Treatment of Patients with Obese Type 2 Diabetes with Tantalus-DIAMOND® Gastric Electrical Stimulation: Normal Triglycerides Predict Durable Effects for at Least 3 Years.

The objectives of the present work are to evaluate long-term benefit of nonexcitatory gastric electrical stimulation (GES) by the DIAMOND(®) device on glycemic control and body weight in patients with type 2 diabetes inadequately controlled with oral agents and to determine the magnitude of the modulating effects of fasting plasma triglyceride (FTG) levels on these effects of GES. Sixty one patients with type 2 diabetes [HbA1c > 7.0% (53 mmol/mol) to < 10.5% (91 mmol/mol)] were implanted with the DIAMOND(®) GES device and treated with meal-mediated antral electrical stimulation for up to 36 months. The effects of baseline HbA1c and FTG on glycemic control, body weight, and systolic blood pressure were measured. GES reduced mean HbA1c by 0.9% and body weight by 5.7%. The effects were greater in patients with normal fasting plasma triglycerides (NTG) as compared to those with hypertriglyceridemia. The mean decrease in HbA1c in patients with NTG averaged 1.1% and was durable over 3 years of follow-up. ANCOVA indicated that improvement in HbA1c was a function of both baseline FTG group (p = 0.02) and HbA1c (p = 0.001) and their interaction (p = 0.01). Marked weight loss (≥ 10%) was observed in a significant proportion of NTG patients by 12 months of treatment and persisted through the 3 years. GES improves glycemic control and reduces body weight by a triglyceride-dependent mechanism in patients with type 2 diabetes inadequately controlled on oral agents. It is postulated that this is through a gut-brain interaction that modulates effects on the liver and pancreatic islets.

Fasting plasma triglycerides predict the glycaemic response to treatment of type 2 diabetes by gastric electrical stimulation. A novel lipotoxicity paradigm.

BACKGROUND: Non-stimulatory, meal-mediated electrical stimulation of the stomach (TANTALUS-DIAMOND) improves glycaemic control and causes modest weight loss in patients with Type 2 diabetes who are inadequately controlled on oral anti-diabetic medications. The magnitude of the glycaemic response in clinical studies has been variable. A preliminary analysis of data from patients who had completed 6 months of treatment indicated that the glycaemic response to the electrical stimulation was inversely related to the baseline fasting plasma triglyceride level. METHOD: An analysis of 40 patients who had had detailed longitudinal studies for 12 months. RESULTS: Twenty-two patients with fasting plasma triglycerides ≤ 1.7 mmol/l had mean decreases in HbA1c after 3, 6 and 12 months of gastric contraction modulation treatment of -15 ± 2.1 mmol/mol (-1.39 ± 0.20%), -16 ± 2.2 mmol/mol (-1.48 ± 0.20%) and -14 ± 3.0 mmol/mol (-1.31 ± 0.26%), respectively. In contrast, 18 patients with fasting plasma triglyceride > 1.7 mmol/l had mean decreases in HbA1c of -7 ± 1.7 mmol/mol (-0.66 ± 0.16%), -5 ± 1.6 mmol/mol (-0.44 ± 0.18%) and -5 ± 1.7 mmol/mol (-0.42 ± 0.16%), respectively. Pearson's correlation coefficient between fasting plasma triglyceride and decreases in HbA1c at 12 months of treatment was 0.34 (P < 0.05). Homeostasis model assessment of insulin resistance was unchanged during 12 months of treatment in patients with high baseline fasting triglycerides, while it progressively improved in patients with low fasting plasma triglycerides. Patients with low fasting plasma triglycerides had a tendency to lose more weight than those with high fasting plasma triglycerides, but this did not achieve statistical significance. CONCLUSIONS: The data presented suggest the existence of a triglyceride lipotoxic mechanism that interferes with gastric/neural mediated pathways that can regulate glycaemic control in patients with type 2 diabetes. The data suggest the existence of a triglyceride lipotoxic pathway that interferes with gastric/neural mediated pathways that can regulate glycaemic control.

Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation.

OBJECTIVES: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8-10 h) i.v. DFO. PATIENTS: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. RESULTS: The median age at diagnosis of cardiac disease was 17.5 yr (range 14-21), and the median follow-up time was 84 months (range, 36-120). In the majority of patients (seven of eight) high-dose DFO (mean 95 +/- 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 +/- 2016 ng/mL to 1585 +/- 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 +/- 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. CONCLUSIONS: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8-10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM.

Clinical and laboratory manifestations of congenital dyserythropoietic anemia type I in young adults.

OBJECTIVES: Congenital dyserythropoietic anemia (CDA) type I is a rare autosomal recessive macrocytic anemia whose natural history is not well documented. The aim of the present study was to evaluate the clinical picture of the disease in young adults. METHODS: The study sample consisted of 17 patients of mean age 11.9 +/- 5.4 yr (range 18-33 yr) and one older patient (age 44 yr), all Israeli Bedouins. The degree of anemia was evaluated as well as the extent of development of gallstones and iron overload. In each subject we determined the hemochromatosis gene mutations and the uridine dyphosphate-glucoronosyltransferase (UGT-1A) gene polymorphism associated with Gilbert's syndrome. RESULTS: The patients were found to have moderate anemia, with the women displaying lower mean hemoglobin levels than the men (8.2 +/- 0.9 g dL(-1) vs. 10 +/- 1.3 g dL(-1); P=0.0059). The majority of patients (59%) had received at least one blood transfusion, with the women having a significantly higher transfusion requirement. Although delayed puberty was noted, final height and weight were within normal limits, and eight patients had progeny. Biliary stones were found in three of 16 patients, two of whom were homozygous for UGT-1A gene polymorphism. None of the patients carried the common hemochromatosis gene mutation, although serum ferritin levels were moderately elevated (788 +/- 332 ng mL(-1)). CONCLUSIONS: CDA type I in young adults is characterized by moderate macrocytic anemia, more severe in women, and a tendency to cholelithiasis and secondary progressive iron overload. We suggest that iron overload in this patient population should be monitored and chelation therapy initiated when indicated to prevent organ damage

A randomized, controlled clinical trial of the homeopathic medication TRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem cell transplantation.

BACKGROUND: Stomatitis is a common consequence of chemotherapy and a condition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL S(R), in the management of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in 32 patients ages 3-25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a minimum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis. RESULTS: A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P < 0.01). CONCLUSIONS: This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation.

Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children.

BACKGROUND: Acute invasive diarrhea is a potentially serious condition in children. Because of the increasing resistance of enteric pathogens to commonly used oral antibiotics, intramuscular ceftriaxone has become the routine drug in the treatment of acute invasive diarrhea requiring an emergency visit in southern Israel. The inconvenience of this parenteral regimen created an increased need for oral pediatric formulations for the treatment of invasive diarrhea. OBJECTIVES: To evaluate the efficacy and safety of a suspension formulation of ciprofloxacin in the treatment of acute invasive diarrhea in infants and children. PATIENTS AND METHODS: From July 1996 through December 1997, 201 evaluable children ages 6 months to 10 years (35% <1 year; 70% <3 years) presenting with acute invasive diarrhea at the Pediatric Emergency Room were randomized to receive either ciprofloxacin suspension (10 mg/kg twice a day + im placebo; n = 95) or im ceftriaxone (50 mg/kg/day + placebo suspension; n = 106) for 3 days in a double blind manner. Stool cultures for Shigella, Salmonella, Campylobacter spp. and diarrheagenic Escherichia coli were obtained on Days 1, 3, 4 to 5 and 21 +/- 5. Clinical response and safety were assessed on Days 1, 2, 3, 4 to 5 and 21 +/- 5. RESULTS: We isolated 127 pathogens from 121 (60%) patients: 73 (57%) Shigella; 23 (18%) Salmonella; 18 (14%) E. coli; and 13 (10%) Campylobacter. Overall bacteriologic eradication on Day 4 to 5 was 99% for Shigella, 77% for Salmonella and 77% for Campylobacter, with no difference between the 2 groups. Clinical cure or improvement was observed in 100 and 99% of the ciprofloxacin and ceftriaxone groups, respectively. Serum ciprofloxacin values determined on Day 3 of the treatment were higher in the majority of patients than were the MIC50 and MIC90 values for the Shigella and Salmonella spp. isolated. Possible drug-related adverse events occurred in 13 patients [ciprofloxacin, 8 (8%); ceftriaxone, 5 (4.7%)] and were mild and transient. Joint examination was normal during and after completion of therapy in all patients. CONCLUSION: Oral ciprofloxacin was as safe and effective as intramuscular ceftriaxone for the empiric treatment of acute invasive diarrhea in ambulatory pediatric patients requiring an emergency room visit.

Ciprofloxacin 250 mg twice daily versus ofloxacin 200 mg twice daily in the treatment of complicated urinary tract infections in women.

In a multicenter, prospective, double-blind, double-dummy randomized study conducted in Israel and Germany, the efficacy and safety of ciprofloxacin 250 mg b.i.d. versus ofloxacin 200 mg b.i.d. was compared in the treatment of women with complicated lower urinary tract infection. A total of 465 women were enrolled in the study, 427 of whom were included in the intent-to-treat analysis. Two hundred fourteen received ciprofloxacin 250 mg b.i.d. and 213 received ofloxacin 200 mg b.i.d. Both regimens were administered for 7 days. The primary efficacy parameter was the microbiologic result obtained 5-9 days after cessation of therapy; secondary efficacy parameters were urine cultures obtained 28-42 days after the end of therapy and clinical outcome 5-9 days and 28-42 days post-therapy. There were no relevant differences in the primary efficacy parameter or in any secondary efficacy parameter between the average response rate of patients who received ciprofloxacin and that of patients who received ofloxacin: 90.1% of the ciprofloxacin group and 87.2% of the ofloxacin group had sterile urine 5-9 days after the end of therapy; 77.1% and 76.1% had sterile cultures, respectively. Clinical cure was achieved in 97.2% of both groups 5-9 days after cessation of therapy and a month later in 87.7% and 87.3%, respectively. Adverse events were mild and similar in both groups. In conclusion, for the primary efficacy parameter as well as for all secondary efficacy parameters, ciprofloxacin 250 mg b.i.d. is at least as effective as ofloxacin 200 mg b.i.d. in women with complicated lower urinary tract infection.

Safety of long-term therapy with ciprofloxacin: data analysis of controlled clinical trials and review.

We reviewed the literature and the manufacturer's U.S. clinical data pool for safety data on long-term administration of ciprofloxacin (Bayer, West Haven, CT). Only controlled clinical trials including patients treated for >30 days were selected. We identified 636 patients by literature search and 413 patients in the Bayer U.S. database who fulfilled our search criteria; the average treatment duration for these patients was 130 and 80 days, respectively. Main indications for long-term therapy were osteomyelitis, skin and soft-tissue infection, prophylaxis for urinary tract infection, mycobacterial infections, and inflammatory bowel disease. Adverse events, premature discontinuation of therapy, and deaths occurred at a similar frequency in both treatment arms. Most adverse events occurred early during therapy with little increase in frequency over time. As with short-term therapy, gastrointestinal events were more frequent than central nervous system or skin reactions, but pseudomembranous colitis was not observed. No previously unknown adverse events were noted. We conclude that ciprofloxacin is tolerated as well as other antibiotics when extended courses of therapy are required.

Deferoxamine (Desferal)-induced ocular toxicity.

A 4-year-old girl with juvenile chronic myeloid leukemia relapsed after an allogeneic bone marrow transplantation (BMT) and became refractory to conventional chemotherapy. Treatment with two courses of high-dose deferoxamine, an iron chelator (130-180 mg/kg/day), along with low-dose ARA-c (5 mg/kg/day) caused a remarkable decrease of the WBC and fetal Hb. Three days following the last dose of deferoxamine, the patient experienced an acute visual loss, confirmed by electroretinogram (ERG) and visual evoked response (VER). Slight improvement occurred a few days later, but the patient developed severe pancytopenia and died of Klebsiella septic shock. The ocular manifestations were attributed to deferoxamine toxicity in light of the rapid onset after first exposure, the electrophysiological pattern of metabolic damage in the ERG and VER, and the long interval between the last chemotherapy and BMT. The pathogenesis of deferoxamine toxicity is discussed.