due to an effect on theVmax and not on theKm for Na+. In the presence of CaM and ATP, Ca2+ caused a concentration-dependent inhibition of Na+ uptake, with an effect 50% of maximum occurring at 120nm. This Ca2+ concentration dependence was similar to the Ca2+ concentration dependence of Ca2+/CaM-dependent phosphorylation of specific proteins in the vesicles. The Ca2+/CaM/ATP-inhibition of Na+/H+ exchange was reversed by W13, a Ca2+/CaM antagonist, but not by a hydrophobic control, W12, or by H-7, a protein kinase C antagonist. we conclude that Ca2+, acting through CaM, regulates ileal brush-border Na+/H+ exchange, and that this may be involved in the regulation of neutral linked NaCl absorption.

Regulation of the rabbit ileal brush-border Na+/H+ exchanger by an ATP-requiring Ca++/calmodulin-mediated process.

Brush-border vesicles purified from rabbit ileal villus cells were used to evaluate how Ca++/calmodulin (CaM) regulates the neutral linked NaCl absorptive process, part of which is a Na+/H+ exchanger. After freezing and thawing to allow incorporation of macromolecules into the vesicles, the effect of Ca++/CaM on brush-border Na+ uptake with an acid inside pH gradient, and on Na+/H+ exchange was determined. Freezing and thawing vesicles with 0.85 microM free Ca++ plus 5 microM exogenous CaM failed to alter Na+/H+ exchange as did the addition of exogenous ATP plus an ATP regenerating system, which was sufficient to elevate intravesicular ATP to 47 microM from a basal level of 0.4 microM. However, the combination of Ca++/CaM plus ATP inhibited Na+ uptake in the presence of an acid inside pH gradient and inhibited Na+/H+ exchange, while Na+ uptake in the absence of a pH gradient was not altered. This effect required a hydrolyzable form of ATP, and did not occur when the nonhydrolyzable ATP analogue, AMP-PNP, replaced ATP. Under the identical intravesicular conditions used for the transport studies, Ca++ (0.85 microM) plus exogenous CaM (5 microM), in the presence of magnesium plus ATP, increased phosphorylation of five brush-border peptides. These data are consistent with Ca++/CaM acting via phosphorylation to regulate the ileal brush-border Na+/H+ exchanger.

Magnesium hydroxide: new insights into the mechanism of its laxative effect and the potential involvement of prostaglandin E2.

Surgicalhe mechanism by which Mg(OH)2 acts as a laxative is unknown. To explore the mechanism, six volunteers more than 55 years old, with normal bowel habits, were enrolled in a dose-response, randomized, placebo-controlled, double-blind, crossover design study. Each subject was studied for four inpatient periods of 5 days each on a metabolic ward with 9 days off of all medication between studies. In the hospital, all patients were on a diet fixed in calories, fluid volume, Na+, fiber, and Ca2+. At 8 p.m. on each study day, each subject took 45 ml containing either placebo or 1,200, 2,400, or 3,600 mg of Mg(OH)2 plus 240 ml of water. On the fourth and fifth hospital days of each period, 24-h stool output was quantified and analyses performed. Compared to placebo, Mg(OH)2 caused the following dose-dependent results: (a) increased number of bowel movements; (b) increased percentage of stool Mg2+; and (e) increased total stool 24-h prostaglandin E2 (PGE2), with mean 24-h excretions as follow: placebo, 95 ± 18 pg/24 h; 1,200 mg Mg(OH)2, 260 ± 100; 2,400 mg Mg(OH)2, 357 ± 117; and 3,600 mg Mg(OH)2, 525 ± 196. There was a significant correlation between stool PGE2 excretion and stool water consistent with a causative relationship. However, the concentration of stool prostaglandin was lower than the concentration found to alter intestinal electrolyte transport in vitro. In summary, the laxative effect of Mg(OH)2 is associated with increased output of stool PGE2. The contribution of the stool PGE2 to the laxative effect of Mg(OH)2 is unknown.

Pancreatic Cholera Syndrome Due to a Vasoactive Intestinal Polypeptide- Producing Tumor: Further Insights Into the Pathophysiology

This case report describes a patient with pancreatic cholera caused by a vasoactive intestinal polypeptide-producing pancreatic tumor. The case presents several unusual characteristics of this disease. The primary tumor was a mucinous adenocarcinoma of the pancreas. The serum vasoactive intestinal polypeptide level of 2400 pmol/L is the highest reported. At this vasoactive intestinal polypeptide level, the somatostatin analogue SMS 201-995 at doses up to 2 mg/24 h did not control the 21 L/24 h stool output. Fecal incontinence due to a manometrically documented hypotonic internal anal sphincter occurred. Using surgically created stomas, the segmental gastrointestinal fluid and sodium losses were shown to be greatest from the jejunum, whereas potassium losses from the colon and small intestine were equal. The cellular mechanism for the small intestinal potassium secretion is not known.

Increased tear secretion in pancreatic cholera: a newly recognized symptom in an experiment of nature

Hormone producing non-B islet cell tumors can be considered experiments of nature because the clinical manifestations allow determination of the pathophysiologic or pharmacologic functions of the peptides produced, and suggest physiologic functions as well. The roles of gastrin as a normal regulator of hydrogen secretion by the stomach and of vasoactive intestinal peptide (VIP) as a regulator of sodium and chloride transport by the intestine were strongly suggested by the clinical manifestations of tumors producing these respective peptides [l]. Herein, we describe a patient with a VIP-producing pancreatic adenocarcinoma who had secretory diarrhea and increased tearing. This case suggests a role for VIP in regulation of human lacrimal gland secretion. CASE REPORT A 35-year-old woman with a previous diagnosis in 1982 of pancreatic cholera secondary to a VIP-producing metastatic pancreatic adenocarcinoma [2] was admitted in September 1986 for refractory diarrhea secondary to metastatic VIPoma. The patient complained of continual tearing and epiphora (overflow tears) that were worse at night. She denied associated ocular irritation or eye pain. At this time, her stool volume was 21 liters per 24 hours, her serum VIP level was 2,394 pmol/liter (normal less than 30 pmolfliter), and her serum pancreatic polypeptide level was 28,661 pmol/liter (normal less than 300 pmovliter).

Diffuse Hepatic Calcification Following Ischemic Insult in the Setting of Impaired Renal Function

t p a i s A man who had undergone liver transplantation 21 years earlier for fulminant hepatitis was admitted to he hospital for elective kidney transplantation for renal failure econdary to calcineurin inhibitor (tacrolimus) toxicity. Postperatively, the patient became profoundly hypotensive from assive intra-abdominal hemorrhage, leading to acute tubular ecrosis and failure of the transplanted kidney. Physical examnation at that point showed mild jaundice and well healed ncision from the surgery. Laboratory findings included: calium 8.1 mg/dL, phosphate 8.5 mg/dL, aspartate transaminase 1,212 U/L, alanine aminotransferase 4884 U/L, total bilirubin .9 mg/dL, direct bilirubin 4.8 mg/dL, and international noralized ratio 1.6. An abdominal computed tomography scan emonstrated focal areas of low attenuation in the liver Figure A, white arrow) consistent with ischemic injury. After resuscitation, the patient’s liver enzymes improved. A repeat computed tomography scan performed 3 weeks later revealed diffuse calcifications throughout the liver, most prominently in the areas of ischemic injury, as well as in muscle tissue (Figure B, white arrows). Liver biopsy showed marked hepatocytic and canalicular cholestasis without any calcium deposits in the endothelium (Figure C). After supportive therapy, the patient’s clinical condition stabilized, and he was discharged to a rehabilitation center. Hepatic calcifications can be grossly characterized as vascular, parenchymal, and capsular.1 While various infections (eg, hisoplasmosis, brucellosis, coccidioidomycosis, and tuberculosis) r neoplastic conditions (eg, primary hepatoma, cholangioma, nd hemangioma) can result in focal calcium deposits in the iver, diffuse hepatic calcification is quite rare.2 Scant case reports have described this condition secondary to dystrophic calcification and calciphylaxis. The term calciphylaxis (calcific uremic arteriolopathy) has been coined to describe the condition where calcium phosphate deposits in the skin and in the intima of medium to small size arterioles of hemodialysis patients. Calciphylaxis has occasionally been described in other organs, such as the lungs, stomach, and heart. Liver calciphylaxis has only been described when hepatic ischemia occurs in the setting of renal failure and a high calcium-phosphorous product.1 Dystrophic calcification, on the other hand, occurs at he site of tissue injury due to ischemia or trauma, and calcium hosphorous product can either be normal or high. In the bsence of any pathologic evidence of hepatocytic or intimal nvolvement of the liver in the above case, we will attribute this triking radiological finding to dystrophic calcification.

Protein-Losing Enteropathy in a Post-partum Female Secondary to Metastatic Melanoma of the Gut: Report of a Case

Malignant melanoma (MM) is a common metastatic tumor of the gastrointestinal (GI) tract. Although 60% of malignant melanoma patients will have post-mortem evidence of gastrointestinal involvement, only limited numbers (1–4%) of patients will actually be diagnosed with it [1]. Clinical presentation varies depending upon the site involved. We report a rare case of metastatic GI melanoma manifesting as protein-losing enteropathy.