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PubMed2002

Oxybutynin chloride: alterations in drug delivery and improved therapeutic index.

Oxybutynin chloride (Ditropan, Alza) is widely regarded as the most efficient antimuscarinic agent for the treatment of bladder detrusor dysfunction resulting in urinary urgency, frequency and urge incontinence. Oxybutynin metabolism occurs primarily in the proximal gastrointestinal tract and the hepatic circulation and is mediated by the cytochrome P450 3A4 isozyme. The major degradation products are desethyloxybutynin, which possesses pharmacological activity, and phenylcyclohexylglycolic acid, which is metabolically inert. A major limitation to long-term compliance with immediate-release oxybutynin remains the necessity for twice- or thrice-daily dosing regimens to provide sustained pharmacological efficacy. Side effects induced by cytochrome P450 metabolism of oxybutynin into the primary metabolite desethyloxybutynin within the gut wall substantially affect the tolerability of the compound within the individual. The oral osmotic delivery system provides unique advantages for drug delivery and substantially alters the tolerability profile of the oxybutynin chloride compound. This extended-release formulation consists of a two component core encapsulated by a semi-permeable membrane. The osmotic gradient between the surrounding environment and the inner core of the delivery system remains constant and water absorption within the capsule is controlled by the semipermeable membrane causing a controlled release of drug, which is sustained over 24 h. Herein are reviewed the various pre- and post-approval trials which have documented the overall therapeutic index of the oral osmotic oxybutynin (Ortho-McNeil Pharmaceuticals). Subsequent post-market surveillance issues are reviewed as are new developments in oxybutynin delivery.

Animals↗
PubMed1999

Systematic review and guide to selection of selective serotonin reuptake inhibitors.

A meta-analysis of 20 short term comparative studies of 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) has shown no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. There were suggestions that fluoxetine caused more agitation, weight loss and dermatological reactions than the other SSRIs. More patients discontinued fluvoxamine and fewer patients stopped sertraline because of adverse effects than their comparator SSRIs. The most common adverse reactions to the SSRIs were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache and tremor). Data from the Committee on Safety of Medicines showed more reports of suspected reactions (including discontinuation reactions) to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine, than the other SSRIs during their first 2 years of marketing. Prescription-event monitoring revealed a higher incidence of adverse events related to fluvoxamine than its comparators. There were higher incidences of gastrointestinal symptoms, malaise, sedation and tremor during treatment with fluvoxamine and of sedation, tremor, sweating, sexual dysfunction and discontinuation reactions with paroxetine. Fluoxetine was not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs. Patients have survived large overdoses of each of the compounds, but concern has been expressed over 6 fatalities following overdoses of citalopram. Drug interactions mediated by cytochrome P450 enzymes are theoretically less likely to occur during treatment with citalopram and sertraline, but there is a sparsity of clinical data to support this. Methodological difficulties and price changes do not allow choice for recommendations on the choice of SSRI based on pharmacoeconomic data. Taking into account the strengths and weaknesses of the methods used to compare drugs, guidelines to the selection of individual SSRIs in clinical practice are proposed. Citalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions, while paroxetine should be avoided if previous discontinuation of treatment was troublesome. When in doubt about the risks of drug interactions, citalopram or sertraline should be considered given the lower theoretical risk of interactions.

Humans↗
PubMed2005

Unusual findings during abdominal placement of a ventriculoperitoneal shunt: report of three cases.

The authors present three cases of infants born with myelodysplasia. Each infant underwent closure of a myelomeningocele and within 2 to 4 days placement of a ventriculoperitoneal (VP) shunt. In each case, on opening the peritoneal cavity, the authors observed egress of a dark or creamy dark fluid. None of the patients had a history of abdominal birth trauma. The decision was made to continue the procedures and send samples of the unusual fluids to the laboratory for culture and analysis. The cultures proved to be nondiagnostic and the characteristics of the fluid samples were most consistent with those of blood-tinged chyle. The authors hypothesize that, occasionally, the mechanical tautness that is created with repair of myelomeningoceles is sufficient to rupture small lymphatic vessels and accompanying blood vessels of the abdomen. An alternative hypothesis is that abdominal compression due to closure of the myelomeningocele may temporarily compress the liver, leading to raised intraportal pressures and resulting in weeping of chyle from the gastrointestinal tract. This abnormal fluid accumulation did not lead to chronic ascites, VP shunt infection, or dysfunction at long-term follow-up examination and abdominal visceral function has not been an issue.

Ascitic Fluid↗
PubMed2001

The prevalence of faecal incontinence and constipation in a general New Zealand population; a postal survey.

AIMS: To determine the prevalence of constipation and faecal incontinence in the community. METHODS: A 20-question multi-field postal questionnaire was sent to 1500 adults (over 18 years) randomly selected from the electoral roll in the Canterbury region. Questions detailed frequency of bowel function, time spent at the toilet, incidence and severity of faecal incontinence, constipation, and the effect of disordered bowel function. RESULTS: Of 1500 questionnaires, 717 (48%) were returned (male: female 388:329). The median age was 46 years (range 18-70). 24 (4%) had self-reported gastrointestinal disease. There was a median frequency of seven bowel motions per week (BM/wk) (range 1 to 70) with 89% having between two motions a day and one every two days. Faecal incontinence affected lifestyle in 58 (8.1%). Incontinence of solid stool at least once a month occurred in 70 (9.8%), of liquid stool in 91 (12.7%), of gas in 459 (64%), while 12 (2%) regularly wore a pad. Those with self-reported gastrointestinal disease had a significantly higher (p<0.05) bowel motion frequency (17 vs 7 BM/wk) and median faecal incontinence score (2.5 vs 0). Laxatives were used by 4.9% of the population, while 26.2% increased fibre to avoid constipation. CONCLUSIONS: The normal frequency of bowel motions (+/- 2SD) was 2-17 per week. Faecal incontinence affecting life style affected 8.1%, while constipation requiring regular laxative use affected 4.9% of people. There is acceptance in the community that a moderate degree of bowel dysfunction is normal. Stool frequency and faecal incontinence scores can be used to predict those most likely to have organic gastrointestinal disease.

Adolescent↗
PubMedDate not supplied

Calcium pyrophosphate dihydrate deposition disease and familial hypomagnesemia.

A 40-year-old woman presented with calcium pyrophosphate synovitis and chondrocalcinosis. She was subsequently found to have hypomagnesemia, as did her 22-year-old son. Metabolic studies demonstrated normal gastrointestinal absorption of magnesium, and impaired renal conservation of magnesium without other evidence of renal tubular dysfunction. It seems likely that a genetically determined abnormality of magnesium metabolism was responsible for the occurrence of chondrocalcinosis in this patient.

Adult↗
PubMed1994

[Disorders of the hemostasis system in patients with mitral valve prolapse].

Mitral prolapse is frequently encountered in association with other manifestations of mesenchymal dysplasia (skin hyperelastosis, joint hypermobility, dislocations, etc.) and occasional bleedings. Of 35 cases reported, 17 had petechiae and ecchymoses, 1 had hematuria, the rest suffered from bleedings: nasal (22 cases), profuse menstrual (19 cases), long-term extraction and cut bleedings (9 cases), gastrointestinal (3 cases). Hemorrhages of different sites often occurred in combination. Hemostatic investigations revealed: platelet aggregation dysfunction, Willebrand syndrome, end coagulation disturbances, lack or anomalies of factors VII, X and II (14, 17, 12 and 4 patients, respectively).

Adolescent↗
PubMed1994

A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.

OBJECTIVE: To compare escalating doses of immediate-release (IR) and sustained-release (SR) niacin for effectiveness in reducing levels of low-density lipoprotein cholesterol and triglycerides and increasing levels of high-density lipoprotein cholesterol, and for the occurrence of adverse reactions, especially hepatotoxicity. DESIGN: Randomized, double-blind, parallel comparison of IR and SR niacin administered sequentially at 500, 1000, 1500, 2000, and 3000 mg/d, each for 6 weeks. SETTING: Cholesterol research center. PATIENTS: Forty-six adults, 23 in each group, with low-density lipoprotein cholesterol levels greater than 4.14 mmol/L (160 mg/dL) after 1 month of a step 1 National Cholesterol Education Program diet. OUTCOME MEASURES: Fourteen-hour fasting lipid and lipoprotein cholesterol levels, results of clinical laboratory tests, a symptom questionnaire, and withdrawal rates. RESULTS: The SR niacin lowered low-density lipoprotein cholesterol levels significantly more than IR niacin did at the dosage of 1500 mg/d and above, while IR niacin increased high-density lipoprotein cholesterol levels significantly more than SR niacin did at all dosage levels. The reduction in triglyceride levels was similar with IR and SR niacin. Nine (39%) of the 23 patients assigned to the IR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were vasodilatory symptoms, fatigue, and acanthosis nigricans. Eighteen (78%) of the 23 patients assigned to the SR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were gastrointestinal tract symptoms, fatigue, and increases in levels of liver aminotransferases, often with symptoms of hepatic dysfunction. None of the patients taking IR niacin developed hepatotoxic effects, while 12 (52%) of the 23 patients taking SR niacin did. CONCLUSION: The SR form of niacin is hepatotoxic and should be restricted from use. The IR niacin is preferred for the management of hypercholesterolemia but can also cause significant adverse effects and should be given only to patients who can be carefully monitored by experienced health professionals.

Adult↗
PubMed1991

The gastrointestinal management of patients undergoing heart transplantation.

Between March 1985 and December 1989, 86 patients underwent heart (80) or heart-lung (6) transplantation. Thirty-seven (43%) developed one or more significant gastrointestinal problems. Dyspepsia and gallbladder disease were common, but easily managed. Cytomegalovirus disease occurred in 25 patients (29%) and required aggressive investigation and early therapy with ganciclovir; all patients so treated responded satisfactorily. Features of acute peritonitis were seen in 6 patients and required exploratory laparotomy in 4. Non-Hodgkin's lymphoma of the stomach in one patient has regressed following a combination of reduction in immunosuppressive therapy and a course of chemotherapy. The development of hepatitis or severe liver dysfunction of unknown cause has been associated with significant morbidity and mortality. Since this study was undertaken, the incidence of gastrointestinal complications has been greatly reduced by modifications to our immunosuppressive and anti-infection prophylactic drug protocols. Nevertheless, such complications still occur and it is important that the gastroenterologist should understand the need for urgent and intensive investigation and therapy.

Female↗
PubMed2001

The role of serotonin in the pathophysiology of irritable bowel syndrome.

Coordinated activities of the central, autonomic, and enteric nervous systems modulate intestinal motor, sensory, and secretory activities that may contribute to the triad of dysfunction (altered motility, altered sensation, and psychosocial distress) observed in patients with irritable bowel syndrome (IBS). Autonomic modulation of gastrointestinal (GI) function occurs via the actions of neurotransmitters and neuromodulators such as serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine, and dopamine. Of those modulators, serotonin has received the most attention with respect to disorders of GI function. Serotonin exerts its effects via neurocrine, paracrine, and endocrine pathways. Recent studies have demonstrated that serotonin, acting primarily through 5-HT3 and 5-HT4 receptors, is intricately involved in initiating the peristaltic reflex and facilitating intraluminal secretions. Serotonin receptors mediate reflex control of GI motility and secretion and may influence the perception of bowel function and pain under some circumstances. GI motor activity and sensory dysfunction in patients with IBS may be a result of alterations in serotonin levels or associated 5-HT receptors. Serotonin agonists and antagonists such as tegaserod, a 5-HT4 agonist, may offer new treatments that normalize GI motor and sensory functions in patients with disorders of GI function.

Clinical Trials as Topic↗
PubMed1999

The autonomic nervous system in functional bowel disorders.

Communications along the brain-gut axis involve neural pathways as well as immune and endocrine mechanisms. The two branches of the autonomic nervous system are integrated anatomically and functionally with visceral sensory pathways, and are responsible for the homeostatic regulation of gut function. The autonomic nervous system is also a major mediator of the visceral response to central influences such as psychological stress. As defined, functional disorders comprise a constellation of symptoms, some of which suggest the presence of altered perception, while other symptoms point to disordered gastrointestinal function as the cause of the symptoms. A growing number of reports have demonstrated disordered autonomic function in subgroups of functional bowel patients. While a number of different methods were used to assess autonomic function, the reports point to a generally decreased vagal (parasympathetic) outflow or increased sympathetic activity in conditions usually associated with slow or decreased gastrointestinal motility, while other studies found either an increased cholinergic activity or a decreased sympathetic activity in patients with symptoms compatible with an increased motor activity. Under certain conditions, altered autonomic balance (including low vagal tone and increased sympathetic activity) may alter visceral perception. Autonomic dysfunction may also represent the physiological pathway accounting for many of the extraintestinal symptoms seen in irritable bowel syndrome patients and some of the frequent gastrointestinal complaints reported by patients with disorders such as chronic fatigue and fibromyalgia.

Autonomic Nervous System↗
PubMedDate not supplied

Clinical significance of changes of flora in the upper digestive tract.

Dysbiosis does not necessarily mean disease. Typical clinical picture of disease caused by metabolic activity of dysbiotic microflora is the microbial over-growth syndrome. We studied case histories of 434 patients without consideration of their basic illnesses and correlated them with types of dysbioses of duodenal juice. 55% of 314 patients with gastrointestinal disorders revealed a dysbiosis. A dysbiosis could also be found in up to 64% of pancreatic diseases, whereas intestinal dysfunctions and chronic inflammatory diseases usually show normal colonization. These cases express alteration of milieu conditions and disturbed interorganic connections. We only treated cases with objective pathological findings, obtaining best results with chemotherapeutic treatment of dysbioses with only one species.

Bacterial Infections↗
PubMed2000

Neuromuscular dysfunction in the jejunum and colon of human leukocyte antigen B27 transgenic rats.

HLA-B27 transgenic rats are a model of spontaneous gastrointestinal inflammation associated with expression of human leukocyte antigen (HLA) B27 and beta(2)-microglobulin. Our goal was to investigate in vitro enteric nerve regulation and contractile activity in isolated longitudinal muscles from the jejunum and colon of HLA-B27 rats. Nontransgenic age-matched Fisher 344 rats were used as controls. Intestinal inflammation and tissue injury, quantified histologically and through tissue myeloperoxidase activity, were evident in both the jejunum and colon of HLA-B27 rats. Although resting tension and spontaneous activity of the jejunal and colonic muscles from HLA-B27 rats did not differ significantly from controls, responses to both enteric nerve stimulation or direct muscle activation were significantly inhibited. In muscles from HLA-B27 rats, electrical field stimulation (0.5 ms, 0.5-20 Hz) induced low-amplitude contractions (maximal reduction 60-65%) compared with respective controls. In the presence of atropine and guanethidine, nonadrenergic and noncholinergic contractile responses to higher frequencies of stimulation (8-20 Hz) were also of lower amplitude. These changes were accompanied by a shift in neurally mediated contractions from predominantly cholinergic in the jejunum and colon of Fisher 344 rats to predominantly nonadrenergic and noncholinergic in HLA-B27 rats. Furthermore, maximal contractions to carbachol or KCl depolarization were reduced (up to 2.7-fold) compared with respective controls. In the jejunum of HLA-B27 rats the EC(50) level for carbachol was decreased. The data indicate that gastrointestinal inflammation induced by expression of HLA-B27 is associated with hypocontractility and inhibition of enteric cholinergic control of the longitudinal muscle in both the small and large intestine.

Adrenergic Agents↗
PubMed2000

The role of radioactive iodine in salivary gland dysfunction.

The use of radioactive iodine has become an important adjunct to the treatment of thyroid cancer. Many normal tissues--including salivary glands, gastrointestinal mucosa, gonads, and lactating breast tissue--have the ability to concentrate radioactive iodine under normal circumstances. Although the mechanism is just beginning to be elucidated, it is this ability that might contribute to the immediate and long-term complications associated with radioactive iodine treatment. In some patients, the salivary complications can be permanent and might compromise daily functioning. In this article, we examine the salivary gland complications associated with radioactive iodine therapy, and we suggest potential protective mechanisms to circumvent these problems.

Cytoprotection↗
PubMed2004

Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT.

We developed a questionnaire to assess autonomic symptoms in patients with Parkinson's disease (PD) and evaluated its reliability and validity. Based on the results of a postal survey in 46 PD patients, 21 multiple system atrophy patients, and 8 movement disorders specialists, items were included according to their frequency, burden, and clinical relevance. The questionnaire was evaluated in 140 PD patients and 100 controls, and test-retest reliability was established in a sample of 55 PD patients. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction. Test-retest reliability was good. Autonomic problems increased significantly with increasing disease severity for all autonomic regions, except sexual dysfunction. We conclude that SCOPA-AUT is a reliable and valid questionnaire that evaluates autonomic dysfunction in PD.

Aged↗
PubMed1998

Quality of life in different gastrointestinal conditions.

In recent years, there has been increasing interest in how gastrointestinal symptoms relate to and impact on patients' health-related quality of life. This is particularly the case for functional gastrointestinal disorders that are characterized by a lack of biological markers for disease activity. There is only a slight variation in the type of gastrointestinal symptoms reported with different gastrointestinal disorders, and patients with dyspepsia or irritable bowel syndrome, for example, often describe a variety of gastrointestinal symptoms with considerable overlap between them. The same pattern has been observed in patients with gastroesophageal reflux disease, even though heartburn and acid regurgitation are easier to distinguish from other gastrointestinal symptoms, particularly in patients in whom objective reflux is verified. Most aspects of health-related quality of life in patients with gastrointestinal disorders are compromised, irrespective of diagnosis. Patients with functional disorders seem, if anything, to display more emotional distress than those with organic disorders. Given the considerable overlap between different gastrointestinal symptom clusters, it is not surprising that these conditions have a similar impact in terms of perceived health status and quality of life. The key factors associated with the degree of perceived distress and dysfunction relate to disease severity and the presence of abdominal pain symptoms.

Attitude to Health↗
PubMed2003

Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group.

Oxaliplatin, which was recently approved by the US Food and Drug Administration for the treatment of advanced colorectal cancer, is often administered to patients with altered liver function caused by hepatic metastases. Because of the absence of data on the clearance of oxaliplatin in patients with liver dysfunction, and to develop dosing recommendations for the safe use of oxaliplatin in this clinical setting, the Organ Dysfunction Working Group of the National Cancer Institute performed a phase I and pharmacokinetic trial of this drug in patients displaying a wide range of liver function abnormalities. Sixty patients grouped into five classes of liver function were enrolled in this study, including a 12-patient control group with normal liver function, 15 patients with "mild," 16 patients with "moderate," and 16 with "severe" liver dysfunction, as well as one patient who had undergone liver transplantation. The patients had a median age of 62 years and a Eastern Cooperative Oncology Group performance status of 0. All patients had received prior systemic chemotherapy, and 70% had a diagnosis of a gastrointestinal malignancy. The control patients were treated with 130 mg/m(2) oxaliplatin intravenously every 21 days; the starting doses for patients with mild, moderate, or severe liver dysfunction or post-liver transplantation were 105, 80, or 60 mg/m(2), respectively. Cohorts of three or more patients were escalated from these starting doses to 130 mg/m(2) if dose-limiting toxicities were not observed, and pharmacokinetic evaluations were performed at each dose level for every category of liver dysfunction. We found that oxaliplatin was well tolerated at its recommended dose and schedule of 130 mg/m(2) every 21 days in patients with all levels of liver dysfunction, and that there was no apparent alteration in the clearance of either total or ultrafilterable platinum species from plasma, even in patients with severe hepatic functional abnormalities.

Antineoplastic Agents↗
PubMed2000

Characterization of intracellular cytokine profile of CD4(+) T cells in peripheral blood and tumor-draining lymph nodes of patients with gastrointestinal cancer.

BACKGROUND: Analysis of serum cytokine levels has shown that cancer-bearing hosts have lower levels of IL-2 and IFN-gamma, suggesting that Th1-type immunity is impaired by cancer. However, the mechanisms of the Th1 dysfunction are not clearly understood. METHOD: The frequencies of Th1 cells in CD4(+) helper T cells were evaluated with an intracytoplasmic cytokine staining method in peripheral blood lymphocytes (PBL) and lymph node lymphocytes (LNL) of patients with gastrointestinal cancer. RESULTS: Activation of lymphocytes with PMA + Ionomycin induced the expression of IL-2 and IFN-gamma in each lymphocyte population. Compared with PBL of non-malignant donors, PBL in cancer patients contained significantly lower frequencies of CD4(+) T cells that produced IL-2 and IFN-gamma. LNL in cancer patients also contained lower levels of IL-2- and IFN-gamma-producing CD4(+) T cells, although the percentages did not show significant differences from those of PBL in the same patients. CONCLUSION: Our data suggest that suppression of Th1 cytokine in cancer patients is, at least in part, due to the decreased frequency of Th1 cells with CD4(+) phenotype.

CD4-Positive T-Lymphocytes↗