Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome

Purpose

In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m²) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Effects of Dietary Plant Sterols and Stanol Esters with Low- and High-Fat Diets in Chronic and Acute Models for Experimental Colitis

In this study, we evaluated the effects of dietary plant sterols and stanols as their fatty acid esters on the development of experimental colitis. The effects were studied both in high- and low-fat diet conditions in two models, one acute and another chronic model of experimental colitis that resembles gene expression in human inflammatory bowel disease (IBD). In the first experiments in the high fat diet (HFD), we did not observe a beneficial effect of the addition of plant sterols and stanols on the development of acute dextran sulphate sodium (DSS) colitis. In the chronic CD4CD45RB T cell transfer colitis model, we mainly observed an effect of the presence of high fat on the development of colitis. In this HFD condition, the presence of plant sterol or stanol did not result in any additional effect. In the second experiments with low fat, we could clearly observe a beneficial effect of the addition of plant sterols on colitis parameters in the T cell transfer model, but not in the DSS model. This positive effect was related to the gender of the mice and on Treg presence in the colon. This suggests that especially dietary plant sterol esters may improve intestinal inflammation in a T cell dependent manner.     

Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors

Background and Purpose

Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D₂, D₃, D₄ and D₅ receptors but with a low affinity for the dopamine D₁ receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson''s disease (PD).

Experimental Approach

The binding of rotigotine to human dopamine D₁, D₂, D₃, D₄ and D₅ receptors was determined in radioligand binding studies using [³H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined.

Key Results

[³H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D₁, D₂ and D₃ receptors and, to a lesser extent, D₄ and D₅ receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors.

Conclusions and Implications

Rotigotine is a high-potency agonist at human dopamine D₁, D₂ and D₃ receptors with a lower potency at D₄ and D₅ receptors. These studies differentiate rotigotine from conventional dopamine D₂ agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D₁ and D₅ receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties.     

Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic malignancies and pulmonary infiltrates

Infectious complications are a major cause of morbidity and mortality in immunosuppressed patients. Febrile patients with hematologic malignancies and pulmonary infiltrates have high mortality rates, especially if mechanical ventilation is required. The diagnostic value of fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) in these patients is controversial. We retrospectively analyzed the microbiological results of BAL samples obtained during 249 FOB examinations from 199 febrile patients with hematologic malignancies and pulmonary infiltrates (underlying diseases: acute leukemia 103 patients, lymphoma 84 patients, other malignancies 12 patients). Two hundred forty-six examinations could be evaluated. Seventy-three out of 246 BAL samples were sterile; 55 samples showed microbiological findings classified as contamination or colonization. One hundred eighteen samples showed positive microbiological results of bacteria and/or fungi classified as causative pathogens. Thereof, in 70 samples, only bacterial pathogens were detectable (Gram-positive, 35; Gram-negative, 30; mixed Gram-positive and Gram-negative, 5). Thirteen samples showed both fungi and bacterial pathogens. In 33 samples, only fungi were detectable, thereof, in 15 samples Aspergillus species, in 16 samples Candida species, and in 2 both. In two samples, a viral pathogen could be detected. Three nonlethal complications (bleeding, arrhythmia) occurred that required early termination of FOB. In 94 (38.2%) patient episodes, antibiotic treatment was modified as a result of microbiological findings in BAL samples. Our results show that FOB with BAL is a valuable diagnostic tool with low complication rates in high-risk febrile patients with hematologic malignancies and pulmonary infiltrates, contributing crucial results for the individual case, and also improving epidemiologic knowledge.     

Is serial determination of inspiratory muscle strength a useful prognostic marker in chronic heart failure?

BACKGROUND: Little data exists on the prognostic role of inspiratory muscle strength (PImax) in chronic heart failure (CHF). Training studies, however, frequently use it as a therapeutic target and surrogate marker for prognosis. The prognostic value of changes of PImax that allow this extrapolation is unknown. DESIGN: Patients with stable CHF were prospectively included and 1-year and all-time event rates recorded for endpoint analysis. METHODS: In 158 patients (85% men; New York Heart Association functional class: 2.4+/-0.6), PImax was measured along with clinical evaluations at two visits, the initial visit and the second visit, 6.4+/-1.4 months apart. The mean follow-up was 59+/-34 months. RESULTS: Overall, 59 patients (37%) reached the primary endpoint of death or hospitalization (endpoint positive), and overall mortality rate (secondary endpoint) was 26% (42 patients). PImax did not differ between endpoint-negative and endpoint-positive patients, both at the initial and at the second visit (8.3+/-5.6 vs. 7.3+/-3.4 kPa and 8.8+/-6.0 vs. 7.9+/-3.6 kPa, respectively; P=NS), and both groups showed increased PImax (0.6+/-2.6 vs. 0.6+/-2.8 kPa; P=NS). Cox analyses found neither the absolute nor the relative change of PImax to be significant predictors for the primary and secondary endpoints (P=NS for both), both for the 1-year and for the all-time event rates. Endpoint rates did not differ between patients showing increasing or decreasing PImax (P=NS; relative risk (RR): 0.77; 95% confidence interval: 0.47-1.27). CONCLUSION: Trials focusing on inspiratory muscle function should use the actual levels of PImax as a surrogate marker to represent prognostic information, rather than relative or absolute changes. This is the first study to investigate the prognostic information of the changes of PImax over time, regarding both short-term and long-term morbidity and mortality in patients with stable CHF.     

Non-invasive mechanical ventilation improves walking distance but not quadriceps strength in chronic respiratory failure

BACKGROUND: In patients with chronic respiratory failure (CRF) nocturnal mechanical ventilation (NMV) confers increased exercise tolerance. The hypothesis tested in the present study was that the increased exercise performance is associated with increased quadriceps strength. METHODS: In 28 patients with CRF due to chronic obstructive pulmonary disease and restrictive thoracic disease (post-tuberculosis-sequelae, scoliosis and obesity-hypoventilation) NMV was started. Before and after 2-month NMV the exercise tests, namely shuttle and 6-min walking distance, were performed. Furthermore, quadriceps strength was measured as the twitch tension elicited by magnetic stimulation the femoral nerve (TwQ) and the maximum voluntary contraction force (MVC). RESULTS: After 2 months therapy with NMV there was significant clinical and blood gas improvement. NMV significantly improved the walking distance by approximately 18% but there was no improvement in TwQ or MVC, the data could exclude a 15% improvement in TwQ with 82% confidence. CONCLUSION: The strength of quadriceps does not change after 2 months of effective NMV in patients with CRF despite a marked increase in endurance time. Factors other than quadriceps strength account for the improved performance.     

Immunocytochemical detection of p21 ras expression in fresh human leukaemic cells and cell lines

Summary The expression of p21 ^ras proteins was investigated by immunocytochemistry in permanent cell lines and in fresh human leukaemic cells. While high and low levels of p21 ^ras could be detected in most of the cell lines, no significant p21 ^ras immunoreactivity was noted in cells of ten human acute and chronic leukaemias. Thus, notwithstanding its possible role in the initial transformation process in human leukaemias, p21 ^ras expression appears not to be an irrevocable requirement for the maintenance of the transformed state.     

Patients with Persistent Atrial Fibrillation Taking Oral Verapamil Exhibit a Lower Atrial Frequency on the ECG

Background: While there is agreement that verapamil attenuates the AF‐ induced refractory period shortening when given before AF induction, controversy exists regarding its effects when given after the onset of persistent AF. This study aimed to compare atrial fibrillatory frequency obtained from the surface ECG in patients with persistent atrial fibrillation (AF) with oral verapamil treatment to those without this treatment. Methods and Results: Surface ECG recordings were performed in 57 patients (34 male, 23 female, mean age 59 ± 11 years) with persistent AF (> 7 days). The frequency content of the fibrillatory baseline was quantified using digital signal processing (filtering, QRST complex averaging and subtraction. Fourier transformation). In 27 patients with verapamil treatment (120 or 240 mg/day for at least 7 days) mean fibrillatory frequency measured 6.4 ± 0.2 Hz, compared to 7.0 ± 0.4 Hz (P = 0.012) in 30 patients without verapamil. In a subset of 20 randomly selected patients (10 with, 10 without verapamil treatment) a 24‐hour Holter ECG recording was performed and fibrillatory frequency determined at 4 PM, 10 PM, 4 AM, and 10 AM. While there was a significant frequency reduction in the verapamil treated patients at night (P = 0.011), it remained constant over time in the other patients. Conclusion: In patients with persistent AF, fibrillatory frequency assessed by spectral analysis of the surface ECG is lower in patients taking verapamil. A.N.E. 2002;7(2):92–97     

Neoadjuvant, adjuvant, and palliative treatment of pancreatic cancer

Pancreatic cancer remains a highly malignant disease. Curative treatment is only possible for patients diagnosed at a very early stage. Therefore, the vast majority of pancreatic cancer patients receive palliative treatment. Surgical palliation is offered to patients who are found not to have a resectable tumor. The treatment of obstructive jaundice is managed by stenting of the common bile duct or by a surgical bypass. The best possible surgical procedure should be based on the factors that influence hospital mortality, length of survival, and quality of life. In patients with a life expectancy of longer than 3 months, surgical bypass is recommended, with hepaticojejunostomy the treatment of choice. In the same surgical procedure, the relief of duodenal obstruction with a gastroenteric bypass should be achieved. Chemotherapy, radiotherapy, or a combination of both is employed as a neoadjuvant measure, as an adjuvant treatment, or, in most patients, as palliation. As palliative chemotherapy alone, 5-fluorouracil (5-FU) plus folinic acid is still the treatment of choice; however, newer drugs, such as gemcitabine, seem to have similar or marginally better results. Palliative radiochemotherapy with external-beam radiation plus 5-FU and folinic acid seems to lead to better local control of tumor progression but not to better survival, for which distant metastases are the limiting factor.     

Generation of highly effective and stable murine alloreactive Treg cells by combined anti‐CD4 mAb,TGF‐β, and RA treatment

The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long‐term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti‐CD4 antibody (aCD4). Here, we investigated whether adding TGF‐β and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg‐cell generation and function. Murine CD4⁺ T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF‐β+RA or aCD4+Rapa. Addition of TGF‐β+RA or Rapa resulted in an increase of CD25⁺Foxp3⁺‐expressing T cells. Expression of CD40L and production of IFN‐γ and IL‐17 was abolished in aCD4+TGF‐β+RA aTreg cells. Additionally, aCD4+TGF‐β+RA aTreg cells showed the highest level of Helios and Neuropilin‐1 co‐expression. Although CD25⁺Foxp3⁺ cells from all culture conditions displayed complete demethylation of the Treg‐specific demethylated region, aCD4+TGF‐β+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF‐β+RA aTreg cells suppressed effector T‐cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF‐β+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells.