S. Bingaman

Low-Dose Naltrexone Therapy Improves Active Crohn's Disease

OBJECTIVES:Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues. In an open-labeled pilot prospective trial, the safety and efficacy of low-dose naltrexone (LDN), an opioid antagonist, were tested in patients with active Crohns disease.METHODS:Eligible subjects with histologically and endoscopically confirmed active Crohns disease activity index (CDAI) score of 220–450 were enrolled in a study using 4.5 mg naltrexone/day. Infliximab was not allowed for a minimum of 8 wk prior to study initiation. Other therapy for Crohns disease that was at a stable dose for 4 wk prior to enrollment was continued at the same doses. Patients completed the inflammatory bowel disease questionnaire (IBDQ) and the short-form (SF-36) quality of life surveys and CDAI scores were assessed pretreatment, every 4 wk on therapy and 4 wk after completion of the study drug. Drug was administered by mouth each evening for a 12-wk period.RESULTS:Seventeen patients with a mean CDAI score of 356 ± 27 were enrolled. CDAI scores decreased significantly (P = 0.01) with LDN, and remained lower than baseline 4 wk after completing therapy. Eighty-nine percent of patients exhibited a response to therapy and 67% achieved a remission (P < 0.001). Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were noted. The most common side effect was sleep disturbances, occurring in seven patients.CONCLUSIONS:LDN therapy appears effective and safe in subjects with active Crohns disease. Further studies are needed to explore the use of this compound.

Therapeutic Effect of Vitamin D Supplementation in a Pilot Study of Crohn’s Patients

OBJECTIVES:Low vitamin D status may be associated with Crohn’s disease. A pilot study was performed in patients with mild-to-moderate Crohn’s disease to determine the dose of vitamin D needed to raise serum vitamin D levels above 40 ng/ml.METHODS:Patients were evaluated for severity of symptoms using the Crohn’s disease activity index (CDAI) and patients with mild-to-moderate (150–400 CDAI scores) Crohn’s disease were entered into the study (n=18). Vitamin D3 oral therapy was initiated at 1,000 IU/d and after 2 weeks, the dose was escalated incrementally until patients’ serum concentrations reached 40 ng/ml 25(OH)D3 or they were taking 5,000 IU/d. Patients continued on the vitamin D supplements for 24 weeks. CDAI, quality of life measures, bone mineral density, dietary analyses, cytokines, parathyroid hormone, calcium, and several other laboratory measurements were evaluated at baseline and after 24 weeks supplementation.RESULTS:Fourteen of eighteen patients required the maximal vitamin D supplement of 5,000 IU/d. Vitamin D oral supplementation significantly increased serum 25(OH)D3 levels from 16±10 ng/ml to 45±19 ng/ml (P<0.0001) and reduced the unadjusted mean CDAI scores by 112±81 points from 230±74 to 118±66 (P<0.0001). Quality-of-life scores also improved following vitamin D supplementation (P=0.0004). No significant changes in cytokine or other laboratory measures were observed.CONCLUSIONS:Twenty-four weeks supplementation with up to 5,000 IU/d vitamin D3 effectively raised serum 25(OH)D3 and reduced CDAI scores in a small cohort of Crohn’s patients suggesting that restoration of normal vitamin D serum levels may be useful in the management of patients with mild–moderate Crohn’s disease.

Gastric myoelectrical activity in patients with gastric outlet obstruction and idiopathic gastroparesis

Objective:The cause of gastroparesis may be uncertain in some patients. Mechanical obstruction of the stomach or duodenum should be excluded in patients with idiopathic gastroparesis. The objective of this study was to compare gastric myoelectrical activity in patients with idiopathic gastroparesis with that of patients with gastroparesis due to mechanical obstruction of the stomach or duodenum.Methods:Electrogastrography techniques were used to record gastric myoelectrical activity in 20 patients with idiopathic gastroparesis and in nine patients with gastroparesis secondary to gastric outlet obstruction. Four of these nine patients initially were thought to have idiopathic gastroparesis. Electrogastrograms (EGGs) were recorded from 29 healthy subjects who served as controls. EGGs were recorded for 20–30 min 2 h after a standard 200-Kcal meal and were analyzed visually and by computer.Results:Patients with gastroparesis due to outlet obstruction had high-amplitude and excessively regular 3–cycles-per-minute (cpm) EGG patterns, whereas patients with idiopathic gastroparesis had primarily 1- to 2-cpm patterns and little 3-cpm EGG activity. The percentage of total EGG power in the 3-cpm range was approximately 50% in patients with gastric outlet obstruction compared with 20% in patients with idiopathic gastroparesis (p < 0.001). The percentage of EGG power in the normal 3-cpm range was greater in the obstructed patients (50%) than in the healthy controls (35%; p < 0.052).Conclusions:Gastric myoelectrical patterns recorded in the EGG distinguish mechanical and idiopathic causes of gastroparesis and may be useful in evaluating patients with nausea, vomiting, and gastroparesis of unknown cause.

Treatment of advanced pancreatic cancer with opioid growth factor: phase I.

Opioid growth factor (OGF) is an endogenous pentapeptide that inhibits growth of human pancreatic cancer cells in culture, as well as xenografts in nude mice. To establish the maximum tolerated dose (MTD), and determine safety and toxicity of OGF, a phase I trial was performed in patients with advanced unresectable pancreatic cancer. Patients with unresectable pancreatic adenocarcinoma were treated with escalating doses of OGF for 30 min i.v. to determine the MTD. The s.c. route of administration also was evaluated. Once the MTD was established, a group of patients was treated chronically, and monitored for safety and toxicity. Hypotension was the dose-limiting toxicity, resulting in a MTD of 250 μg/kg i.v. Due to limited solubility of OGF in small volumes, a maximum dose of 50 μg/kg twice daily was determined by the s.c. route of administration. No adverse events were reported for oxygen saturation, cardiac rhythm, laboratory values or neurological status in either the acute or chronic parts of the study with the i.v. or s.c. routes. During the chronic i.v. phase, two subjects had resolution of liver metastases and one showed regression of the pancreatic tumor. Mean survival from the time of diagnosis was 8.7 months (range 2–23 months) in the i.v. group and 9.5 months (range 1–18 months) in the s.c. group. We conclude that OGF can be safely administered to patients with advanced pancreatic cancer. Further studies are needed to determine the efficacy of OGF alone or in combination with present modes of therapy for the treatment of pancreatic cancer.

Gastric myoelectrical activity in premature and term infants

Electrogastrography is a non‐invasive method for recording gastric myoelectrical activity. The aims of this study were to record gastric myoelectrical activity in newborn infants using electrogastrographic methods and to compare frequency distributions of postprandial electrogastrograms (EGGs) recorded after gavage feedings. Nineteen infants with gestational ages ranging from 28 weeks to term were studied. Group I subjects were studied only after formula feedings (n = 15) and were divided by age into subgroups A, B and C: A (term, n = 4), B (33–36 weeks, n = 4), and C (28–32 weeks, n = 7). Group II infants (32–34 weeks, n = 4) were studied before and after gavage feeding. The percentage of total EGG power was calculated for four frequency ranges: 1–2.4 cpm (bradygastria); 2.5–3.6 cpm (normal range); 3.7–9.9 cpm (tachygastria); and 10–15 cpm (duodenal/respiratory). Results showed no significant differences in postprandial EGG power in these frequency ranges among the Group I infants of different gestational ages. The power in these EGG frequency ranges did not change significantly after gavage feedings in the Group II infants. In conclusion: (a) EGGs may be recorded successfully from preterm and term infants, (b) postprandial gastric myoelectrical activity in all frequency bands is similar among groups of premature and term infants, and (c) gavage feedings in premature infants did not increase 3 cpm EGG activity.

Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer

BACKGROUND: Advanced pancreatic cancer carries the poorest prognosis of all gastrointestinal malignancies. Once the tumor has spread beyond the margins of the pancreas, chemotherapy is the major treatment modality offered to patients; however, chemotherapy does not significantly improve survival. OBJECTIVE: Opioid growth factor (OGF; [Met(5)]-enkephalin) is a natural peptide that has been shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The purpose of this study was to evaluate the effects of OGF biotherapy on subjects with advanced pancreatic cancer who failed chemotherapy. METHODS: In a prospective phase II open-labeled clinical trial, 24 subjects who failed standard chemotherapy for advanced pancreatic cancer were treated weekly with OGF 250 µg/kg intravenously. Outcomes measured included clinical benefit, tumor response by radiographic imaging, quality of life, and survival. RESULTS: Clinical benefit response was experienced by 53% of OGF-treated patients compared to historical controls of 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU), respectively. Of the subjects surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for OGF-treated patients was three times that of untreated patients (65.5 versus 21 days, p < 0.001). No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with OGF. LIMITATIONS: Measurements other than survival were not allowed in control patients, and clinical benefit comparisons were made to historical controls. CONCLUSION: OGF biotherapy improves the clinical benefit and prolongs survival in patients with pancreatic cancer by stabilizing disease or slowing progression. The effects of OGF did not adversely alter patient quality of life. The use of OGF biotherapy at earlier stages of disease or in combination with other chemotherapeutic agents may further improve the outcome of this malignancy.

SAFETY AND TOLERABILITY OF LOW DOSE NALTREXONE THERAPY IN CHILDREN WITH MODERATE TO SEVERE CROHN’S DISEASE: A PILOT STUDY

Background: There is an unmet need for safe and effective medicines to treat children with Crohn’s disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. Aims: The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn’s disease. Methods: A pilot clinical trial was conducted in children with moderate to severe Crohn’s disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn’s Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey. Results: Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn’s disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ⩽10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035). Conclusions: Naltrexone therapy seems safe with limited toxicity when given to children with Crohn’s disease and may reduce disease activity.

Visceral perceptions and gastric myoelectrical activity in healthy women and in patients with bulimia nervosa

Bulimia nervosa remains a common eating disorder in young women. Little is known about upper gastrointestinal symptoms or gastric motility in patients with bulimia nervosa. The aim of this study was to measure gastric myoelectrical activity and hunger/satiety and stomach emptiness/fullness before and after a non‐nutrient water load and solid‐phase gastric emptying in hospitalized patients with bulimia nervosa (n = 12) and in healthy women (n = 13). Gastric myoelectrical activity was measured by means of cutaneous electrodes; visual analogue scales were used to measure perceptions of hunger/satiety and stomach emptiness/fullness. Before and after a standard water load the bulimia patients reported significantly greater stomach fullness and satiety compared with control subjects (P < 0.01). The percentage of gastric myoelectrical power in the normal 3 cpm range was significantly less in bulimics compared with controls. Power in the 1–2 cpm bradygastria range was significantly greater in bulimia patients before and after the water load compared with the control subjects (P < 0.05). Solid‐phase gastric emptying studies using radio‐isotope‐labelled scrambled eggs showed the lag phase was shortened in the bulimic patients (16 ± 4 min vs 31 ± 4 min in controls, P < 0.01), but the percentage of meal emptied at 2 h was similar to control values. In conclusion: bulimia patients had exaggerated perceptions of stomach fullness and satiety in response to water; and abnormal gastric myoelectrical activity and accelerated lag phase of gastric emptying were objective stomach abnormalities detected in hospitalized patients with bulimia nervosa.

Amantadine therapy for chronic hepatitis C: a dose escalation study.

OBJECTIVES:Amantadine reduces liver transaminase levels in some patients with chronic hepatitis C at doses of 200 mg daily and may improve the sustained virological response (SVR) when given with interferon and ribavirin. The primary purpose of the present investigation was to study the safety and toxicity of higher doses of amantadine in subjects who previously failed or were intolerant to interferon. The secondary aim was to test the efficacy of higher dose of amantadine against hepatitis C.METHODS:An open-labeled prospective study was conducted starting with amantadine 200 mg daily and increasing to 500 mg daily while monitoring for safety, toxicity, and efficacy. An amantadine blood level exceeding 1,600 ng/ml was considered toxic requiring dose reduction. The patients symptoms, laboratory tests, and quality of life were monitored.RESULTS:One hundred patients enrolled in the study. Normalization of alanine aminotransferase (ALT) for each dose was as follows: 200 mg (35%), 300 mg (49%), 400 mg (53%), and 500 mg (56%). The incidence of toxic amantadine plasma levels increased with dose, i.e., 200 mg (0%), 300 mg (6%), 400 mg (27%), and 500 mg (49%). The frequency and severity of arthralgias and fatigue improved at all dosages administered. No changes in the occurrence or severity of headache, insomnia, or depression were reported. Serious adverse events included myocardial infarction and suicide attempt. Other side effects included impotence, confusion, alopecia, and hoarseness.CONCLUSIONS:Amantadine given at a dose of 300 mg daily is safe, and significantly lowers ALT blood levels more than 200 mg daily. The enzyme response rate does not significantly improve above 300 mg, but toxicity increases.

Amantadine Therapy for Chronic Hepatitis C

OBJECTIVE: Although treatment of hepatitis C has improved, up to 50% do not respond to standard therapy with interferon regimes or cannot tolerate the treatment due to side effects. The purpose of the present investigation was to evaluate the safety and effectiveness of the antiviral drug amantadine for the treatment of hepatitis C in those who had either previously failed interferon therapy or were not candidates for interferon.DESIGN: A prospective double-blind randomized placebocontrolled trial.SETTING: Outpatient research clinic of a teaching hospital.PATIENTS/PARTICIPANTS: One hundred fifty-two patients with confirmed hepatitis C with abnormal liver enzymes, detectable hepatitis C RNA in the blood, and abnormal liver histology by biopsy were randomized to receive treatment or placebo.MEASUREMENTS AND MAIN RESULTS: Patients received either amantadine 100 mg twice daily by mouth or placebo for 6 months. After 6 months, placebo-treated patients were crossed over and treated with amantadine for 6 months and amantadine-treated subjects received 6 additional months of therapy. Amantadine therapy resulted in a significant decline in serum alanine aminotransferase compared to placebo (P=.03). Nine percent cleared the virus at the end of therapy and 6.8% had a sustained virologic response 6 months after discontinuation of amantadine, but this was not statistically significant. Side effects were minimal, and the social quality of life survey improved with 12 months of amantadine (P=.02).CONCLUSIONS: Oral amantadine may provide a safe alternative treatment for those patients who are intolerant or unresponsive to interferon.