Toward modulation of the endocannabinoid system for treatment of gastrointestinal disease: FAAHster but not "higher".

Cannabis has been used to treat various afflictions throughout the centuries, including nausea, vomiting, and pain. It has also been used recreationally for its psychotropic properties, which can include a pleasurable 'high' feeling and a decrease in anxiety and tension; however, other may experience dysphoria. Changes in cognition and psychomotor performance are also well-known with cannabis use. In recent years, our understanding of the endocannabinoid system (ECS) has progressed dramatically; the objective of identifying agents which may allow modulation of the ECS without significant psychotropic side effects may be possible. Inhibition of fatty acid amide hydrolase (FAAH), an important enzyme for the degradation of anandamide and other endogenous cannabinoids, is a promising target to achieve this goal. In this issue of Neurogastroenterology and Motility, Fichna and colleagues report on a novel selective FAAH inhibitor, PF-3845, with potent antinociceptive and antidiarrheal effects in a mouse model. In this context, we briefly review the components of the ECS, discuss pharmacologic targets for indirect cannabinoid receptor stimulation, and describe recent research with cannabinoids for gut disorders.

A prospective clinical trial of cholecalciferol 2000 IU/day in colorectal cancer patients: evidence of a chemotherapy-response interaction.

BACKGROUND: We have previously reported a negative correlation between the effect of chemotherapy and 25-hydroxy vitamin D(3) (25-D(3)) levels in patients with colorectal cancer. Based on this finding, we hypothesized that the response to vitamin D(3) supplementation may be attenuated in patients with colorectal cancer. AIM: To determine 25-D(3) response to 2000 IU/day vitamin D(3) supplementation in patients with colorectal cancer. MATERIALS AND METHODS: Fifty evaluable colorectal cancer patients were treated with vitamin D(3) at 2000 IU/day for 6 months. Serum 25-D(3) levels were measured at baseline, 3, and 6 months of supplementation. RESULTS: The mean 25-D(3) level was 17.5 ng/ml at baseline, 31.6 ng/ml at 3 months, and 33.8 ng/ml at 6 months. The most important factor in determining 25-D(3) response was chemotherapy status. A rise in 25-D(3) of ≥10 ng/ml at the 3-month interval was observed in 92% of chemotherapy-free patients vs. 39% of chemotherapy patients. Similar differences in response were noted at the 6-month interval. CONCLUSION: Depressed 25-D(3) levels are common in patients with colorectal cancer. Active chemotherapy is associated with an attenuated response to 2000 IU of D(3) supplementation in this patient population. Alternative vitamin D(3) dosing schedules need further investigation in colorectal cancer patients undergoing chemotherapy.

Design, implementation and testing of an implantable impedance-based feedback-controlled neural gastric stimulator.

Functional neural gastrointestinal electrical stimulation (NGES) is a methodology of gastric electrical stimulation that can be applied as a possible treatment for disorders such as obesity and gastroparesis. NGES is capable of generating strong lumen-occluding local contractions that can produce retrograde or antegrade movement of gastric content. A feedback-controlled implantable NGES system has been designed, implemented and tested both in laboratory conditions and in an acute animal setting. The feedback system, based on gastric tissue impedance change, is aimed at reducing battery energy requirements and managing the phenomenon of gastric tissue accommodation. Acute animal testing was undertaken in four mongrel dogs (2 M, 2 F, weight 25.53 ± 7.3 kg) that underwent subserosal two-channel electrode implantation. Three force transducers sutured serosally along the gastric axis and a wireless signal acquisition system were utilized to record stimulation-generated contractions and tissue impedance variations respectively. Mechanically induced contractions in the stomach were utilized to indirectly generate a tissue impedance change that was detected by the feedback system. Results showed that increasing or decreasing impedance changes were detected by the implantable stimulator and that therapy can be triggered as a result. The implantable feedback system brings NGES one step closer to long term treatment of burdening gastric motility disorders in humans.

Comparative gastric motility study of Enterra ™ Therapy and neural gastric electrical stimulation in an acute canine model.

BACKGROUND: Gastric electrical stimulation (GES) is an avenue for treating gastroparesis and obesity by controlling gastric motility using electrically mediated gastric contractions. Neural gastrointestinal electrical stimulation (NGES) is a GES modality capable of producing strong lumen-occluding local gastric contractions. Conversely, Enterra ™ Therapy, a commercial implantable gastric electrical stimulator, has been utilized to treat symptoms of gastroparesis, but its nominal electrical parameters are not capable of generating lumen-occluding contractions. However, comparative studies between these two stimulation modalities are lacking. METHODS: Strain gauge transducers complemented by endoscopic monitoring have been utilized to register gastric contractions invoked with NGES and Enterra neurostimulators in four acute dogs. Mucosal and serosal electrode implantations, 'nominal' and 'maximum' electrical parameters, and longitudinal and transverse electrode placements have been tested with each neurostimulator type. KEY RESULTS: Strong lumen-occluding, circumferential contractions were induced with a wide variety of NGES parameters utilizing both transverse and longitudinal electrode configurations from the serosal side of the stomach. Similarly, local gastric contractions were observed with the Enterra neurostimulator programmed at its 'maximum' electrical parameters but only when utilizing transverse serosal electrode implantation. Under 'maximum' electrical parameters Enterra was not capable of producing registerable gastric contractions with longitudinally implanted serosal electrodes. Mucosal electrode implantations did not result in GES-invoked gastric contractions in both stimulation modalities. CONCLUSIONS & INFERENCES: Enterra Therapy is capable of producing gastric contractions under 'maximum' parameters and transverse electrode configuration. Neural gastrointestinal electrical stimulation produces stronger, lumen-occluding contractions under a wider range of electrode configurations and parameters.

Panton Valentine leukocidin MSSA leading to multi-organ failure.

We report a case of a 15-year-old boy who developed multiple organ failure secondary to a sport injury leading to infection with a Panton Valentine Leukocidin (PVL) secreting Community-Acquired Methicillin Sensitive Staphylococcus Aureus (CA MSSA). Aggressive antibiotic therapy eventually led to recovery.

Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone.

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M(2), 300 mg/M(2), and 400 mg/M(2)) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered. (Blood. 2000;95:1580-1587)

A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings.

OBJECTIVE: To evaluate neuronal dysfunction in the motor region subcortical white matter in ALS using volumetric localized proton magnetic resonance spectroscopy (1H-MRS). METHODS: Sixteen patients with E1 Escorial definite, probable, or possible ALS and eight healthy age-matched control subjects were studied. The ALS patients were divided into those with limb onset (n = 8) and those with bulbar onset (n = 8). Measurements of the metabolic ratios N-acetylaspartate (NAA)/creatine and phosphocreatine (Cr+PCr), NAA/choline (Cho), and Cho/(Cr+PCr) were correlated with clinical assessments. RESULTS: We found no differences in the metabolic peak area ratios in the motor region when comparing the total ALS group and the control subjects. However, correlations were found between the NAA/(Cr+PCr) ratio and the E1 Escorial category (p = 0.03), the ALS severity scale (p = 0.01), and the Medical Research Council score (p = 0.06). No correlations were found between the NAA/(Cr+PCr) ratio and the Ashworth Spasticity Scale, reflex score, or disease duration (p > 0.16). Bulbar-onset patients had a lower NAA/(Cr+PCr) ratio in the motor region compared with limb-onset patients (p = 0.03). CONCLUSION: In vivo 1H-MRS of the subcortical white matter in the motor region is unlikely to be sensitive enough to detect early disease changes in ALS because there is considerable overlap between the metabolic peak area ratios from patients with ALS and normal control subjects. However, changes in the NAA/(Cr+PCr) metabolic peak area ratios correlate with clinical measures of disease severity, and this measure may be useful in monitoring disease progression.

Iron pre-load for major joint replacement.

Patients undergoing total hip or knee replacement frequently receive blood transfusion. Homologous blood transfusion carries appreciable risks and should therefore be reduced to a minimum. We have investigated the use of preoperative oral iron supplements to optimize haemoglobin concentration and iron stores prior to surgery. All patients attending a preadmission clinic 4 weeks prior to primary hip or knee replacement had a haemoglobin measurement. If the haemoglobin concentration (Hb) was less than 12 g dL-1 they were given a four week course of ferrous sulphate. If it was greater than or equal to 12 g dL-1 they were randomized to a control group or given a supplementation course of ferrous sulphate. One hundred patients were seen. Of these 18 (18%) had haemoglobin less than 12 g dL-1 and 16 were treated with iron. The mean Hb was 10.8 g dL-1 and mean cell volume (MCV) 86. These patients increased their Hb by a mean 1.1 g dL-1 prior to admission (P = 0.008). MCV was the best predictor of response (r = -0.63, P < 0.02). This group dropped their haemoglobin by a mean 1.4 g dL-1 in the first post-operative week. In the study groups there was no significant preoperative rise in Hb. However, the control group dropped their Hb by a mean 1.3 g dL-1 in the week following surgery compared with 0.4 g dL-1 in the group which had received iron supplements (P < 0.001). We conclude that at least 18% of patients attending for hip or knee replacement in this region are frankly anaemic and benefit significantly from preoperative iron supplements over 4 weeks. Iron supplementation in patients without obvious anaemia protects against a fall in Hb during the immediate post-operative period, suggesting a widespread underlying depletion of iron stores in this group despite a normal Hb. Preoperative iron supplements may reduce transfusion requirements as part of a co-ordinated strategy in this group of patients.

Gabapentin: a new agent for the management of epilepsy.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of gabapentin, a new antiepileptic drug (AED). Gabapentin's potential role in the treatment of epilepsy also was assessed. DATA SOURCE: A MEDLINE search was performed to identify all published literature (manuscripts and abstracts). Abstracts presented at the American Epilepsy Society, International Epilepsy Congress, and American Academy of Neurology meetings from 1991 to 1993 also were reviewed. A copy of the proceedings from the Food and Drug Administration Peripheral and Central Nervous System Advisory Committee meeting and package insert were obtained from Parke Davis. STUDY SELECTION: All pertinent literature was reviewed. Emphasis was placed on published information, particularly placebo-controlled clinical trials. DATA SYNTHESIS: Gabapentin is effective as adjunctive treatment for patients with partial seizures with or without secondary generalization refractory to the standard AEDs. It has a unique pharmacokinetic profile for an AED, including no binding to plasma proteins, primary elimination by the kidney, and dose-dependent oral absorption at high dosages. No drug interactions occur with the other AEDs. The most frequent adverse reactions noted in patients receiving gabapentin have been mild and transient central nervous system effects. No serious hypersensitivity or systemic reactions have been observed. CONCLUSIONS: Gabapentin appears to be a useful new AED. Further studies evaluating its use as monotherapy, in higher dosages, and in pediatric and elderly patients are required to better delineate its therapeutic role relative to that of other AEDs.

The dose-dependent effect of BHT (butylated hydroxytoluene) on vitamin K-dependent blood coagulation in rats.

Earlier studies have reported a reduction of vitamin K-dependent blood clotting factor activity and incidence of haemorrhagic death in rats fed butylated hydroxytoluene (BHT); however, the vitamin K status of the animals used in these studies was claimed to be inadequate. The aim of the study reported here was to determine the effect of BHT on vitamin K-dependent clotting factors in vitamin K-sufficient and vitamin K-supplemented rats. Rats given BHT (3000 mg/kg body weight) for up to 21 days, in a diet containing a minimum of 3 ppm vitamin K3 (six times the recommended requirement), showed decreased vitamin K-dependent blood clotting factor activities, demonstrated by increases in factor-specific clotting time assays. Clotting times were prolonged within 7 days, significantly increased within 14 days (P < 0.001) and maximally increased 5.5-fold at 21 days (P < 0.05). Supplementation with a further 250 ppm vitamin K3 reversed this effect. BHT did not increase prothrombin time (PT), the usual index of clotting. However, in a similar 14-day investigation, a small but significant increase in PT (up to 151%, P < 0.005) was seen within 7 days. Further vitamin K supplementation was incapable of reversing this effect completely. A similar trend was shown by activated partial thromboplastin time. The 1/51 dilution Thrombotest, a more sensitive indicator of vitamin K-dependent clotting factor activity in the rat, was significantly increased (more than four fold, P < 0.01) within 7 days. This increase was fully reversed by further vitamin K supplementation. Prolongation of Thrombotest time was significant at a BHT dose level of 600 mg/kg body weight per day and this could be reversed by further supplementation of only 3.0 ppm vitamin K. However, at dose levels of 125 mg BHT/kg body weight per day or less, no clotting defects were observed. These studies confirm that chronic administration of more than 600 mg BHT/kg/day to rats supplied with recommended amounts of vitamin K can depress clotting factors and precipitate haemorrhagic deaths. When further vitamin K is provided, these deaths could be prevented even though not all clotting abnormalities may be reversed. This study disapproves the proposal that BHT-related clotting factor defects are confined to rats of inadequate vitamin K status, but shows that such effects do not occur at dose levels lower than 600 mg/kg/day. The results further indicate that rats receiving a high dose of BHT have a higher vitamin K requirement than would otherwise be considered necessary. However, as BHT produces no clotting defects in these animals receiving an intake 1000 times the acceptable daily intake, such clotting effects are most unlikely to indicate a human safety problem for BHT.

Efficacy of hyperimmune bovine colostrum for prophylaxis of cryptosporidiosis in neonatal calves.

Twelve neonatal calves were experimentally infected with oocysts of Cryptosporidium parvum. Six calves in group A fed hyperimmune colostrum at birth had significantly less diarrhea and shed oocysts for less time than did 6 calves in group B fed colostrum from cows that were not hyperimmune. Calves in group A had diarrhea for 0-4 days (means = 2.3 days), whereas calves in group B had diarrhea for 4-6 days (means = 5.0 days). Calves in group A shed oocysts for 4-9 days (means = 6.2 days), whereas calves in group B shed oocysts for 7-11 days (means = 8.5 days). These findings indicate that passive lacteal immunity conferred partial protection against cryptosporidiosis. Whether such protection was provided by the immunoglobulins that were highly elevated in the colostrum (greater than 1:200,000 for IgG1, IgM, and IgA) and constituted a large part of the circulating antibody in the calves, or by other biologically active factors, such as cytokines, is undetermined.

Testicular seminoma. Results of a program of megavoltage irradiation.

Between April 1962 and March 1984, 61 patients with a diagnosis of testicular seminoma were seen at Hahnemann University Hospital. Of these patients, 52 had long-term follow-up after definitive treatment with megavoltage irradiation. In 30 patients, disease was classified as stage I, in 21 patients, stage II, and in one patient, stage III. Treatment techniques are described. Overall relapse-free survival rate for all stages was 92% with an adjusted survival rate of 96%. Treatment policies for each stage are presented.