Ventricular contractility evaluated by mechanical perturbation of the myocardium--experimental and clinical approach adopting small amplitude vibration input.

Small amplitude mechanical vibration has been reported to depress the function of the isolated left ventricle in an amplitude dependent manner. We examined, 1) contractility and preload dependency of the magnitude of functional depression (VID) by applying 50 Hz, 2 mm amplitude vibration to the epicardium of the canine left ventricle and 2) whether VID is present in the failing human ventricle. The magnitude of VID was independent of preload in the physiological range of LV volume showing peak LV pressure greater than 75 mmHg, and VID was correlated with Emax at each inotropic state. In the in-situ condition, VID appeared only in the failing condition with a sensitive increase at a mild level of heart failure. In a study during routine cardiac catheterization (n = 27), the presence of VID has been demonstrated in the human ventricle (n = 18). The magnitude of VID was correlated with ejection fraction (EF) as, VID in peak LV pressure (mmHg) = 80.6 - 110 x EF, r = 0.84, p less than 0.01 in patients with EF less than or equal to 0.7 (n = 14). Therefore, we concluded that VID could be a clinical tool for evaluation of mild heart failure.     

Treatment with Thalidomide and Cyclophosphamide (TCID) is Superior to Vincristine (VID) and to Vinorelbine (VRID) Regimens in Patients with Refractory or Recurrent Multiple Myeloma

Treatment of relapsed or refractory multiple myeloma remains a challenge and novel treatment regimen are required. Here, a matched pair analysis was performed comparing TCID (thalidomide, cyclophosphamide, idarubicin, dexamethasone) treatment to the treatment of patients with VID (vincristine, idarubicin, dexamethasone) or with VRID (vinorelbine, idarubicin, dexamethasone) for relapsed or refractory multiple myeloma. In total, 197 patients were enrolled in multicenter trials. After matching for important prognostic variables 46 matched-pairs (total of 138 patients) could be analysed with regard to survival, toxicity and efficacy. Interestingly, a significant improvement of overall response rate (ORR) for TCID treatment compared to VID and VRID was found. In addition, TCID treatment also led to a significantly higher overall survival (OS) as well as progression-free survival (PFS) compared to VID and VRID. In conclusion, TCID treatment appears to be superior to VRID and VID treatment in patients with progressive or refractory myeloma.     

Pacing in heart failure: improved ventricular interaction in diastole rather than systolic re-synchronization.

AIMS: To determine the mechanism by which left ventricular and biventricular pacing works. BACKGROUND: Pacing for congestive heart failure patients is employed in those with left bundle branch block on the basis that it will improve discoordinated contraction; however, the response is unpredictable. The authors propose that the mechanism of benefit is rather related to improvement of ventricular interaction in diastole (VID). VID is found in patients with a high left ventricular end-diastolic pressure (> 15 mmHg). Left ventricular pacing in these patients will delay right ventricular filling and allow greater left ventricular filling before the onset of VID. METHODS: The study group consisted of 18 congestive heart failure patients with an ejection fraction < 30% and with no more than Grade 1 mitral regurgitation. Group I comprised 10 patients with pulmonary capillary wedge pressure > 15 mmHg, four patients had a normal QRS duration and six had left bundle branch block. Group II comprised eight patients with pulmonary capillary wedge pressure < 15 mmHg, of whom five had a normal QRS duration. Haemodynamics were measured at baseline and during VDD pacing from either the left ventricle or right ventricle. RESULTS: The ratio of stroke volume/pulmonary capillary wedge pressure was calculated as an index of the relationship between left ventricular end-diastolic pressure and contractile function. This ratio was lower in group I than in group II patients (P = 0.005). In group I, haemodynamics were improved with left ventricular pacing (stroke volume/pulmonary capillary wedge pressure increased from 2.2 +/- 0.9 to 4.4 +/- 3.6, P = 0.03). In group II there was no response to either left ventricular or right ventricular pacing. The improvement with left ventricular pacing was unrelated to QRS duration (r = 0.09). CONCLUSIONS: Left ventricular pacing acutely benefits congestive heart failure patients with pulmonary capillary wedge pressure > 15 mmHg irrespective of left bundle branch block. The present data suggest that the mechanism of response may be an improvement in left ventricular filling rather than ventricular systolic re-synchronization.     

Bioavailability, pharmacokinetics, and clinical effects of an oral preparation of etoposide

Bioavailability of an oral preparation of the antineoplastic drug etoposide (VP-16) was studied in 13 patients with advanced malignancies. An initial pilot study involving three patients suggested that approximately 50% of an orally administered dose was absorbed. Ten additional patients were randomized to receive either 100 mg/m2/day iv or 200 mg/m2/day orally. Three weeks later, the alternate dose schedule was administered. Plasma samples were assayed for VP-16 using a high-pressure liquid chromatography technique. Comparison of the area under concentration-time curves (C X t) revealed that 17%-72% (mean, 52%) of an orally administered dose was absorbed. Absorption was less than 40% for only one patient. For oral and iv preparations, mean peak plasma VP-16 concentrations were 9.6 and 13.0 micrograms/ml, mean alpha-half-lives were 0.96 and 0.82 hour, mean beta-half-lives were 7.2 and 6.8 hours, mean C X t values were 75.9 and 75.3 mg/L/hour, mean plasma clearances were 1.44 and 1.45 L/hour/m2, and mean extrapolated volumes of distribution were 15.2 and 16.9 L/m2, respectively. The half-life for oral absorption was 0.44 hour and peak plasma concentrations were noted 0.5-3 hours after oral drug administration. Granulocyte count nadirs tended to be lower in patients with high C X t values and low plasma clearance values. Granulocytopenia was dose-limiting. Gastrointestinal toxicity was extremely mild. We recommend doses of oral VP-16 of 800 mg/m2/course over 3-5 days for patients with a moderate amount of prior treatment. It is probable that previously untreated patients will tolerate a higher dose and that heavily pretreated patients will require a lower dose.     

Differentiating enterocutaneous fistulae from suture abscesses complicating Crohn's disease using oral administration of indocyanine green

BACKGROUND AND AIM: Clinicians encounter difficulties distinguishing enterocutaneous fistulae from postoperative suture abscesses solely by diagnostic imaging in patients with Crohn's disease. The aim of this study was to examine whether use of intraintestinal administration of indocyanine green (ICG) could differentiate the conditions. METHODS: Twenty-four patients with Crohn's disease and a possible enterocutaneous fistula at the abdominal wall based on manifestations of pus drainage and exudate were enrolled. A positive test was defined by macroscopic confirmation of staining by ICG dye, which had been administered orally, on the gauze dressing applied to the lesion site. RESULTS: Positive responses occurred in 16 of the 24 patients. In 13 of the 16 positive patients, a fistulous communication between the lesion and the gastrointestinal tract was documented by either surgery or X-ray examination. In the remaining three, fistulae were completely closed after administration of infliximab. The positive predictive value of the oral ICG test was 16/16 (100%). Six of the eight negative oral ICG test patients (75%) had subcutaneous (silk-suture) abscesses that were easily closed following fistulotomy. The other two patients had fistulas confirmed either by surgery or fistulography, indicating a false negative response from the oral ICG test. The negative predictive value of the oral ICG test was 6/8 (75%); thus, the ability of the oral ICG test to correctly diagnose was 22/24 (92%). CONCLUSIONS: This oral ICG test offers a suitable methodology for those patients possessing an occult fistulous lesion at an early stage, and where a differential diagnosis is difficult using diagnostic imaging.     

Third-line chemotherapy with CAVP (CCNU, melphalan, etoposide and prednisone) in refractory Hodgkin's disease

Thirty-one patients affected by recurrent Hodgkin's disease have been treated with an oral combination chemotherapy including lomustine (CCNU 90 mg/sqm, on day 1), melphalan (Alkeran, 7.5 mg/sqm on days 1-5), etoposide (VP-16, 100 mg/sqm on days 6-10) and prednisone (40 mg/sqm on days 1-10). MOPP and ABVD regimens administered sequentially or in alternating fashion had been employed as first choice treatment. The majority of patients had extranodal (80%) and a progressive disease resistant to previous chemotherapy (80%). Complete and partial remission were induced in 8 (26%) and 5 patients (16%), respectively, with an overall response rate of 42%. Median duration of complete remission was 10 months. Patients who did not respond to previous chemotherapies had a significantly lower complete response rate (16%). Myelosuppression was the most frequent complication, with one patient dying of a thrombocytopenic hemorrhage. The oral administration of drugs allowed good patients', compliance with treatment. CAVP is an effective regimen in the management of patients with refractory Hodgkin's disease and the results obtained are comparable with other third-line chemotherapies.     

Use of methotrexate in refractory Crohn's disease: the Edinburgh experience

BACKGROUND: In the two benchmark controlled trials in Crohn's disease (CD) supporting its use, methotrexate (MTX) was used as the immunosuppressant of choice in immunomodulatory-naive patients. However, in daily clinical practice MTX is used generally after thiopurine analogs have failed. METHODS: The data are reported using intramuscular (IM) MTX (25 mg/week) in the induction of remission and oral MTX (15 mg/week) in 39 CD patients with a median age of 32 years, assessed retrospectively. In all, 97% patients had failed azathioprine and/or mercaptopurine therapy due to lack of efficacy in 14 (36%) and side effects in 24 (61%) patients; 21 patients (53%) were steroid-dependent with a median dose of 27.5 mg prednisolone/day for over a year. RESULTS: In all, 72% of patients tolerated an induction regimen of 25 mg/week of IM MTX; 10% managed a reduced dose and 18% were intolerant. Remission was achieved in 71% of patients at 16 weeks. In the patients taking corticosteroids, withdrawal was achieved in 26% of patients and reduction in 47% at 16 weeks. Oral MTX therapy was continued in 22 patients after induction. In this group the probability of relapse was 78% at 50 weeks of oral therapy. CONCLUSIONS: Parenteral MTX therapy is efficacious in inducing remission in steroid-dependent CD patients, although its use is limited by side effects in approximately 30% of patients. Low-dose oral therapy does not maintain long-term remission and is not a suitable alternative.     

Long-term oral administration of etoposide (VP-16) for the patients with refractory or relapsed acute non-lymphocytic leukemia

We investigated the efficacy of oral etoposide (VP-16) for the patients with acute non-lymphocytic leukemia (ANLL) in relapse or refractory to the standard chemotherapy. Patients were given etoposide orally at the dose of 50 mg/body/day on consecutive days until the leukemic cells in the bone marrow were reduced less than 5%. The duration of administration of oral etoposide ranged from 16 days to 50 days (average 30 days). Seven patients were given very low dose cytosine arabinoside (5 approximately 10 mg X 2/day i.s.c.) combination with oral etoposide. Six patients (66.7%) out of 9 achieved complete remission (CR) and 3 patients had no response. Adverse effects such as abdominal discomfort and appetite loss were observed in 3 patients, but they were mild and tolerable. The duration of CR ranged from 2 to 24 (+) months, and the median CR duration is 7 months. The over all CR rate (66.7%) in this group of patients with refractory or relapsed ANLL were encouraging. Further studies, however, are needed to evaluate the efficacy of long term oral administration of etoposide for the patients with leukemia.     

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) versus oral administration of methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with active RA (Disease Activity Score in 28 joints >or= 4) were eligible for the study if they had not previously taken biologic agents and had not taken disease-modifying antirheumatic drugs for 2 weeks prior to randomization. Patients were randomly assigned to receive 15 mg/week of MTX either orally (2 7.5-mg tablets plus a dummy prefilled syringe; n=187 patients) or SC (prefilled syringe containing 10 mg/ml plus 2 dummy tablets; n=188 patients) for 24 weeks. At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner. The primary outcome was an ACR20 response at 24 weeks. RESULTS: At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration >or= 12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups. CONCLUSION: This 6-month prospective, randomized, controlled trial is the first to examine oral versus SC administration of MTX. We found that SC administration was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability.     

Additional chenodiol therapy after partial dissolution of gallstones with two years of treatment

During the National Cooperative Gallstone Study, therapy with chenodiol, 750 or 375 mg/d, for 2 years resulted in confirmed, complete gallstone dissolution in 14% and 5% of patients, respectively, and partial dissolution (greater than 50%) in 27% and 18%. The present study was done to determine the frequency with which complete dissolution occurs in patients having partial dissolution of gallstones who receive additional therapy. Eighty-six of one hundred thirty-eight eligible patients continued to receive 750 mg/d (61 patients) or 375 mg/d (25 patients) of chenodiol for 1 year. Patients whose oral cholecystogram at the end of the year showed further (greater than 50%) dissolution continued to receive chenodiol, (28 patients at 750 mg/d and 11 patients at 375 mg/d) for a second year (total duration of therapy, 4 years). A final oral cholecystogram was taken at the end of the fourth year. Complete dissolution occurred in 23% and 16% of patients receiving chenodiol, 750 or 375 mg/d, respectively, for an additional 1 or 2 years.     

Biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral and oropharyngeal squamous cell carcinoma, with emphasis on smoking, protein p16(INK4a) expression, and HPV status

The aim of this study is to evaluate the biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinoma, with emphasis on smoking, protein p16(INK4a) (p16) expression, and human papillomavirus (HPV) status.The study sample consisted of 48 patients with OSCC and 44 patients with OPSCC. Half of the patients were nonsmokers and the other half were gender-, age- and tumor localization-matched smokers. p16 expression was detected in 17/48 (35 %) OSCCs and in 36/44 (82 %) OPSCCs and HPV DNA was present in 7/48 (15 %) OSCCs and in 35/44 (80 %) OPSCCs. The sensitivity and specificity of p16 expression for HPV DNA presence were 0.74 and 0.88, respectively. The OPSCCs were more frequently basaloid (p < 0.001) while the OSCCs were more frequently conventional (p < 0.000001). The OSCCs were more likely to recur locally and to be the cause of death (p = 0.009 in both parameters).The HPV-positive tumors were more frequently localized in oropharynx, were basaloid SCCs and were p16- and HPV-positive (p < 0.000001 in all 4 parameters). The HPV-negative tumors were more frequently localized in oral cavity (p < 0.000001), more frequently asociated with local, regional and locoregional recurence (p = 0.011, p = 0.019 and p = 0.030, respectively) and with tumor-related death (p = 0.003). There was no significant difference with regard to smoking history (p > 0.05). The survival of patients with HPV-positive tumors was significantly longer (median 112 months; 95% CI 54 - 112 months) than that of patients with HPV-negative tumors (median 17 months; 95% CI 12 - 39 months) (p < 0.001). The HPV status of OSCC/OPSCC is an important biological and prognostic parameter and should be examined in all cases, using PCR or immunohistochemical detection of surrogate marker p16. Smoking itself does not seem to be an important prognostic factor.     

Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised, double blind, crossover, placebo controlled study

BACKGROUND: High dose growth hormone, glutamine, and a high carbohydrate diet may improve intestinal function in short bowel patients. AIMS: To investigate if growth hormone with glutamine and no change in diet improved intestinal function. PATIENTS AND METHODS: Eight short bowel patients were randomised in a double blind crossover study between placebo and growth hormone (mean 0.12 mg/kg/day) with oral (mean 28 g/day) and parenteral glutamine (mean 5.2 g/day) for 28 days. Balance studies were performed at baseline and five days after placebo and treatment were terminated. Dietary energy, carbohydrate, and fat were maintained as usual. RESULTS: Growth hormone with glutamine did not improve intestinal absorption of energy (baseline, placebo, treatment, mean: 46%, 48%, 46% of oral intake, respectively), carbohydrate (71%, 70%, 71%), fat (20%, 15%, 18%), nitrogen (27%, 18%, 19%), wet weight (37%, 39%, 31%), sodium (-16%, -16%, -36%), potassium (43%, 47%, 33%), calcium (-16%, -16%, -15%) or magnesium (-3%, 4%, 2%) compared with placebo or baseline (p>0.05) five days after treatment was terminated. All patients experienced adverse effects. CONCLUSIONS: Combined high dose growth hormone and glutamine administered for four weeks did not improve intestinal absorption five days after treatment was terminated in short bowel patients on their usual diet.     

Evaluation of bepridil efficacy by electrophysiologic testing in patients with recurrent ventricular tachycardia: Comparison of two regimens

Summary The purpose of the study was to evaluate this effect of different doses of intravenous and oral bepridil on the induction of ventricular tachycardia. Thirty-eight patients underwent electrophysiologic evaluation for recurrent ventricular tachycardia (VT). Sustained monomorphic VT was induced by programmed ventricular stimulation, using up to three extrastimuli in all patients. The effects of intravenous bepridil (2 mg/kg) were evaluated during the initial study. Intravenous bepridil prevented the induction of sustained VT in eight patients (21%). Electrophysiologic study was repeated after oral bepridil. In six patients the study was stopped because of adverse effects or VT recurrence. Thirty-two patients underwent repeat study 7 days later, taking oral bepridil, 500 mg/day (n=16) or 900/day (n=16). A dose of 500 mg/day of bepridil prevented the induction of sustained VT in only one patient. A dose of 900 mg/day of bepridil prevented the induction of sustained VT in eight patients. There were no significant clinical adverse effects, except in one patient receiving intravenous bepridil. The response to intravenous bepridil did not predict the response to oral bepridil. The response to intravenous or oral bepridil was not related to the plasma level of bepridil but was related to a higher left ventricular ejection fraction. Eight patients (21%) in whom VTs were noninducible on oral bepridil were discharged on 300 mg/day of bepridil if their initial loading dose was 500 mg/day or on 600 mg/day if their initial loading dose was 900 mg/day. They remained free of VT during a follow-up of at least 6 months. In conclusion, this study suggests that oral bepridil at the dose of 600 mg/day may be of value in patients with recurrent VT.     

Flecainide: PVC Reduction in Children with Ventricular Dysrhythmias

Flecainide appears to be a promising new Class I_c antiarrhythmic drug. In this study, 16 children aged 18 days to 20 years (mean 8.0 years, median 6.8 years) with frequent PVCs and refractory ventricular tachycardia (VT) were evaluated. In all patients, a mean total of 3.5 antiarrhythmic agents were tried unsuccessfully prior to initiation of flecainide. We performed 24-hour ambulatory monitoring 2 days prior to oral flecainide administration and repeated monitoring after 48 hours of oral therapy. All studies were scanned by superimposition by computer and well-trained technician.
Twelve of 16 children demonstrated reduced numbers of PVCs following oral flecainide therapy with an overall mean reduction in PVCs of 70%. Mean numbers of PVCs fell from 377 PVCs/hour preflecainide to 113 PVCs/hour postflecainide therapy. Eight of 12 patients demonstrated a > 60% reduction of PVCs. Five of 12 children achieved nearly total abolishment of PVCs (e.g., <10 PVCs/hour) following flecainide treatment. Four of 16 children failed to exhibit PVC reduction during the study. Serum flecainide levels ranged from 0.1–1.1 meg/mL with a mean drug level of 0.39 mcg/mL. Success or failure did not correlate significantly with patient age, sex, anatomic diagnosis, previous therapy, or serum flecainide levels.
In summary, oral flecainide appears to be effective in reducing PVCs in children with ventricular tachycardia and consequently may decrease their risk for reentrant VT.     

Use of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope.

The usefulness of esmolol in predicting the efficacy of treatment with an oral beta-adrenergic blocking agent was evaluated in 27 consecutive patients with neurocardiogenic syncope. Seventeen patients had a positive head-up tilt test response at baseline and 10 patients required intravenous isoproterenol for provocation of hypotension. All patients were then given a continuous esmolol infusion (500 micrograms/kg per min loading dose for 3 min followed by 300 micrograms/kg per min maintenance dose) and rechallenged with a head-up tilt test at baseline or with isoproterenol. Of the 17 patients with a positive baseline tilt test response, 11 continued to have a positive response to esmolol challenge. Sixteen patients (including all 10 patients with a positive tilt test response with isoproterenol) exhibited a negative response to upright tilt during esmolol infusion. Irrespective of their response to esmolol infusion, all patients had a follow-up tilt test with oral metoprolol after an interval of greater than or equal to 5 half-lives of the drug. All 16 patients (100%) with a negative tilt test response during esmolol infusion had a negative tilt test response with oral metoprolol. Of the 11 patients with a positive tilt test response during esmolol infusion, 10 (90%) continued to have a positive response with oral metoprolol. It is concluded that in the electrophysiology laboratory, esmolol can accurately predict the outcome of a head-up tilt response to oral metoprolol. This information may be helpful in formulating a therapeutic strategy at the initial head-up tilt test in patients with neurocardiogenic syncope.     

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16?mg/kg or 8?mg/kg) and i.v. BU to 38 others (total dose 12.8?mg/kg or 6.4?mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.     

不同剂量厄贝沙坦治疗慢性肾小球肾炎患者后尿蛋白的变化

目的 观察慢性肾小球肾炎患者应用厄贝沙坦治疗后尿蛋白的变化,探讨高剂量厄贝沙坦治疗对尿蛋白的疗效.方法 32例经肾活检确诊的慢性肾小球肾炎患者,所有患者24 h尿蛋白≥0.5 g/d,随机分为常规剂量组(口服厄贝沙坦0.15 g/d,n=16)和高剂量组(口服厄贝沙坦0.3 g/d,n=16),治疗8周后观察24 h尿蛋白和血钾、血肌酐及尿素氮水平.结果 受试患者服用厄贝沙坦后尿蛋白均下降,常规剂量组尿蛋白较治疗前减少40%,而高剂量组尿蛋白较治疗前减少63%,两组血清钾、血肌酐及尿素氮水平均无明显改变.结论 对慢性肾小球肾炎患者,高剂量厄贝沙坦在减少尿蛋白方面更为显效,且患者耐受性、医从性均较好.     

Efficacy of miltefosine for Bolivian cutaneous leishmaniasis

Oral miltefosine (2.5 mg/kg/d for 28 days) was compared with intramuscular antimony (20 mg/kg/d for 20 days) in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Palos Blancos, Bolivia. The cure rates with 6 months of follow-up were statistically similar: 36 of 41 evaluable miltefosine patients (88%) versus 15 of 16 (94%) evaluable antimony patients. However, antimony cured more rapidly, because, by 1 month after therapy, 31 of 44 miltefosine patients (70%) compared with 16 of 16 antimony patients (100%) had achieved cure. The two conclusions from this work are that oral miltefosine can be used for cutaneous disease in this part of Bolivia and that miltefosine was more effective for L. braziliensis in this region than for L. braziliensis in Guatemala. Chemotherapy needs to be evaluated in each endemic region, even if the "same" species of Leishmania causes disease in these locales.     

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.     

Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.