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Biomedical subjects

E Y Eaker

Publications and source records attributed to E Y Eaker.

31 records · Page 2Linked to original sources
PubMed1995

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction.

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20-33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2 +/- 0.3 AFs/4 hr, 2.7 +/- 0.7 min, and 85 +/- 23 min mm Hg to 4.1 +/- 0.8 AFs/4 hr, 5.5 +/- 0.7 min, and 152 +/- 24 min mm Hg, respectively (P < 0.05). Antral activity was decreased from 63 +/- 14 to 23 +/- 8% by octreotide (P < 0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

Adult↗
PubMed1994

Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy.

We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin. Gastric emptying was evaluated using a solid-phase radio-labeled meal. Patients were studied after erythromycin 200 mg intravenously (N = 9) and after an oral suspension of erythromycin 200 mg (N = 7) each given 15 min after ingestion of the meal. Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr. Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125-250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin. Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P < 0.01) in seven of nine patients with postsurgical gastroparesis [baseline T1/2 154 +/- 15 min; after intravenous erythromycin, T1/2 56 +/- 17 min (mean +/- SEM)]. Oral erythromycin enhanced (P < 0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baseline T1/2 146 +/- 16 min; after oral erythromycin, T1/2 87 +/- 20 min). Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks. In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.

Administration, Oral↗
PubMed1994

The distribution of novel intermediate filament proteins defines subpopulations of myenteric neurons in rat intestine.

BACKGROUND/AIMS: Recent studies with neurofilament antibodies as neuronal markers have shown subpopulations of myenteric neurons that do not contain neurofilament proteins. Novel neuronal intermediate filament proteins alpha-internexin, peripherin, and nestin have been identified. The aim of this study was to examine the distribution of these novel intermediate filaments in comparison with neurofilaments in myenteric plexus neurons. METHODS: Using indirect immunofluorescence techniques in whole-mount cryostat sections from neonate and adult rat small intestine and in primary cultures of myenteric neurons, the distribution of neurofilaments, alpha-internexin, peripherin, and nestin was studied in comparison with the neuronal marker protein gene product (PGP) 9.5 in myenteric neurons. RESULTS: Sixty-five percent of neurons contained neurofilament triplet proteins. alpha-Internexin and/or peripherin were found in the neurofilament-negative neurons. PGP 9.5 was present in 80% of the myenteric neurons. Of the neurons that were PGP negative, > 95% contained peripherin or alpha-internexin. Nestin was not found in either neonate or adult myenteric neurons but was seen in glial cells in culture. CONCLUSIONS: The results suggest that a subpopulation of myenteric neurons lacks neurofilament triplet proteins but contains either peripherin, alpha-internexin, or both. This selective distribution of intermediate filaments in subpopulations of enteric neurons may support differential roles in these structurally unique neurons.

Animals↗
PubMed1994

Antimyenteric neuronal antibodies in scleroderma.

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, double-labeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera (> or = 1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process.

Adolescent↗
PubMed1993

Myenteric plexus neurons have developmentally acquired differences in the medium molecular weight subunit of neurofilament protein.

We have previously shown that neurofilaments in enteric neurons are immunologically distinct from those found in the central nervous system. In particular, one monoclonal antibody to the medium molecular weight neurofilament subunit, called NN18, stained the perikarya of enteric neurons very weakly, if at all, although other medium molecular weight neurofilament subunit antibodies clearly showed the presence of significant amounts of medium molecular weight neurofilament subunit. We have since located the epitope for NN18 in a peptide sequence at the carboxy terminal tail of medium molecular weight neurofilament subunit and have now looked for further neurofilament antibodies that stain the same region. We found two monoclonal antibodies, RMO1 and RMO59, that recognize the same peptide. These antibodies also show much reduced staining in myenteric neurons compared to those in the central nervous system, suggesting that this region of the medium molecular weight neurofilament subunit is specifically modified in certain cells. In the developing enteric nervous system, we found that all the antibodies show strong staining of enteric neurons in the neonatal rat, but that with NN18, RMO1, and RMO59, the staining intensity decreases during further development, and by postnatal day 21 all three demonstrate decreased or absent staining identical to the adult. These results indicate that myenteric neurons, in contrast to the brain, have a developmentally regulated modification in a specific region of the medium molecular weight neurofilament subunit, which may reflect adaptation to structural stress by myenteric neurons.

Alkaline Phosphatase↗
PubMed1991

Evidence against impaired brain microtubule protein polymerization at high glucose concentrations or during diabetes mellitus.

Previous studies suggest that brain microtubule protein exposed to high glucose levels or isolated from diabetic rats can become glucosylated and that this impairs GTP-induced microtubule polymerization. We set out to extend that investigation to define the mechanistic basis for inhibition of microtubule assembly during diabetes or on incubation at high glucose levels. Rat and bovine brain microtubule protein was purified by cycles of polymerization/depolymerization. When microtubules were incubated for 1 h in either buffer or buffer containing glucose (up to 165 mM), there was no difference in polymerization, a finding contrary to the earlier study. Other rats were injected with vehicle or streptozotocin (90 mg/kg) to induce diabetes as evidenced by serum glucose in excess of 300 mg%, and at 4 weeks, brain microtubule protein was isolated by the polymerization cycling method. Again, there was no difference in the amount or purity of isolated microtubule protein between control or diabetic rats. We also observed no increase in microtubule glucosylation, and GTP-induced polymerization in vitro was indistinguishable for protein derived from brains of normal rats and rats with diabetes as measured by turbidity or electron microscopy. Our results suggest that in vitro incubation with glucose or in vivo elevation of glucose during diabetes fails to impair microtubule polymerization, pointing to other mechanisms for the neuropathy associated with diabetes.

Animals↗
PubMed1990

Neurofilament immunoreactivity in myenteric neurons differs from that found in the central nervous system.

Neurofilaments are 10-nm diameter protein fibers found within neurons and are composed predominantly of a triplet of polypeptides usually referred to as low-, medium-, and high-molecular-weight subunits. We describe the results of a study of myenteric plexus neurons using a panel of neurofilament triplet protein antibodies and indirect immunofluorescence techniques. Polyclonal antibodies to each of the three neurofilament subunits reliably stained myenteric neurons and their processes, indicating the presence of all three proteins in these cells. However, several well-characterized monoclonal antibodies to epitopes on high- and medium-molecular-weight subunits showed immunoreactivity in brain tissue but not in myenteric neurons and their processes. Some of the antibodies that do not stain recognize only phosphorylated epitopes, indicating that the level of neurofilament phosphorylation is very low in enteric neurons. Other antibodies that are not thought to be sensitive to the level of neurofilament phosphorylation show reduced or no staining of enteric neurons, suggesting the presence of immunologically distinct neurofilaments in these cells. These results suggest the presence of modified neurofilament structures in enteric neurons, possibly reflecting their unique mechanical character within the moving intestinal wall.

Animals↗
PubMed1989

Effect of berberine on myoelectric activity and transit of the small intestine in rats.

The motility of the small intestine in unanesthetized rats receiving berberine sulfate (0.2, 2.0, and 20.0 mg/kg i.p.) was investigated. Motility was determined by two methods: myoelectric activity was monitored with indwelling bipolar electrodes, and intestinal transit was measured by the movement of radiochromium (Na51CrO4). The 20.0-mg/kg dose caused a marked inhibition of spike activity for 21.8 +/- 7.0 min and disrupted activity fronts of the migrating myoelectric complex for 212.3 min. Berberine, 2.0 mg/kg i.p., disrupted migrating myoelectric complexes for 64.6 min but spike inhibition was not observed. Transit of the small intestine was significantly (p less than 0.001) delayed at 15 and 100 min after the highest dose of berberine. Naloxone blocked the spike inhibition noted with 20.0 mg/kg of berberine but failed to improve transit. Phentolamine blocked spike inhibition and was associated with a significantly earlier return of activity fronts of the migrating myoelectric complex. Animals pretreated with this antagonist tended toward a higher geometric center in transit studies than those injected with berberine alone. Berberine was also administered by various routes (intraperitoneal injection, intravenous injection, orogastric gavage, and intraluminal injection). An intraperitoneal injection was 10-fold more potent than an intravenous injection. Orogastric gavage and intraluminal administration of berberine did not alter intestinal motility. In summary, berberine sulfate significantly inhibits myoelectric activity and transit of the small intestine. This appears to be partially mediated by opioid and alpha-adrenergic receptors. The antidiarrheal properties of berberine may be mediated, at least in part, by its ability to delay small intestinal transit.

Administration, Oral↗
PubMed1989

Systemic lupus erythematosus presenting initially with acute pancreatitis and a review of the literature.

A patient with systemic lupus erythematosus is reported whose initial clinical presentation was that of acute pancreatitis, confirmed by pancreatic isoamylase elevation and pancreatic enlargement on computerized tomography. A lack of a correlation with steroid therapy and a need to document pancreatitis in a multisystem disease like lupus with radiographic evidence as well as pancreatic isoamylase elevations is emphasized.

Acute Disease↗
PubMed1988

Dopamine and norepinephrine in the gastrointestinal tract of mice and the effects of neurotoxins.

Evidence is lacking for neurons containing dopamine and acting as a neurotransmitter in the gastrointestinal tract. The relative percentage of dopamine to norepinephrine in noradrenergically innervated tissues (e.g., spleen) is known to be relatively constant within a species, and an increased percentage in any given tissue supports the premise that dopaminergic cells are present. We measured levels of norepinephrine, dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) from segments of the gastrointestinal tract of mice after injection of: 1) saline (control); 2) 6-hydroxydopamine (6-OHDA); or 3) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In control tissues the ratio of dopamine/norepinephrine was higher (P less than .001) than in the spleen; DOPAC was present and the DOPAC/dopamine ratios were similar to those in the central nervous system (where dopaminergic neurons are present). Dopamine and norepinephrine were decreased by 6-OHDA in most myenteric plexus/smooth muscle tissues compared with controls and DOPAC was unmeasurable in most samples after 6-OHDA. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine decreased norepinephrine but not dopamine in the smooth muscle/myenteric plexus. High dopamine/norepinephrine percentages, 6-OHDA depletion of dopamine and presence of DOPAC together suggest the presence of dopamine-containing neurons in the myenteric plexus of the gastrointestinal tract of mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

WHR 1049, a potent metabolite of lidamidine, has antidiarrheal and antimotility effects on the small intestine in rats.

Lidamidine HCl has been suggested to be effective in treating certain motor disorders of the gastrointestinal tract. Lidamidine has alpha-2 agonist as well as local anesthetic properties. We studied the antimotility and antidiarrheal activity of WHR 1049, a hepatic metabolite of lidamidine known to have some activity and to persist longer in the serum than does lidamidine. We recorded the intestinal myoelectric activity of fasted unanesthetized rats with bipolar electrodes implanted on their proximal jejunum. We found that lidamidine HCl, given by gavage, inhibited fasting myoelectric activity in a dose-dependent manner (using 0.5-4.0 mg/kg). Neither saline nor tetracaine inhibited myoelectric activity. WHR 1049 given by gavage also inhibited myoelectric activity and was 30 times as potent as lidamidine (milligram per milligram, using 0.0625- to 0.25-mg/kg doses). Pretreatment with yohimbine (5 mg/kg s.c.), before administration of WHR 1049, decreased the myoelectric activity inhibition by two-thirds (but did not completely block it). Castor oil (1 ml/200 g b.wt.) was given to induce diarrhea and did so when given alone or with saline (vehicle) pretreatment. When these animals were pretreated with 0.25 mg/kg of WHR 1049, the same dose of castrol oil did not induce diarrhea for a 6-hr observation period. We conclude that WHR 1049 is a potent metabolite of lidamidine that inhibits myoelectric activity, has significant alpha-2 agonist activity and blocks induced diarrhea. Because tetracaine does not inhibit myoelectric activity we suggest that the local anesthetic properties of lidamidine do not account for any of the myoelectric activity inhibition. WHR 1049 may account for much of the antimotility and antidiarrheal activity of lidamidine.

Action Potentials↗
PubMed1987

Chronic alterations in jejunal myoelectric activity in rats due to MPTP.

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗