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In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat.

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta-frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC(50)), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar K(i) values. At a total serum ketoconazole of 2 microg/ml (3.76 microM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.

Algorithms↗

Effectiveness of the auscultatory method in predicting feeding tube location.

A clinical study was conducted to determine the extent to which sounds generated by air insufflations through feeding tubes could be used to predict where the tubes' ports ended in the gastrointestinal tract (esophagus, stomach or proximal small intestine), and to differentiate between gastric and respiratory placement. Sounds generated by a series of air insufflations through the tubes of 85 acutely-ill adult subjects were recorded. One hundred fifteen usable tape-recordings of sound sequences were obtained. The principal investigator later played the tapes for the research team members (who were also skilled clinicians) so that they could independently record their impressions of the sounds. (No identification of subjects or tube positions were given on the tapes; however, each site of auscultation was announced.) The results were collated and compared against the hypotheses and actual tube location (as determined by X-ray). Overall, the average percentage of correct classifications of each tape was 34.4%. Descriptive data were reported for three subjects with feeding tubes inadvertently positioned in the respiratory tract; air insufflations were clearly audible in 2 of the 3 cases. Clinicians should not rely on the auscultatory method to differentiate gastric from intestinal placement, nor gastric from respiratory placement of feeding tubes.

Adult↗

Absorption of isosorbide-5-mononitrate at specific sites in the gastrointestinal tract.

As part of a development program for controlled- and extended-release formulations of isosorbide-5-mononitrate (ISMN), the rate and extent of drug absorption was evaluated after site-specific delivery in the gastrointestinal (GI) tract. Seven healthy male subjects received, on separate occasions, 20 mg of ISMN solution orally and via nasogastric tube to the jejunum, terminal ileum, and ascending colon. Compared with oral administration (AUC 2,963 hr x ng/mL, Cmax 442 ng/mL, Tmax 0.81 hr), placement of drug directly into the jejunum did not change the extent (AUC 2,844 hr x ng/mL) but increased the rate of absorption (Cmax 630 ng/mL, Tmax 0.28 hr) due to direct placement of drug into the intestine. Administration to the terminal ileum resulted in a rate of absorption comparable to that from the jejunum (Tmax 0.28 hr) but a reduction in extent (mean AUC 2,377 hr x ng/mL). Delivery to the ascending colon resulted in a further decrease in the extent (AUC 2,017 hr x ng/mL) and a "slowing" of the rate of absorption compared with the two intestinal sites (Cmax 392 ng/mL, Tmax 0.68 hr). Overall, bioavailability throughout the GI tract was sufficient to support development of controlled- and extended-release formulations.

Administration, Oral↗

Continuous pump-tube enteric hyperalimentation.

The enteric route remains an overlooked site of alimentation. An intact functioning gastrointestinal tract can and should be used, even if the patient will not or cannot eat. The use of continuous pump-tube feeding of liquid diets through a small caliber feeding tube into the distal part of the duodenum or proximal portion of the jejunum is superior to previous methods of bolus tube feeding through large bore tubes placed in the stomach. A small tube has been developed which is inserted easily and positioned in the distal portion of the duodenum or proximal part of the jejunum. This tube has excellent patient tolerance. A suitable pump is essential to success. Elemental diets are not needed for routine enteric alimentation. They are expensive and, because of their hyperosmolarity, require a period of patient adaptation. Isocal, a complete liquid diet, essentially isotonic and lactose-free, provides 1 calorie per milliliter and has been used successfully as a pump-tube feeding diet. It rapidly converts the nitrogen balance of patients from negative to positive when given in quantities exceeding 30 calories per kilogram of body weight.

Aged↗

Surgical palliation of small bowel obstruction due to metastatic carcinoma.

Seventy-three patients with small bowel obstruction due to metastatic carcinoma were seen in the years 1960 to 1979. Twenty-nine patients were seen in the first decade and 44 patients in the second. The most common primary tumor causing metastatic small bowel obstruction was colonic carcinoma, followed by gastric carcinoma. Plain x-ray examinations supplemented by an upper gastrointestinal series with small bowel follow-through were the most useful diagnostic tests. Seventy per cent (51/73) of these patients were initially treated with intravenous fluids and gastrointestinal decompression using a short (32/51) or long (19/51) tube. In eight of 51 patients, nasogastric decompression relieved the obstruction, but in all but one of these patients symptoms and signs of obstruction recurred promptly after tube removal. At laparotomy, the majority of patients underwent either a bypass procedure or resection. The mean survival for the patients bypassed varied from four to seven months; for those that had resection it varied from five to nine months. The mortality rate was high--41 per cent in the first decade and 25 per cent in the second. Of the last 12 patients, eight received hyperalimentation before and after surgery. The operative mortality rate was 12.5 per cent and the mean survival was eight months. It is concluded that: 1) Colonic carcinoma is the most common primary tumor causing metastatic small bowel obstruction. 2) Tube decompression is rarely effective and surgical relief is necessary in the vast majority of cases. 3) Operative mortality has been reduced, partially because of more vigorous support, i.e., hyperalimentation, but the mean duration of survival has not changed significantly.

Abdominal Neoplasms↗

Inductive pathways leading to rat tear IgA antibody responses.

PURPOSE: To define the inductive pathways leading to rat tear IgA antibody responses. METHODS: Fluoresceinated dinitrophenylated bovine serum albumin was encapsulated in poly(lactide-co-glycolide) microparticles and was administered by intranasal, ocular topical, or gastrointestinal routes. Histologic methods were used to determine the microparticles' ability to access tissues associated with mucosal inductive pathways. Rats were immunized with microencapsulated antigen by intranasal or ocular topical routes. Tear IgA and serum IgG antibody concentrations were assessed by radioimmunoassay. The frequency of antibody-secreting cells in tissues, postulated to function in tear IgA induction, was measured by enzyme-linked immunospot assay. RESULTS: Although uptake of microencapsulated antigen was greatest at the site of delivery, ocular topical administration resulted in antigen uptake in the conjunctiva and in nasal-associated lymphoid tissue. Intranasal immunization resulted in earlier and significantly higher tear IgA and serum IgG antibody responses and in higher frequencies of antibody-secreting cells in corresponding draining cervical lymph nodes and lacrimal glands than did ocular topical immunization. CONCLUSIONS: Nasal-associated lymphoid tissue functions as a primary inductive site for tear IgA antibody responses by contributing triggered IgA-committed B cells to the lacrimal gland.

Administration, Intranasal↗

Comparison of nutritive and nonnutritive stimuli in intestinal and oral conditioned taste aversion paradigms.

The intestinal taste aversion paradigm has previously demonstrated that animals could orally discriminate between carbohydrate and fat subsequent to pairing a gastrointestinal (GI) infusion of 1 nutrient with lithium chloride (LiCl), whereas they could not discriminate between 2 nonnutritive flavors (A. L. Tracy, R. J. Phillips, M. M. Chi, T. L. Powley, & T. L. Davidson, 2004). The present experiments assessed the relative salience of nutritive and nonnutritive stimuli when presented either intestinally or orally. Two compound stimuli, each comprising 1 nutrient and 1 nonnutritive flavor, were presented in training and were paired with LiCl or saline. Subsequent oral intake of the nutrients alone, the flavors alone, or the compounds was measured. Results showed that rats discriminated both nutrients and flavors independently after GI or oral training, whereas the compounds were discriminated only after oral training, indicating substantive differences in the processing of these stimuli. This suggests that nutrient activation of the GI tract may potentiate learning about nonnutritive flavors analogously to taste-potentiated odor conditioning. The ability to learn about the oral properties of stimuli in the GI tract suggests a new account of delayed taste aversion learning as well as learning about the positive nutritive consequences of food consumption.

Analysis of Variance↗

A pharmacokinetic model describing pulsatile uptake of orally-administered carbon tetrachloride.

Many rodent bioassays have been conducted using oral gavage for delivery of test chemicals. Highly lipophilic compounds are generally administered to rodents dissolved in corn oil, a dosing vehicle shown to influence xenobiotic toxicity, carcinogenicity and pharmacokinetics by altering chemical absorption processes. In this paper, we present a multi-compartmental description of the gastrointestinal (GI) tract linked to a physiologically based pharmacokinetic (PB-PK) model to describe the complex oral uptake of carbon tetrachloride (CCl4) administered in corn oil and 0.25% Emulphor. The GI submodel was described using a series of subcompartments, each subcompartment described with an absorption constant (Ka, 1/h), a bioavailability term (A, unitless), and a compartment emptying time (T, h). The model was parameterized by fitting multi-peak blood and exhaled breath chamber concentration-time profiles following oral gavage of CCl4 in corn oil and aqueous vehicles to male Fischer 344 rats. Successful fitting of experimental data was accomplished by varying values of Ka, A, and T until adequate fits were obtained. Values of Ka and A required to fit data from aqueous gavage were greater than corn oil. Utilization of the multi-compartmental GI tract submodel provided increased precision in fitting complex oral uptake profiles compared to previously used one- and two-compartment oral uptake models. This model provides estimates of absorption rate constants and bioavailabilities as well as providing a framework for generation of more complete, physiologically-realistic descriptions of oral absorption.

Administration, Oral↗

The effect of selective decontamination of the digestive tract on gastrointestinal enterococcal colonization in ITU patients.

OBJECTIVE: The effect of selective decontamination of the digestive tract (SDD) on Intensive Therapy Unit (ITU)-acquired enterococcal infection and colonization was studied. Changes in the predominant species isolated and resistance patterns to antimicrobial agents were also studied. DESIGN: Three groups were investigated: historical control (HC), contemporaneous control (CC) and patients receiving SDD (topical polymyxin, amphotericin B and tobramycin throughout ITU stay with intravenous ceftazidime for the first 3 days only). SETTING: Adult general ITU with 7 beds. PATIENTS: Patients with a nasogastric tube in situ and who were likely to remain in ITU for 48 h or longer were recruited. RESULTS: Enterococcal infections occurred in 3 of 84 HC patients and 2 of 91 CC patients. There were no unit-acquired enterococcal infections in the SDD group. There were 140 episodes of enterococcal colonization occurring in 112 patients, with significantly more in the SDD and CC groups (p < 0.05. There were no significant differences in antibiotic sensitivities between the three groups. Enterococcus faecalis was the most frequently isolated species. CONCLUSION: SDD does not predispose to enterococcal infection but does encourage colonization in patients receiving the regimen and other patients in ITU at the same. There is a complex interaction of factors which influence faecal flora and the likelihood of patients becoming colonized or infected with enterococci.

Administration, Buccal↗

Creating a continent tubeless gastrostomy.

Standard tube feeding gastrostomy is associated with a myriad of problems among which leakage of gastric contents is the most serious. Over the years many methods of creating tubeless gastrostomy have been unsuccessful because of the extent of surgery required and the persistent leakage of gastric fluids. By using gastrointestinal staplers to create a gastric tube and by incorporating a reverse intussusception valve at its base, we created a continent tubeless feeding gastrostomy in 23 patients aged 10 to 81 years. Eight had head injuries, 12 had cerebrovascular strokes, and 3 had head and neck disorders leading to aphagopraxia. Twelve of the procedures were performed with local anesthesia and the remainder with general anesthesia. The GIA stapler was used to create a 5 cm gastric tube after which circumferential stitches were placed to intussuscept 2 cm of the tube into the stomach to create a valve. A 1 cm stoma was created at skin level. Operative time was 47 to 90 minutes and there were no operative deaths or complications. Stomal necrosis occurred in two patients so they were converted to a standard tube gastrostomy by leaving a Foley catheter in place. After 16 months of follow-up, one stricture developed at 4 months and two were electively closed under local anesthesia. None is incontinent. The tubeless continent feeding gastrostomy is convenient for both patients and nursing staff and should replace the standard feeding gastrostomy when long-term nutritional support is needed.

Adolescent↗

Radiologic gastrojejunostomy and percutaneous endoscopic gastrostomy: a prospective, randomized comparison.

PURPOSE: To compare the efficacy of radiologic guided placement of percutaneous gastrojejunostomy (PGJ) and percutaneous endoscopic gastrostomy (PEG). MATERIALS AND METHODS: Patients were randomized to PGJ (n = 66) or PEG (n = 69). Indications for gastrostomy were need for prolonged enteral nutrition (97%) or gastrointestinal decompression (3%), with etiologies of neurologic impairment (81%), head and neck neoplasm (12%), bowel obstruction (3%), or other (4%). Mean follow-up was 202 days and 30-day follow-up was obtained for 85% of patients. RESULTS: PEG was successful in 63 of 69 (91%) patients, while PGJ established access in all of 66 attempts (100%) (P = .014). Average procedural time was 53 minutes for PGJ and 24 minutes for PEG (P = .001). At 30-day follow-up, there were 33 and 45 complications in the PGJ and PEG groups, respectively. This difference was due to the greater incidence of pneumonia in the PEG group (P = .013). Long-term tube-related complications occurred with 17 PGJs and four PEGs (P = .007). The PGJ cost more than PEG, but this advantage was offset by the cost of complications. CONCLUSION: PGJ had higher success rate and fewer complications, due to a lower incidence of pneumonia. PEG took less time to perform, cost less, and required less tube maintenance.

Adolescent↗

[Early enteral nutrition in gastrointestinal surgery].

In a series of twenty similar patients, having a healthy small intestine and having undergone elective surgery, two protocols of alimentation were studied. Beginning from the 8th post-operative hour, enteral alimentation is carried out by means of access to the jejunum and continued for ten days. The volume of liquid in the alimentary canal is progressively increased allowing the intravenous route to be stopped on average after 3,9 days. The high amount of the nitrogen and calory supply limits the post-operative nitrogen catabolism and rapidly restores a positive nitrogen balance. In other respects the weight loss is less than 2%, the biological constants are stable and no serious complications are linked with this technique. The early use of GI tract deals with the alimentational and electrolyte needs of the post-operative patient and diminishes the risks of iatrogenic complications of long term intravenous infusions. Relying on experimental data proving the absence of cessation of peristalsis of the small intestine in the immediate post-operative period and also the continuation of its capacity for absorption, this work demonstrates the possibility of early enteral alimentation. A better knowledge of the indications and contra-indications of this technique of feeding, of its methods of administration, and of the capabilities of absorption of the alimentary canal, must extend its indications to the high risk operative patients.

Adult↗

Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition.

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague-Dawley rats following central intracerebroventricular administration of MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.

Animals↗

A prospective study on the use of water-soluble contrast follow-through radiology in the management of small bowel obstruction.

BACKGROUND: The purpose of this prospective study was to determine the value of water-soluble contrast follow-through radiology in predicting the outcome in patients with small bowel obstruction. METHODS: Patients with clinical and radiological evidence of small bowel obstruction were selected according to pre-set criteria. A water-soluble contrast follow-through examination using 76% urografin was carried out within 24 h of hospital admission. The result was interpreted as 'significant obstruction' if the contrast failed to reach the caecum in 4 h or if there was a clear cut-off in the gastrointestinal tract. The result was interpreted as 'insignificant obstruction' if the contrast reached the caecum within 4 h. The surgeon was blinded to the result of the contrast examination in the patient management, and the decision to operate was based entirely on conventional clinical grounds. RESULTS: Fifty-one patients in an 18 month period underwent the contrast examinations. Thirty-four patients (67%) had previous abdominal operations. The results showed that significantly more patients who had 'significant obstruction' on contrast radiology required surgery to relieve the intestinal obstruction (17/19) than those who had "insignificant obstruction' (1/32; Fisher's exact test, P < 0.0001). This difference was found to be significant in both patient subgroups: patients with or without previous abdominal operation. There was no major morbidity or mortality related to the contrast radiology procedure. CONCLUSIONS: Urografin follow-through examination is a safe procedure; using 4 h as the cut-off it is highly predictive of the outcome in small bowel obstruction in patients with or without previous abdominal operation.

Abdomen↗

Disease progression in gastro-oesophageal reflux disease as determined by repeat oesophageal pH monitoring and endoscopy 3 to 4.5 years after diagnosis.

OBJECTIVES: Reflux oesophagitis may progress to complications such as Barrett's mucosa and stricture formation. However, few studies have assessed long-term disease progression in oesophagitis patients and fewer still have considered disease progression in the significant proportion of gastro-oesophageal reflux disease (GORD) patients who do not have oesophagitis at diagnosis. The aim of this study was to reassess GORD patients 3 to 4 years after initial diagnosis and determine whether or not disease progression had occurred. METHODS: Prospective follow-up of 101 GORD patients at least 32 months after initial assessment with oesophageal pH monitoring and upper gastrointestinal endoscopy. Patients were invited to complete a symptomatic questionnaire and undergo repeat investigation with the same techniques. RESULTS: Seventy-seven (76%) patients responded (mean follow-up period 39 months, range 32-54 months) of whom 28 initially had oesophagitis (group A), 17 had normal endoscopy but abnormal pH monitoring (group B) and 32 had normal investigations but typical reflux symptoms (group C). At the time of follow-up, 57 (74%) patients either had frequent heartburn or were taking daily acid suppression therapy. Fifty-two (68%) responders had at least one repeat investigation: 44 (57%) had repeat pH monitoring; 43 (56%) had repeat endoscopy. Three (11% of the 28 responders) group A patients had developed Barrett's mucosa, 4 (24% of responders) group B patients had developed oesophagitis and 10 (31% of responders) group C patients had developed abnormal pH monitoring (4), oesophagitis (4) or both (2). CONCLUSION: Three-quarters of GORD patients still have troublesome symptoms at least 3 years after diagnosis and a significant proportion show endoscopic progression of the condition's severity.

Adult↗

Conservative management of pneumatosis intestinalis.

BACKGROUND: Pneumatosis intestinalis is a rare condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract; it may be associated with bowel ischemia, perforation, and a high mortality rate. As a result, many authorities advocate an aggressive surgical approach in patients with pneumatosis intestinalis. CASE: A 53-year-old female with recurrent, metastatic uterine leiomyosarcoma underwent resection of the pelvic recurrence, low anterior rectal resection with primary anastomosis, and partial hepatectomy for liver metastasis. Her postoperative course was notable for a small bowel obstruction and the finding of pneumatosis intestinalis on radiologic studies. The patient developed mild abdominal pain. She did not develop tenderness or fevers. She was managed with bowel rest, nasogastric tube decompression, total parenteral nutrition, and broad-spectrum antibiotics. The finding of pneumatosis intestinalis resolved over the ensuing 6 days. Her diet was slowly advanced, and she was discharged home in stable condition without further surgical intervention or recurrence of the obstruction or pneumatosis. Currently, her only evidence of disease is pulmonary metastases. CONCLUSIONS: In select patients, the outcome of a conservative approach to the management of pneumatosis intestinalis is not much different than surgical re-exploration for highly selected patients. The clinical condition of the patient, not solely the finding of pneumatosis intestinalis, should drive management in these cases.

Anti-Bacterial Agents↗

Reevaluation of routine gastrointestinal decompression after gastrectomy for gastric cancer.

BACKGROUND/AIMS: We reviewed postoperative courses of patients with gastric cancer who underwent gastrectomy to evaluate the need for routine postoperative gastrointestinal decompression. METHODOLOGY: Three hundred patients who underwent gastrectomy during 1998 and 1999 were enrolled in this study. A nasogastric tube was placed in all patients just after induction of the anesthesia. The patients were divided into two groups, 150 patients for each. In group 1, the nasogastric tube was maintained until the passage of flatus per rectum. In group 2, the nasogastric tube was removed immediately after the operation. RESULTS: The return of bowel function, return to a diet and postoperative length of hospital stay were similar in both groups. In group 1, only one patient (0.7%) had abdominal distension and no patient vomited, while four patients (2.7%) had abdominal distension and one patient (0.7%) vomited in group 2. There were no significant differences in the incidence of respiratory complications, anastomotic leakage and wound complications between the two groups. Postoperative death was rare, with the incidence of 0.7% in each group. There was a significantly high incidence of patient's discomfort in group 1. The major complaint was sore throat and it caused sleep disturbance when severe. CONCLUSIONS: It is desirable to insert a nasogastric tube while the patient is in the anesthetized state and keep it during operation and remove it immediately after operation, when no active bleeding is detected.

Decompression, Surgical↗

Enteral feeding in infants <1250 g starting within 24 h post-partum.

UNLABELLED: Establishing enteral feeding in the very low birth weight infant as soon as possible after birth has been shown to promote growth and reduce the need for intravenous lines. Human milk can be administered either as a continuous infusion or as intermittent boluses. The aim of this study was to investigate the effect of continuous versus bolus feeding on gastrointestinal tolerance, time to reach 120 ml/kg, 150 ml/kg and full enteral feeding, regain birth weight, duration of intravenous lines, incidence of septicaemia, persistent ductus arteriosus and necrotising enterocolitis. A retrospective analysis of hospital records was performed. Infants with a birth weight < 1250 g born during a 12-month period at Aker and Ullevål University hospitals in Oslo, who survived the first 21 days, were included in the study. A Total of 49 infants (25 continuous and 24 bolus) fulfilled the entry criteria and data from these infants were analysed. Enteral feeding volumes (120 ml/kg, 150 ml/kg and full) were attained significantly faster with continuous feeding (7 versus 12 days, 8 versus 14 days, 9 versus 12 days). Consequently the bolus group had a significantly longer duration of intravenous lines (14 versus 9 days). There were no differences regarding time to regain birth weight, the incidence of septicaemia, persistent ductus arteriosus or necrotising enterocolitis. CONCLUSION: infants of birth weight < 1250 g can be fed breast milk already from the 1st day of life and achieve full enteral feeds faster than previously reported even in more mature infants. Full enteral feeds are attained faster with continuous versus bolus feedings and continuous feeding therefore results in shorter need for intravenous fluids.

Enteral Nutrition↗