Increased Incidence of Angioedema with ACE Inhibitors in Combination with mTOR Inhibitors in Kidney Transplant Recipients

Background and objective: The clinical manifestation of angioedema ranges from minor facial edema up to life-threatening swelling of mouth and throat. Hereditary defects, drugs, and food allergies may play a role in the development of angioedema. We systematically investigated the incidence of angioedema in renal allograft recipients treated with mTOR inhibitors (mTORis).Design, setting, participants, & measurements: All patients in the authors'' electronic database who had received mTORis (n = 309) between 2000 and 2008 were identified. Of these, 137 were additionally treated with angiotensin-converting enzyme inhibitors (ACEis).Results: Nine patients (6.6%, 3.8 per 100 treatment years) developed angioedema after a mean period of 123 days under combined therapy with mTORi and ACEi. Among the remaining 172 patients on mTORi, including 119 patients treated with angiotensin-receptor blockers, only two developed angioedema (1.2%, 0.5 per 100 treatment years, P = 0.01). In patients receiving mycophenolate and ACEi (n = 462), 10 instances of angioedema were found (2.1%, 0.8 per 100 treatment years, P = 0.004).Conclusions: This systematic investigation demonstrated a noticeable incidence of 6.6% angioedema under combined therapy with mTORi and ACEi in kidney transplant recipients. Treatment with either ACEi or mTORi alone resulted in a significantly lower incidence of angioedema, suggesting that this combination should be avoided.Depending on its magnitude and localization, the clinical picture of angioedema varies widely from moderate self-limiting facial edema up to life-threatening swelling of lips, tongue, or throat. Underlying etiologies include hereditary defects of complement inhibitor C1, drugs, and food allergies (1,2). Increased bradykinin levels may play a role in the development of angioedema; however, the exact pathophysiology of angioedema remains unclear (3). One of the most frequent causes of angioedema is use of angiotensin-converting enzyme inhibitors (ACEis), which are estimated to be responsible for 10% to 25% of all cases of angioedema (4). ACEis are widely used in patients with hypertension, heart failure, kidney diseases, or diabetes because of their convincing efficacy. It has been suggested that ACEi increases the risk of angioedema, most likely due to vasodilatation as a consequence of reduced bradykinin degradation (3). Initial data on the occurrence of angioedema under ACEi therapy came from registration trials and pharmacovigilance registries, but only recent large prospective trials provided reliable insight on the incidence of this rare side effect.In the randomized, double-blind OCTAVE trial with >12,000 patients, angioedema occurred in 0.68% of ACEi-treated patients (5). More recently, an overall incidence of 0.3% (n = 25 of 8576) angioedema was reported for ACEi during the ONTARGET study (6). In contrast, the use of angiotensin-receptor blockers (ARBs) was associated with a much lower risk of angioedema (0.1%; n = 10 of 8542 patients) in this trial. Thus, ARBs may be applied to patients with ACEi-induced angioedema, although 2 of 26 patients with angioedema due to ACEi therapy had also angioedema with ARBs (7). Approximately 60% of ACEi-induced angioedemas start within 1 week, but ACEi-induced angioedema may occur even after years (8).Higher incidence of angioedema under treatment with mTOR inhibitor (mTORi) in organ-transplanted patients has been implicated in case series and several case reports (9–13). Because we were confronted with similar patients in our outpatient clinic, we initiated a systematic search in our database to investigate frequency and clinical course of angioedema in a larger cohort of kidney transplant recipients.     

Are health states ‘timeless’? A case study of an acute condition: post‐chemotherapy nausea and vomiting1

Rationale, aims and objectives The objective was to test whether individuals’ responses to standard gamble (SG) and visual analogue scale (VAS) questions do not depend on the time horizon of the health scenario presented. Methods Face‐to‐face interviews were conducted in a convenience sample of 18 women aged 22–50 years with no history of breast cancer or cancer requiring chemotherapy. Data were collected from March 2000 to June 2000 at a university in the Midwest of the United States of America. Preference weights were estimated using SG top‐down titration method and VAS scaled from zero (death) to one (perfect health). Subjects were asked to rate their preferences if faced with two scenarios: post‐chemotherapy nausea and vomiting (PCNV) occurring for 3 days (scenario 1), and PCNV lasting for the rest of their lives (scenario 2). Three PCNV health states of varying severity were tested: complete alleviation, partial alleviation, and no alleviation. Results Paired‐t‐test analysis showed statistically significantly lower preference weights (P < 0.05) when the health state was for the rest of the respondent's life vs. 3 days. Mean SG weights for scenario 1 vs. scenario 2 were: 0.968 vs. 0.927 (complete alleviation), 0.942 vs. 0.810 (partial alleviation) and 0.866 vs. 0.644 (no alleviation). Mean VAS weights for scenario 1 vs. scenario 2 were: 0.741 vs. 0.676 (complete alleviation), 0.490 vs. 0.307 (partial alleviation) and 0.276 vs. 0.136 (no alleviation). Discussion and conclusions For the majority of respondents the utility independence assumption for SG and VAS did not hold. Similar to Bala et al., the results of this study indicated that preference weights as measured by SG and VAS techniques were not ‘timeless’. Regardless of the preference measure used, both SG and VAS yielded higher scores when PCNV lasted for a shorter period of time.     

Phase II study of liposomal doxorubicin and weekly paclitaxel for recurrent Müllerian tumors

OBJECTIVE: Pegylated liposomally encapsulated doxorubicin (Doxil. Ortho-Biotech) and paclitaxel (Taxol, Bristol Myers Squibb) are both active against Müllerian malignancies. A phase II trial was performed to determine the toxicity and efficacy of these agents when administered in combination. METHODS: Patients were initially treated with 30 mg/m(2) of liposomal doxorubicin every 21 days and 70 mg/m(2) of paclitaxel every week for 18 weeks. The plasma pharmacokinetics of paclitaxel was determined when administered alone and concurrently with liposomal doxorubicin. RESULTS: Forty women with recurrent gynecologic malignancies of Müllerian origin including 34 with ovary and primary peritoneal cancer (85%) were enrolled. Toxicity was evaluated for all 508 cycles of therapy. Paclitaxel and liposomal doxorubicin were delivered at 95% (66.4 mg/m(2)/week) and 77% (7.65 mg/m(2)/week) of their intended weekly dose intensities, respectively. Reductions in the dose of liposomal doxorubicin were frequently required for palmar plantar erythrodysesthesia during the latter cycles of therapy. There were 4 patients with a complete response and 7 with partial responses, for an overall objective response rate of 29%, among the 38 evaluable patients. Response rates for the subset of 13 women with tumor recurrence occurring at least 6 months after prior platinum-based therapy was 54%. The concurrent administration of liposomal doxorubicin did not alter the pharmacokinetic disposition of paclitaxel. CONCLUSION: Liposomal doxorubicin with weekly paclitaxel is active in Müllerian malignancies. The concurrent delivery of the weekly paclitaxel with liposomal doxorubicin may increase liposomal doxorubicin skin toxicity. Liposomal doxorubicin does not alter the pharmacokinetics of paclitaxel.     

Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma

OBJECTIVE: The purpose of this study was to identify poor prognostic factors of low-risk stage IB1 cervical adenocarcinoma METHODS: .All women diagnosed with stage IB1 cervical adenocarcinoma between 1982 and 2002 were identified at our three institutions. Data were extracted from medical records. Patients were retrospectively assigned to a low- or intermediate/high-risk cohort based on the surgical-pathologic eligibility criteria of two randomized controlled trials of adjuvant therapy in early stage cervical cancer, Gynecologic Oncology Group protocols 92 and 109. Multivariate analysis was performed. RESULTS: Two hundred thirty women diagnosed with stage IB1 cervical adenocarcinoma had an overall 5-year survival of 89%. Adenosquamous cell type (P < 0.01) was the only independent risk factor of disease recurrence in the low-risk group (n = 178). The 5-year disease-free survival for low-risk adenosquamous patients was 79%, compared to 96% for other histologic subtypes (P < 0.01). Low-risk case subjects developed fewer disease recurrences than those in the intermediate/high-risk (n = 52) category (7% vs 46%; P < 0.01). The 5-year disease-free survival for intermediate/high-risk patients was 51% and no additional risk factors were identified. CONCLUSION: Adenosquamous histology is predictive of disease recurrence and decreased survival in low-risk stage IB1 cervical adenocarcinoma. This risk factor should be considered in future clinical trials of adjuvant therapy.     

Long-term administration of intravaginal dehydroepiandrosterone on regression of low-grade cervical dysplasia--a pilot study

Although many dysplastic cervical lesions regress spontaneously, treatment is common due to concern for progression. Lesions persist or progress in women whose immune systems are unable to clear infection by human papillomavirus (HPV). Dehydroepiandrosterone (DHEA) is an adrenal steroid that has both immune modulatory and tumor inhibitory activity. A pilot study was conducted to examine the feasibility, safety and potential efficacy of intravaginal DHEA in women with low-grade cervical dysplasia. Twelve women with low-grade dysplasia, confirmed by colposcopic exam, were given 150 mg of intravaginal micronized DHEA daily for up to 6 months. Follow-up evaluations of the cervix were done at 3 and 6 months of use. DHEA, DHEA-S, androstenedione and testosterone levels were also measured. By the end of the study period, 10 of the 12 women (83%) had no evidence of dysplasia; the remaining 2 had normal colposcopic exams but cytology showing atypical cells of undetermined significance. There were no serious side effects. Androstenedione levels were elevated at 3 months, whereas testosterone levels were unchanged over the course of treatment. The results suggest that intravaginal DHEA is safe and well tolerated and may promote regression of low-grade cervical lesions. Further study is needed to establish efficacy.     

Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus

BACKGROUND & AIMS: Starvation decreases insulin sensitivity and glucose tolerance in both lean and obese (OB) non-diabetic subjects. Influence of drastic calorie reduction on insulin resistance in patient with type 2 diabetes (T2DM) is not known. METHODS: We enrolled 10 T2DM (diabetes duration 11.1+/-7.9 years) and 10 OB age and weight-matched subjects and performed isoglycaemic hyperinsulinaemic clamp (two 120 min phases of 60 and 120 mIU min-1 m-2 i.v. insulin) with indirect calorimetry at baseline and after 60 h of fasting. RESULTS: After starvation insulin-mediated glucose disposal decreased significantly in both hyperinsulinaemic phases in T2DM (phase 1: from 46+/-28 to 33+/-17, P<0.04; phase 2 from 122+/-47 to 80+/-30 microg kg-1 min-1, P<0.01) as well as in OB (phase 1: from 94+/-52 to 52+/-24, P<0.04; phase 2: from 131+/-46 to 106+/-43 microg kg-1 min, P<0.01). Both oxidative and non-oxidative components of glucose disposal tended to be reduced after fasting. A change of insulin sensitivity was found to be highly dependent upon pre-starvation conditions: more insulin resistant subjects tended to maintain (or modestly improve) insulin resistance whilst subjects with better insulin sensitivity tended to worse it. CONCLUSION: Insulin sensitivity worsens similarly in both T2DM and OB subjects during 60-h fast. The change is probably predictable according to pre-starvation insulin sensitivity.     

Examining the suitability of mussel digestive gland to serve as a biomonitoring target organ

In coastal marine areas, the level of metallothioneins (MTs) is monitored as the specific response to trace heavy metals and is considered as a biomarker of metal exposure. Laboratory experiments with bivalves indicate that MT synthesis is induced by Cd, Cu, Hg, Ag and Zn ions. The results of our study, conducted with the mussel Mytilus galloprovincialis, deployed 12 months in the "hot spot" area of the Kastela Bay, Dalmatia, Croatia, are evaluated considering the recommendation of MED POL Programme for estimating exposure of mussels to trace heavy metals by means of MTs. Our data clearly indicate that the MT level in the digestive gland of the Mediterranean mussel depends on the biotic and abiotic parameters. Beside MT level, a number of parameters, like digestive gland mass, shell mass, cytosolic metal concentration is needed in order to define if MT level in the digestive gland of mussels is indicative as a biomarker of cadmium exposure.