Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose approach.

Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.

Evaluating the impact of chemotherapy-induced nausea and vomiting on daily functioning in patients receiving dexamethasone-sparing antiemetic regimens with NEPA (netupitant/palonosetron) in the cisplatin setting: results from a randomized phase 3 study.

BACKGROUND: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). METHODS: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. RESULTS: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. CONCLUSION: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. TRIAL REGISTRATION: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.

Efficacy of the dexamethasone-sparing triplet regimen for preventing cisplatin-induced emesis: a combined analysis.

Aim: To further evaluate the antiemetic efficacy of single-dose versus multiple-dose dexamethasone (DEX) against nausea and vomiting caused by cisplatin. Materials & methods: Two similar non-inferiority studies were pooled. Patients were randomized to single-day DEX or multiple-day DEX plus palonosetron and neurokinin-1 receptor-antagonists (NK-1RAs). The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase. Results: The combined analysis included 242 patients. The absolute risk difference between single day versus multi-day DEX for CR was -2% (95% CI, -14 to 9%). Conclusion: Administration of single-dose DEX offers comparable antiemetic control to multiple-day DEX when combined with palonosetron and an NK-1RA in the setting of single-day cisplatin.

We aimed at further evaluating how well the corticosteroid, dexamethasone (DEX), works as measured in two similar clinical studies of single-day versus multiple-day DEX for the prevention of nausea and vomiting caused by cisplatin, a cell-killing drug, which has high potential of triggering nausea and vomiting. In both studies, cancer patients were randomly assigned to 1-day DEX or multiple-day DEX (3­4 days) in combination with palonosetron (this antagonist attaches to a specific receptor for serotonin without triggering nausea and vomiting), and neurokinin-1 receptor-antagonists (NK-1RAs; they attach to the NK-1 receptor without triggering nausea and vomiting). The combined analysis of the two studies, which includes 242 patients, showed that a single dose of DEX is as effective as multiple-day DEX in terms of the number of patients achieving complete response (defined as no vomiting and no 'as-needed' use of antiemetics) during the 5 days after cisplatin administration. Therefore, administration of single-dose DEX offers comparable antiemetic control to multiple-day DEX when combined with palonosetron and an NK-1RA in patients undergoing single-day cisplatin.

Efficacy and safety of netupitant/palonosetron combination (NEPA) in preventing nausea and vomiting in non-Hodgkin's lymphoma patients undergoing to chemomobilization before autologous stem cell transplantation.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is particularly challenging for patients receiving highly emetogenic preparative regimens before autologous stem cell transplantation (ASCT) due to the daily and continuous emetogenic stimulus of the multiple day chemotherapy. While studies have shown effective prevention of CINV during the conditioning phase with NK1 receptor antagonist (NK1RA)-containing regimens, there have been no studies evaluating antiemetic use during chemomobilization prior to ASCT. METHODS: This multicenter, open-label, phase IIa study evaluated the efficacy of every-other-day dosing of NEPA administered during chemomobilization in patients with relapsed-refractory aggressive non-Hodgkin's lymphoma. Eighty-one patients participated. RESULTS: Response rates were 77.8% for complete response (no emesis and no rescue use), 72.8% for complete control (complete response and no more than mild nausea), 86.4% for no emesis, and 82.7% for no rescue use during the overall phase (duration of chemomobilization through 48 h after). NEPA was well tolerated with no treatment-related adverse events reported. CONCLUSION: NEPA, administered with a simplified every-other-day schedule, show to be very effective in preventing CINV in patients at high risk of CINV undergoing to chemomobilization of hematopoietic stem cells prior to ASCT.

Post hoc Analysis of a Randomized, Controlled, Phase 2 Study to Assess Response Rates with Chlormethine/Mechlorethamine Gel in Patients with Stage IA-IIA Mycosis Fungoides.

BACKGROUND: Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Patients can be treated using chlormethine gel, a skin-directed therapy developed and approved for MF. In the randomized, controlled 201 trial, chlormethine gel was found to be noninferior to equal-strength chlormethine ointment. However, there remains a need to gain more insight into outcome measures after treatment. OBJECTIVE: The aim of this study was to further investigate the potential of chlormethine gel treatment through a novel post hoc analysis of the 201 trial data (NCT00168064). METHODS: Patients were randomized to chlormethine gel or ointment; response assessments included Composite Assessment of Index Lesion Severity (CAILS) and total body surface area (BSA). In this post hoc analysis, additional subgroup response analyses were performed for stage IA/IB-IIA MF. Very good partial response (75 to <100% improvement) was included as an additional response category. Time to response and overall response trends were determined. Finally, multivariate time-to-event analyses were performed to determine whether associations were observed between treatment frequency, response, and adverse events. RESULTS: Response rates were significantly higher for patients with stage IA MF for CAILS (intent-to-treat [p = 0.0014] and efficacy-evaluable [EE; p = 0.0036] populations) and BSA (EE population [p = 0.0488]) treated with gel versus ointment. Time to first CAILS response and response trends were better for all-stage gel-treated patients overall. No association was seen between treatment frequency and response or occurrence of adverse events at the following visit. An association was observed between the occurrence of contact dermatitis and improved clinical response at the next visit (p = 0.0001). CONCLUSION: This post hoc analysis shows that treatment with chlormethine gel may result in higher and faster response rates compared with chlormethine ointment, which confirms and expands results reported in the original analysis. The incidence of contact dermatitis may potentially be a prognostic indicator for clinical response; this needs to be confirmed in a larger population.

Dexamethasone-Sparing Regimens with Oral Netupitant and Palonosetron for the Prevention of Emesis Caused by High-Dose Cisplatin: A Randomized Noninferiority Study.

BACKGROUND: To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin-based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low-dose DEX on days 2 and 3, combined with an oral fixed-dose combination of netupitant and palonosetron (NEPA), compared with the guideline-consistent use of 4-day DEX. PATIENTS AND METHODS: In this open-label, multicenter study, chemotherapy-naïve patients undergoing high-dose cisplatin (≥70 mg/m2 ), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2-3 (DEX3), or (c) DEX (4 mg twice daily) on days 2-4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5-day overall phase. The noninferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). RESULTS: Two-hundred twenty-eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX-sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, -12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. CONCLUSION: A simplified regimen of NEPA plus single-dose DEX offers comparable chemotherapy-induced nausea and vomiting prevention throughout 5 days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting of cisplatin-based chemotherapy. IMPLICATIONS FOR PRACTICE: Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy-induced emesis. Although generally considered safe, even short-term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post-chemotherapy with a simplified regimen of netupitant/palonosetron plus single-dose DEX versus the standard 4-day DEX reference treatment in high-dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised.

Single-dose netupitant/palonosetron versus 3-day aprepitant for preventing chemotherapy-induced nausea and vomiting: a pooled analysis.

Aim: In the absence of comparative studies, guidelines consider neurokinin 1 receptor antagonists (RAs) as interchangeable. We evaluated the pooled efficacy from three cisplatin registration trials, each with arms containing netupitant/palonosetron (NEPA), a fixed neurokinin 1 RA (netupitant)/serotonin Type 3 (5-HT3) RA (palonosetron) combination, and an aprepitant (APR) regimen. Materials & methods: Efficacy data were pooled for rates of complete response (CR: no emesis/no rescue medication), complete protection (CR + no significant nausea), total control (CR + no nausea) and no significant nausea during acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) phases post chemotherapy. Results: Among 621 NEPA and 576 APR patients, response rates were similar for the acute phase, and generally favored NEPA during delayed and overall phases. CR rates for NEPA versus APR were 88.4 versus 89.2%, 81.8 versus 76.9% (p < 0.05) and 78.4 versus 75.0% during the acute, delayed and overall phases, respectively. Conclusion: Oral NEPA administered on day 1 was more effective than a 3-day APR regimen in preventing delayed nausea and vomiting associated with cisplatin.

Lay abstract Oral netupitant/palonosetron (NEPA) is an innovative product that combines two drugs (netupitant and palonosetron) in a single capsule to prevent nausea and vomiting associated with certain types of chemotherapy. In this paper we pooled together the results of three studies comparing the efficacy of NEPA to two drugs from the same classes administered separately (aprepitant regimen) in patients with various solid tumors receiving cisplatin, a type of chemotherapy with a high likelihood of causing nausea and vomiting. In summary, NEPA was more effective than the aprepitant regimen in preventing nausea and vomiting in the later days (days 3­5) following chemotherapy.

Netupitant/palonosetron (NEPA) and dexamethasone for prevention of emesis in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide: a multi-cycle, phase II study.

BACKGROUND: NEPA is an oral fixed-dose combination of netupitant, a new highly selective neurokinin-1 receptor antagonist, and palonosetron. This study was conducted to evaluate whether the efficacy of NEPA against chemotherapy-induced nausea and vomiting (CINV) in cycle 1 would be maintained over subsequent chemotherapy cycles in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide (AC). The study also describes the relationship between efficacy on day 1 through 5 (overall period) and control of CINV on day 6 through 21 (very late period) in each cycle. METHODS: In this multicentre, phase II study, patients received both NEPA and dexamethasone (12 mg intravenously) just before chemotherapy. The primary efficacy endpoint was overall complete response (CR; no emesis and no rescue medication use) in cycle 1. Sustained efficacy was evaluated during the subsequent cycles by calculating the rate of CR in cycles 2-4 and by assessing the probability of sustained CR over multiple cycles. The impact of both overall CR and risk factors for CINV on the control of very late events (vomiting and moderate-to-severe nausea) were also examined. RESULTS: Of the 149 patients enrolled in the study, 139 were evaluable for a total of 552 cycles; 97.8% completed all 4 cycles. The proportion of patients with an overall CR was 70.5% (90% CI, 64.1 to 76.9) in cycle 1, and this was maintained in subsequent cycles. The cumulative percentage of patients with a sustained CR over 4 cycles was 53%. NEPA was well tolerated across cycles. In each cycle, patients with CR experienced a significantly better control of very late CINV events than those who experienced no CR. Among the patients with CR, the only predictor for increased likelihood of developing very late CINV was pre-chemotherapy (anticipatory) nausea (adjusted odds ratio = 0.65-0.50 for no CINV events on cycles 3 and 4). CONCLUSION: The high anti-emetic efficacy seen with the NEPA regimen in the first cycle was maintained over multiple cycles of adjuvant AC for breast cancer. Preliminary evidence also suggests that patients achieving a CR during the overall period gain high protection even against very late CINV events in each chemotherapy cycle. TRIAL REGISTRATION: This trial was retrospectively registered at Clinicaltrials.gov identifier (NCT03862144) on 05/Mar/2019.

Impact of dexamethasone-sparing regimens on delayed nausea caused by moderately or highly emetogenic chemotherapy: a meta-analysis of randomised evidence.

BACKGROUND: Nausea can be particularly prominent during the delayed period. Therefore, we performed a meta-analysis of the available randomised evidence to assess the average effect of palonosetron plus one-day dexamethasone (DEX; also called the DEX-sparing strategy) compared with palonosetron plus 3-day DEX for control of chemotherapy-induced nausea and vomiting (CINV), focusing on delayed nausea. METHODS: Eligible studies were identified through MEDLINE, Embase, and CENTRAL. Data on acute and delayed CINV were collected. Efficacy end points were complete response (CR; no vomiting, and no use of rescue medication), complete protection (CP; CR plus no clinically significant nausea), and total control (TC; CR plus no nausea) during the delayed period (days 2-5 after chemotherapy initiation). All randomised studies comparing palonosetron plus single-dose DEX (with or without another active agent) on day 1 followed by either no further DEX or additional DEX doses (both alone or in combination with another active agent) qualified. RESULTS: Of 864 citations screened, 8 studies with 1970 patients were included in the meta-analysis. During the delayed period, the combined odds ratio (OR) for all comparisons was 0.92 (95% confidence interval [CI], 0.76-1.12) for CR, 0.85 (95% CI, 0.71-1.03) for CP, and 0.92 (95% CI, 0.77-1.11) for TC in patients undergoing moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide-containing chemotherapy (AC). The absolute risk difference (RD) computations for all end points in the delayed period did not exceed the threshold of - 4% (range, - 1% to - 4%). The effect was similar in subgroups defined by various study design parameters. The absolute RD computations in the acute period did not exceed the threshold of 1% (range, 0 to 1%). For one-day vs. 3-day DEX, numbers needed to be treated in order for one additional patient to not experience CR, CP and TC over the delayed period were 100, 25 and 50, respectively. CONCLUSIONS: This meta-analysis demonstrates that DEX-sparing regimens do not cause any significant loss in protection against not only vomiting but also nausea induced by single-day MEC or AC during the delayed period. These data should lead clinicians to optimise use of prophylactic DEX in clinical practice.

Improved outcome of patients with relapsed/refractory Hodgkin lymphoma with a new fotemustine-based high-dose chemotherapy regimen.

High-dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third-generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR-HL accrued into a prospective registry-based study. Application of FEAM resulted in a 2-year progression-free survival (PFS) of 73·8% [95% confidence interval (CI), 0·64-0·81] with median PFS, overall survival and time to progression yet to be reached. The 2-year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12-0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose ((18) (F) FDG)-uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had (18) (F) FDG-positrin emission tomography-positive lesions before HDT, the 2-year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12-0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR-HL patients typically pre-exposed to lung-damaging treatments.

Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP.

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.

Epidemiology and outcome of Clostridium difficile infections in patients hospitalized in Internal Medicine: findings from the nationwide FADOI-PRACTICE study.

BACKGROUND: Clostridium difficile (CD) is a leading cause of diarrhoea among hospitalized patients. The objective of this study was to evaluate the rate, the optimal diagnostic work-up, and outcome of CD infections (CDI) in Internal Medicine (IM) wards in Italy. METHODS: PRACTICE is an observational prospective study, involving 40 IM Units and evaluating all consecutive patients hospitalized during a 4-month period. CDI were defined in case of diarrhoea when both enzyme immunoassay for GDH, and test for A/B toxin were positive. Patients with CDI were followed-up for recurrences for 4 weeks after the end of therapy. RESULTS: Among the 10,780 patients observed, 103 (0.96 %) showed CDI, at admission or during hospitalization. A positive history for CD, antibiotics in the previous 4 weeks, recent hospitalization, female gender and age were significantly associated with CDI (multivariable analysis). In-hospital mortality was 16.5 % in CD group vs 6.7 % in No-CD group (p < 0.001), whereas median length of hospital stay was 16 (IQR = 13) vs 8 (IQR = 8) days (p < 0.001) among patients with or without CDI, respectively. Rate of CD recurrences was 14.6 %. As a post-hoc evaluation, 23 out of 34 GDH+/Tox- samples were toxin positive, when analysed by molecular method (a real-time PCR assay). The overall CD incidence rate was 5.3/10,000 patient-days. CONCLUSIONS: Our results confirm the severity of CDI in medical wards, showing high in-hospital mortality, prolonged hospitalization and frequent short-term recurrences. Further, our survey supports a 2-3 step algorithm for CD diagnosis: EIA for detecting GDH, A and B toxin, followed by a molecular method in case of toxin-negative samples.

Should clinicians always administer dexamethasone beyond 24 h after chemotherapy to control delayed nausea and vomiting caused by moderately emetogenic regimens? Insight from the re-evaluation of two randomized studies.

PURPOSE: Data from two noninferiority trials of a dexamethasone-sparing regimen were assessed for the impact of acute nausea and vomiting on delayed outcome in patients undergoing moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC). METHODS: Chemo-naive patients were randomized to receive palonosetron (0.25 mg IV) plus dexamethasone (8 mg IV) on day 1 of chemotherapy, or the same regimen followed by oral dexamethasone on days 2 and 3 in the MEC (n = 237) and AC (n = 380) cohorts. Patients were divided into two groups according to whether or not they experienced vomiting and/or moderate-to-severe nausea during the acute phase (high- and low-risk groups, respectively). Primary efficacy endpoint was the complete protection (CP) against delayed vomiting and moderate-to-severe nausea. Patient's satisfaction (0-100 mm visual analog scale) was also analyzed. RESULTS: Among the 209 low-risk patients undergoing MEC, delayed CP occurred in 82.9% of those who received single-dose dexamethasone and 89.8% of those who received 3-day dexamethasone (P = 0.165). Of the 271 low-risk patients undergoing AC, CP was achieved in 71.7 % of those treated with single-dose dexamethasone and 84.2% treated with 3-day dexamethasone (P = 0.019). In spite of these observations, the patient satisfaction data was not influenced by dexamethasone regimen. In both cohorts, occurrence of acute vomiting or moderate-to-severe nausea was the key independent-predictor for delayed vomiting or nausea, respectively. CONCLUSIONS: The dexamethasone-sparing regimen provides adequate delayed protection in patients undergoing MEC who are at low risk for delayed symptoms, and can still be discussed for low-risk AC patients as the daily difference in control is modest. Additional dexamethasone doses can be customized on the basis of occurrence or absence of acute symptoms in the first cycle of MEC and even AC.

Prulifloxacin vs Levofloxacin for Exacerbation of COPD after Failure of Other Antibiotics.

The chronic course and evolution of chronic obstructive pulmonary disease (COPD) is often characterized by periods of exacerbation of symptoms, which have a negative impact on the quality of life of patients, as well as on the evolution of COPD, and represent a significant cause of medical intervention and hospitalization. Very few data are available on the efficacy of rescue antibiotics in patients with acute exacerbation of COPD (AECOPD) unresponsive to previous treatment. The aim of this study was to evaluate the efficacy of two fluoroquinolones in AECOPD previously treated without success. The FADOI-FLOR study is a randomized, single-blind, non-inferiority comparison between levofloxacin and prulifloxacin. Primary end-point was "therapeutic success" at Day 10 of treatment, defined as disappearance of signs/symptoms or decrease of at least three points of a global score of symptomatology (maximum score = 15). 258 patients were enrolled (128 levofloxacin and 130 prulifloxacin), in 25 centers. A very high proportion of patients in the two groups had therapeutic success at Day-10 (levofloxacin 93.0% vs prulifloxacin 96.7%, population intention-to-treat; 94.6% vs 99.1%, population per-protocol). Earlier therapeutic success (within 7 days) was achieved in 32.0% and 36.2% of patients receiving levofloxacin or prulifloxacin, respectively. At 3-month follow-up, re-exacerbations occurred in 17.8% of patients treated with levofloxacin and 14.2% of those receiving prulifloxacin (p = 0.44). In conclusion, fluoroquinolones are very effective in the treatment of AECOPD resistant to other antibiotics.

Mobilization of hematopoietic stem cells with lenograstim in healthy donors: efficacy and safety analysis according to donor age.

We reviewed and analyzed safety and efficacy data after mobilization with granulocyte colony-stimulating factor (G-CSF) according to healthy donor's (HDs) age as follows: <50 years (HDs-1, n = 161), aged 50 to 59 years (HDs-2, n = 62), and ≥60 years or over (HDs-3, n = 23). Two hundred forty-six HDs were evaluated, and their characteristics were well balanced among age groups: most were male, siblings, and HLA matched. According to age group, the median numbers of CD34(+) cells in the peripheral blood for HDs-1, HDs-2, and HDs-3 were, respectively, 44.5, 34.5, and 26 (HDs-1 versus HDs-2, P = .002; HDs-1 versus HDs-3, P = .036; HDs-2 versus HDs-3, P = n.s.) at day 4 and 65.5, 58, and 46 (HDs-1 versus HDs-2, P = .039; HDs-1 versus HDs-3, P = .002; HDs-2 versus HDs-3, P = n.s.) at day 5. With a median apheresis session of 1, the number of CD34(+) cells/kg recipient body weight collected was not significantly different (6.4 in HDs-1, 6.0 in HDs-2, and 5.7 in HDs-3, P = n.s.). Short- and long-term safety did not differ among age groups. Bone pain was reported as the most frequent short-term adverse event (76.5%). After a median follow-up of 7.8 years, the observed rate of solid tumors, hematological malignancies, and cardiovascular and autoimmune events was similar to the expected incidence for these diseases in Western countries. These results show that G-CSF is effective in the mobilization of older HDs. Moreover, our data contribute to the growing body of evidence in support of the long-term safety of G-CSF for allogeneic donor stem cell mobilization also for elderly HDs.

Pharmacokinetic study between a bilayer matrix fentalyl patch and a monolayer matrix fentanyl patch: single dose administration in healthy volunteers.

AIMS: Transdermal fentanyl is a well established treatment for cancer pain. The aim of the present study is to assess the relative bioavailability of fentanyl from two different transdermal systems by evaluating plasma drug concentrations after single administration of Fentalgon® (test), a novel bilayer matrix type patch, and Durogesic SMAT (reference), a monolayer matrix type patch. In the Fentalgon patch the upper 6% fentanyl reservoir layer maintains a stable concentration gradient between the lower 4% donor layer and the skin. The system provides a constant drug delivery over 72 h. METHODS: This was an open label, single centre, randomized, single dose, two period crossover clinical trial, that included 36 healthy male volunteers. The patches were applied to non-irritated and non-irradiated skin on the intraclavicular pectoral area. Blood samples were collected at different time points (from baseline to 120 h post-removal of the devices) and fentanyl concentrations were determined using a validated LC/MS/MS method. Bioequivalence was to be claimed if the 90% confidence interval of AUC(0,t) and C(max) ratios (test: reference) were within the acceptance range of 80-125% and 75-133%, respectively. RESULTS: The 90% confidence intervals of the AUC(0,t) ratio (116.3% [109.6, 123.4%]) and C(max) ratio (114.4% [105.8, 123.8%] were well included in the acceptance range and the C(max) ratio also met the narrower bounds of 80-125%. There was no relevant difference in overall safety profiles of the two preparations investigated, which were adequately tolerated, as expected for opioid-naïve subjects. CONCLUSIONS: The new bilayer matrix type patch, Fentalgon®, is bioequivalent to the monolayer matrix type Durogesic SMAT fentanyl patch with respect to the rate and extent of exposure of fentanyl (Eudra/CT no. 2005-000046-36).

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

AIM: Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. PATIENTS & METHODS: Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). RESULTS: Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. CONCLUSION: Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

Feasibility and safety of a reduced duration of therapy of colony-stimulating factor in a dose-dense regimen.

PURPOSE: The risk of febrile neutropenia (FN) in cancer patients receiving chemotherapy is mainly due to the type of chemotherapy regimen and the presence of specific risk factors in patients. The recent trend of using a dose-dense treatment schedule has enhanced the risk of FN. In the present prospective study, we evaluated the feasibility of a reduction of duration of therapy with colony-stimulating factor (G-CSF) in a dose-dense regimen. METHODS: Between June 2002 and December 2011, 107 patients with a new diagnosis of non-Hodgkin lymphoma (NHL) receiving dose-dense chemotherapy, every 14 days, were included in the study. The primary endpoint was defined as the completion of planned chemotherapy cycles as scheduled. Secondary endpoints were median number of administered G-CSF doses (vials), incidence of FN, hospitalization and toxicity. RESULTS: The planned chemotherapy cycles (primary endpoint) were completed by 84.1 % of patients. The median number of G-CSF (lenograstim) doses administered for each patient was 24 (range 10-35), which corresponds to a median of five vials (range 0-10) for each cycle. Grades 3-4 toxicities, related to G-CSF administration, included neutropenia and thrombocytopenia (14.0 and 1.9 %, respectively). No grades 3-4 bone pain was detected. The incidence of FN and hospitalization was 9.3 % (10/107) and 4.5 % (5/107), respectively. CONCLUSIONS: Reduced dosage of G-CSF allows dose-dense chemotherapy scheduling, limits exposure to G-CSF and also represents an opportunity for cost savings.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Effects of iloprost on pain-free walking distance and clinical outcome in patients with severe stage IIb peripheral arterial disease: the FADOI 2bPILOT Study.

BACKGROUND: Patients with peripheral arterial disease (PAD) at stage IIb, pain-free walking distance (PFWD) less than 100 m and unsuitable for revascularization have both impaired quality of life and severe clinical outcome. Aim of the study was to evaluate the efficacy of the prostacyclin analogue iloprost, added to standard therapy, in these patients. MATERIAL AND METHODS: Patients were randomized to receive standard medical therapy (Group A) or standard therapy plus iloprost (Group B), for 1 year. Iloprost was administered for 10 days every 3 months. Treadmill test was performed every 3 months, in Group B before starting the 10-day iloprost cycle. RESULTS: Fifty patients in Group A and 51 in Group B were enrolled. Mean baseline and 12-month PFWD values were 75.4 ± 21.3 and 128.9 ± 62.9 for iloprost group and 70.3 ± 21.6 and 99.6 ± 62.6 m for controls. Patients treated with iloprost had significantly higher PFWD at 9 and 12 months. This finding was confirmed after carrying forward the last valid observation (124.7 ± 63.4 vs. 88.4 ± 63.1 m, P < 0.01). Major cardiovascular events occurred in 32.0% and 3.9% of patients in Group A and Group B, respectively (P < 0.001). Five patients in Group A died vs. none in Group B (P = 0.02). No serious unexpected adverse reactions occurred in patients receiving iloprost. CONCLUSIONS: Iloprost, added to standard therapy, significantly increases exercise capacity in patients with PAD at severe stage IIb. The percentage of patients who died or experienced major cardiovascular events was significantly lower in patients receiving iloprost. Future studies should focus on the effects of this therapy on clinical outcome.