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PubMed2002

Successful conversion from cyclosporine to tacrolimus for gastric motor dysfunction in a lung transplant recipient.

BACKGROUND: Conversion after transplantation from cyclosporine to tacrolimus is often performed because of recurrent acute/chronic rejection or unacceptable side effects such as nephrotoxicity, arterial hypertension, and cosmetic disorders. Although gastrointestinal discomfort is often reported after transplantation, it is usually not considered a sufficient reason for conversion, although tacrolimus seems beneficial with regards to gastric motor activity in renal transplant patients. METHODS: A lung transplantation was performed in a 41-year-old woman with alpha-1 antitrypsin deficiency emphysema. Because the patient presented severe symptoms of nausea, vomiting, and dyspepsia, without obvious endoscopic explanation, that resulted in highly variable cyclosporine trough levels, she was converted from cyclosporine to tacrolimus. RESULTS: After conversion, dyspepsia, nausea, and vomiting resolved. Neurological complications caused by a transient high trough level of tacrolimus resolved completely upon dose reduction with tacrolimus trough levels remaining very stable afterwards. CONCLUSION: Tacrolimus may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastric motor dysfunction.

Adult↗

PubMed2002

Arginine: Clinical potential of a semi-essential amino acid..

Arginine, a semi-essential amino acid, is involved in numerous areas of human biochemistry, including ammonia detoxification, hormone secretion, and immune modulation. Arginine is also well known as a precursor to nitric oxide (NO), a key component of endothelial-derived relaxing factor, an endogenous messenger molecule involved in a variety of endothelium-dependent physiological effects in the cardiovascular system. Because of arginine's NO-stimulating effects, it can be utilized in therapeutic regimens for angina pectoris, congestive heart failure, hypertension, coronary heart disease, preeclampsia, intermittent claudication, and erectile dysfunction. In addition, arginine has been studied in the treatment of HIV/AIDS, athletic performance, burns and trauma, cancer, diabetes and syndrome X, gastrointestinal diseases, male and female infertility, interstitial cystitis, immunomodulation, and senile dementia. Toxicity, dosage considerations, and contraindications are also reviewed.

Animals↗

PubMed1993

Physiology of motor function of the sphincter of Oddi.

Human and experimental studies of the sphincter of Oddi have established that the sphincter is not a simple and passive smooth muscle portion of the biliary system; rather, it plays an active role in modulating bile flow into the duodenum in both the fasted and the postprandial states. The sphincter of Oddi in the opossum, and likely in man, demonstrates spontaneous phasic and perhaps peristaltic activity that affects bile flow into the duodenum. The sphincter appears to be under the control of a smooth muscle pacemaking-like region in the proximal sphincter that controls the frequency and direction of propagation of the phasic contractions. Immunohistochemical studies have documented the presence of dense concentrations of neuropeptide-containing myenteric nerves in the sphincter of Oddi. Physiologic studies have confirmed that these peptides, in combination with the classic gastrointestinal hormones, exert significant effects on biliary motility. Experimental studies of the motor physiology of the sphincter of Oddi have advanced our understanding of human biliary motility and dysmotility. A subset of patients experiences biliary-like pain after cholecystectomy. This pain may be attributable to either mechanical stenosis of the papilla or dysfunction of the sphincter of Oddi. No definitive test currently exists to establish the diagnosis with adequate sensitivity or specificity. It is hoped that further development of ultrasonographic, scintigraphic, manometric, or electromyographic techniques will allow a clearer definition of patients who truly have sphincter dysfunction and who might benefit from medical, endoscopic, or surgical therapy.

Animals↗

PubMed2006

Evaluation of the biliary tract in patients with functional biliary symptoms.

The aim of this paper was to describe functional biliary syndromes and methods for evaluation of the biliary tract in these patients. Functional biliary symptoms can be defined as biliary symptoms without demonstrable organic substrate. Two main syndromes exist: Gallbladder dysfunction and sphincter of Oddi dysfunction. The most important investigative tools are cholescintigraphy and endoscopic sphincter of Oddi manometry. In gallbladder dysfunction a scintigraphic gallbladder ejection fraction below 35% can select patients who will benefit from cholecystectomy. Endoscopic sphincter of Oddi manometry is considered the gold standard in sphincter of Oddi dysfunction but recent development in scintigraphic methods is about to change this. Thus, calculation of hilum-to-duodenum transit time and duodenal appearance time on cholescintigraphy have proven useful in these patients. In conclusion, ambient methods can diagnose functional biliary syndromes. However, there are still a number of issues where further knowledge is needed. Probably the next step forward will be in the area of sensory testing and impedance planimetric methods.

Biliary Dyskinesia↗

PubMed2003

A randomized, controlled exploratory study of clonidine in diarrhea-predominant irritable bowel syndrome.

BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy and tolerability of the alpha-2 adrenoreceptor agonist, clonidine, in patients with diarrhea-predominant irritable bowel syndrome (D-IBS) in a double-blind, randomized, parallel-group, placebo-controlled trial. METHODS: A 2-week run-in evaluated baseline symptoms. Patients received 0.05, 0.1, or 0.2 mg clonidine or placebo twice a day for 4 weeks. We evaluated satisfactory relief of IBS by weekly question and stool parameters with a daily diary. Satisfactory relief and overall bowel function were primary end points. Secondary end points were stool frequency, consistency, and ease of passage; gut transit; and fasting and postprandial gastric volumes. Analysis followed intention-to-treat principles. RESULTS: Forty-four D-IBS patients participated; there were 4 treatment-related dropouts: 2/2 in the 0.2-mg and 2/12 in the 0.05-mg clonidine groups. Proportion with satisfactory relief of IBS was 0.46, 0.42, and 0.67 with placebo, 0.05 mg, and 0.1 mg clonidine, respectively. Relief was sustained through 4 weeks of treatment, and bowel dysfunction (firmer stools and easier stool passage [P < 0.05]) was reduced with clonidine, 0.1 mg twice a day. Clonidine did not significantly alter gastrointestinal transit or gastric volumes. Drowsiness, dizziness, and dry mouth were the most common adverse events with the 0.1-mg dose; severity of adverse effects subsided after the first week of treatment. A trial to replicate 20% or more responders with clonidine will require 95 patients per treatment arm. CONCLUSIONS: Clonidine, 0.1 mg twice a day for 4 weeks, relieves bowel dysfunction and appears promising for relief of D-IBS; these effects are unassociated with significant alterations in transit.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Association between prolonged bleeding time and gastrointestinal hemorrhage in 102 patients with liver cirrhosis: results of a retrospective study.

BACKGROUND: Gastrointestinal bleeding is a frequent complication of liver cirrhosis (LC) and represents an important warning sign of imminent death. Platelet dysfunction is an abnormality occurring prevalently in severe liver failure, and could well predispose to bleeding. METHODS: One hundred and two patients with liver cirrhosis diagnosed by needle liver biopsy were studied. According to the Child-Pugh classification, 23 were A class, 42 B class and 37 C class cases. Prothrombin activity, aPTT, fibrinogen, FDPs, XDP and platelet count were measured in each patient; bleeding time was measured in all but 17 of them. Forty (39%) had experienced gastrointestinal bleeding during the last 3 years (2 A class, 12 B class, 26 C class). RESULTS: Patients with a history of previous gastrointestinal bleeding showed lower values for prothrombin activity and fibrinogen, and higher percentage of elevated FDP and XDP levels; moreover, they presented lower platelet counts and more prolonged bleeding times than patients without gastrointestinal blood loss. CONCLUSIONS: While our findings confirm the relationship between hyperfibrinolysis and bleeding, the association between bleeding time prolongation and gastrointestinal blood loss suggests studying platelet function prospectively in LC in order to analyze its role, if any, in favoring hemorrhage activity.

Adult↗

PubMedDate not supplied

Parenteral feeding in a patient with hypertriglyceridemia and increased liver enzyme levels.

OBJECTIVE: To discuss nutritional support in a patient with hypertriglyceridemia and liver dysfunction. METHODS: We describe the hospital course of a critically ill patient with hepatic dysfunction and hypertriglyceridemia who required nutritional support, and we provide an overview of lipid metabolism. RESULTS: A 27-year-old man with hepatic dysfunction and hypertriglyceridemia, who had undergone kidney transplantation 4 months previously, was admitted to the intensive-care unit with upper gastrointestinal bleeding. He was unable to tolerate enteral feeding, and central parenteral nutrition was initiated. Calories from dextrose and fat were limited because of the presence of increased liver enzyme levels and hypertriglyceridemia. A modified regimen of parenteral nutrition was developed for the patient. The short-term reduction of total calories to 75% of the predicted need is safe. CONCLUSION: Nutritional support in patients with liver dysfunction and hypertriglyceridemia is complicated and may require temporary underfeeding because of the need to limit fat and dextrose intake.

Journal Article↗

PubMed1990

Phase I study of oral spirogermanium.

Thirty-three patients with advanced malignancy were treated with oral spirogermanium in a Phase I study to determine a maximum tolerated dose. Patients were entered in the study at doses of 100, 200, and 300 milligrams daily. The dose-limiting toxicity was gastrointestinal with moderate nausea and vomiting occurring with the 300 milligram dose. No myelosuppression or renal dysfunction was noted. Elevations of serum transaminase were seen in 41 percent of the patients at study entry. While abnormalities in hepatic function were recorded during the study, the relationship to spirogermanium could not be determined. No patient exhibited clinical hepatic dysfunction or elevation of serum bilirubin. It is recommended that future studies of oral spirogermanium incorporate careful monitoring of these parameters. Two patients with lymphoproliferative disorders had objective responses to therapy. A dose of 200 milligrams is recommended for further Phase II trials.

Administration, Oral↗

PubMed1991

Effect of the somatostatin analogue octreotide acetate on hemostasis in humans.

Octreotide acetate is a somatostatin analogue that has been shown to ameliorate the side effects of excessive secretion of hormone from benign and malignant tumors. The ability of this drug to inhibit the growth of malignant cells and to control gastrointestinal hemorrhage will prompt additional clinical trials. Because some of these patients may have thrombocytopenia, platelet dysfunction, or a coagulopathy, we studied tests of platelet function and blood coagulation in 15 patients before and after 14 days of therapy with octreotide acetate at a dosage of 500 micrograms three times daily. We found no substantial change in the results of these tests, and no patient experienced bleeding or thrombosis. These results suggest that octreotide acetate does not adversely affect platelet function or the coagulation system in humans.

Adenoma, Islet Cell↗

PubMed2003

Permanent prostate brachytherapy in men with clinically localised prostate cancer.

Permanent prostate brachytherapy techniques are associated with excellent biochemical control for patients with localised prostate cancer. Ten-year data show that permanent prostate brachytherapy is compatible with external beam irradiation or radical prostatectomy. However, treatment protocols and techniques for prostate brachytherapy vary between centres and there is little conformity of treatment protocols. The selection of patients for monotherapy or combined external beam irradiation and brachytherapy is controversial. The role of neoadjuvant androgen deprivation also remains unanswered in patients with localised prostate cancer. In addition, post-implant dosimetry may in fact be more significant for predicting outcome than the addition of adjuvant therapies, and should be a requirement when performing prostate brachytherapy. Data now seem to support specific computed tomography (CT)-based criteria to evaluate implant quality and delivered dose to the prostate. Unfortunately, prostate oedema and poor imaging techniques are limiting factors for evaluating implant dosimetry. Treatment planning techniques that use new treatment planning computers may assist in improving the implant procedure and dosimetry and are now available.

Androgen Antagonists↗

PubMed2003

High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study.

Impaired exocrine pancreatic secretion has been frequently observed in diabetic patients by different methods, including direct function tests. However, the clinical importance remained unclear. In the present study, the fecal fat excretion in patients with type 1 or type 2 diabetes mellitus and exocrine dysfunction according to fecal elastase 1 concentrations <100 microg/g was investigated. Subjects with a history of gastrointestinal cancer, gastrointestinal surgery, alcohol abuse, or inflammatory diseases were excluded. In 101 patients the mean (+/- SD) fat excretion was 9.19 +/- 5.39 g. Only 41 patients (40.6%) had normal fat excretion <7 g/day. In 40 patients (39.6%), it was higher than 10 g/day, indicating relevant steatorrhea. The fat excretion did not correlate with diabetes type, duration, or clinical symptoms. This finding is of some clinical importance and might influence pathophysiological concepts and the management of diabetic patients.

Celiac Disease↗

PubMed2002

The pathophysiological basis of acute-on-chronic liver failure.

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short and long-term prognosis. This review focuses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that the liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver support strategies to enhance the recovery process.

Acute Disease↗

PubMed1998

The influence of apoptosis on intestinal barrier integrity in rats.

BACKGROUND: Apoptosis is a critical step responsible for maintaining the cellular balance between proliferation and death and for controlling tumorigenesis. Although an increase in intestinal apoptotic cells has been considered to be associated with the pathogenesis of gastrointestinal injury, little is understood concerning the role of apoptosis in the development of intestinal barrier dysfunction. METHODS: Apoptosis induced by intraperitoneal injection of doxorubicin in rats was evaluated by transmission electron microscopy and the TUNEL histochemistry method. Treatment with deoxy-D-glucose (a glycolytic pathway inhibitor) or cycloheximide (a protein synthesis inhibitor) was performed after doxorubicin challenge. Passage of human serum albumin from blood to the intestinal interstitium and the intestinal lumen or from the intestine to the intestinal interstitium and blood was evaluated by means of albumin clearance. RESULTS: A significant increase in gut water content, albumin flux, and bidirectional clearance of albumin accompanied by apoptotic epithelial cell increase was noted in doxorubicin-challenged rats treated with saline. The increase in endothelial and epithelial permeability and the increase of apoptosis could partly be prevented by treatment with deoxy-D-glucose or cycloheximide. CONCLUSION: Doxorubicin-increased epithelial apoptosis within the intestine occurs simultaneously with increased bidirectional permeability of the intestinal barrier, probably associated with both glycolytic and protein synthesis pathways. Apoptosis may thus play a role in the pathogenesis of intestinal barrier dysfunction.

Animals↗

PubMed1997

'Tomudex' (raltitrexed) development: preclinical, phase I and II studies.

Raltitrexed ('Tomudex', formerly ZD1694) is a new active drug for advanced colorectal cancer, an area that has been without new drugs for over 40 years. It has a convenient dosing schedule and a potential for lower toxicity which represent important advantages over existing treatments. Advanced colorectal cancer is currently treated with 5-fluorouracil, generally in combination with other agents such as leucovorin. This leads to complex dosing schedules with increased activity but potentially serious toxicity. Raltitrexed is a novel cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other current agents, raltitrexed inhibits thymidylate synthase directly, specifically and non-competitively, which may lead to an improved toxicity profile. It is retained within cells as polyglutamate metabolites, allowing a more convenient dosing schedule than for 5-fluorouracil. Phase I and pharmacokinetic studies established the optimum dosing schedule as 3 mg/m2, administered in a single 15-min intravenous infusion once every 3 weeks. In a phase II study in 177 patients with advanced colorectal cancer, this dose produced a response rate of 26% and median survival of 11.2 months. The safety profile was acceptable, the main adverse events being myelosuppression, gastrointestinal toxicity, asthenia and transient asymptomatic increases in liver transaminases without evidence of any other liver dysfunction. Activity of raltitrexed has also been observed in a range of other solid tumours, including breast, pancreatic, non-small-cell lung and refractory ovarian cancer.

Antimetabolites, Antineoplastic↗

PubMed2006

Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease.

Nitric oxide (nitrogen monoxide) (NO) plays an important role in a wide range of physiologic processes. A major mediator of endothelial function, NO regulates vasodilatory and antithrombotic actions in the vasculature and plays a role in reproductive functions, bronchodilation, bone formation, memory, insulin sensitivity, and gastrointestinal relaxation. NO is formed from NO synthase. Impaired NO bioactivity is strongly associated with endothelial dysfunction and cardiovascular disease, but is also implicated in a broad range of other disorders, including pulmonary hypertension, insulin resistance, erectile dysfunction, and preeclampsia. Numerous therapies designed to target NO are being investigated and developed, including NO donors and stimulants. The recent African-American Heart Failure Trial (A-HeFT) showed that the NO donor isosorbide dinitrate, combined with the vasodilator hydralazine, significantly reduced morbidity and mortality in black patients with moderate-to-severe heart failure. Antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation beta-blockers, are NO stimulants that have demonstrated significant improvement of endothelial function and NO bioactivity. Other cardiovascular therapies that may improve NO bioactivity include statins, l-arginine, and nonpharmacologic approaches such as exercise and dietary changes.

Acetylcholine↗

PubMed1988

Consequences of phosphate imbalance.

Phosphorus is the sixth most abundant element in the body after oxygen, hydrogen, carbon, nitrogen, and calcium. It comprises about 1% of the total body weight of humans. Eighty-five percent of it is stored in the bone in the form of hydroxyapatite crystal; 14% is in the soft tissues in the form of energy-storing bonds with nucleotides (ATP, GTP), nucleic acids in chromosomes and ribosomes, 2,3-DPG in the red blood cells, and phospholipids in the cells' membranes. Less than 1% is in the extracellular fluids. Phosphate balance is maintained by multiple systems. The gut is responsible for the absorption of two thirds of the 4-30 mg/kg/day of phosphate intake. Absorption sites are all along the gut; in humans the most active site is the jejunum. The kidney filters 90% of the plasma phosphate and reabsorbs it in the tubuli. In states of hypophosphatemia the kidney can reabsorb the filtered phosphates very efficiently, reducing the amount excreted in the urine virtually to zero. The healthy kidney can excrete high loads of phosphate and rid the body of phosphate overload. Through the vitamin D-PTH axis the endocrine system regulates the phosphate balance by influencing the kidney, gut, and bone. Other hormones, including thyroid, insulin, glucagon, glucocorticosteroid, and thyrocalcitonin, play a lesser role in regulation of phosphate metabolism. Because of the complex control of phosphate homeostasis, various clinical conditions may lead to hypophosphatemia. These include nutritional repletion, gastrointestinal malabsorption, use of phosphate binders, starvation, diabetes mellitus, and increased urinary losses due to tubular dysfunction. The clinical picture of phosphate depletion is manifested in different organs and is due mainly to the fall in intracellular levels of ATP and decreased availability of oxygen to the tissues, secondary to 2,3-DPG depletion. The various manifestations of phosphate depletion are listed in Table 2. The treatment of hypophosphatemia consists of administering enteral or parenteral phosphate salts. An important aspect of dealing with the potentially serious effects of phosphate depletion is to prevent the depletion from happening in the first place. Hyperphosphatemia can occur in renal failure, hemolysis, tumor lysis syndrome, and rhabdomyolysis. The treatment of hyperphosphatemia usually consists of fluid administration (in the absence of kidney failure). In chronic hyperphosphatemia, phosphate binders such as aluminum and magnesium salts can reduce the phosphate load. The use of these phosphate binders is limited by their potential side effects.

Female↗

PubMed1988

Myocardial failure and shock in iron poisoning.

Shock is a well-known complication of iron poisoning. Its aetiology is multifactorial with hypovolaemia due to gastrointestinal blood loss and myocardial depression due to systemic acidosis contributing to its genesis. Primary myocardial dysfunction has not been considered to play a role. Our clinical experiences and autopsy findings in three fatal cases of iron poisoning support myocardial dysfunction and damage as contributing factors to their cardiovascular collapse. The three patients, all female, were 3 1/2, 16 and 28-years-old. Onset of shock occurred at 1, 2 and 5 days post-ingestion. There was no response to vigorous fluid replacement therapy and aggressive catecholamine infusions. Central venous pressures were elevated. Microscopic examination of postmortem tissue showed myocardial damage and the presence of stainable iron. It is speculated that the myocardial depression is mediated by lipid peroxidation of myocyte organelle membranes due to iron catalysed free radical generation. The presence of myocardial dysfunction has therapeutic implications. Patients with severe iron poisoning require early and serial measurements of arterial blood pressure, central venous pressure and cardiac output. If primary myocardial dysfunction is documented then fluid replacement, inotropic support and afterload reduction should be considered.

Adolescent↗

PubMed2005

Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Adult↗