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AbstractObjective:To compare pharmacokinetics and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous (SC) ceftriaxone administration versus SC ceftriaxone preceded by SC saline placebo or intravenous (IV) ceftriaxone administration.Research design and methods:This Phase I, two-part, placebo-controlled, crossover study was conducted in 54 healthy volunteers. In Part 1 (N24), subjects received 1mL rHuPH20 (150 USP units) or placebo (0.9 sodium chloride) SC, followed by 1 or 2g ceftriaxone (10–350mg/mL). In Part 2 (N30), subjects received 1g ceftriaxone at the Part 1 maximum tolerated concentration (MTC) administered either SC – preceded by SC rHuPH20 or placebo – or IV. Subjects were monitored for adverse events (AEs); blood samples were obtained (Part 2 only) during 48 hours post-dosing for ceftriaxone bioanalysis.Main outcome measures:Part 1 primary endpoint was the SC ceftriaxone (with or without rHuPH20) MTC. Pharmacokinetic parameters were determined in Part 2. Bioequivalence was based on maximum concentration (Cmax) and area under plasma concentration–time curve (AUC).Results:The highest SC ceftriaxone concentration tested in Part 1 (350mg/mL) was selected as the Part 2 MTC. In Part 2, median time to maximum concentration (tmax) was 1 hour earlier (P<0.0001), and Cmaxwas 12 higher (P<0.0001) for ceftriaxone (350mg/mL) administered via rHuPH20-facilitated SC versus SC preceded by placebo. IV ceftriaxone led to higher Cmaxand shorter tmaxvalues than either SC treatment. Ceftriaxone exposure (AUC) was comparable among all three treatments. At least 1 AE was experienced by 100 of subjects after SC ceftriaxone and 76 after IV; most commonly reported AEs were infusion-site reactions.Conclusions:Ceftriaxone AUCdid not differ significantly between the three administration routes. Cmaxwas higher and tmaxshorter with rHuPH20-facilitated SC than SC preceded by placebo. rHuPH20-facilitated SC ceftriaxone was generally well tolerated. This study is limited by evaluation of healthy adults and absence of repeated-dose groups. [ABSTRACT FROM AUTHOR]

The cause of chronic fatigue syndrome (CFS) is still enigmatic. Using indirect immunofluorescence testing for measuring antibody against human herpesvirus 6 (HHV-6), this study investigated the association of CFS with infection by HHV-6. Seventeen patients (group A) fulfilling the Centers for Disease Control (CDC) definition for CFS were compared with eight patients (group B) with chronic fatigue but not meeting the CDC criteria. No significant difference was found between the two groups for 30 parameters including sex, age, exposure to children and serology for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and toxoplasma. Univariate analysis showed that patients in group A complained more frequently of a sore throat, headache and of recurrent type of fatigue. These three parameters are discriminant in identifying patients who will meet the CDC case definition of CFS. The titre of antibody against HHV-6 in group A (1:99) was significantly higher than in group B (1:15) (P=0.007). Elevated HHV-6 titres suggests that this virus could be a cofactor in the pathogenesis of CFS.

A 37-year-old woman with a cadaveric renal allotransplantation required intra-cranial shunting devices after a presumptive episode of tuberculous meningitis. Six months later, she developed a culture-proven cryptococcal meningitis. Without having her ventriculo-auricular shunt removed, she was successfully treated with a short course of amphotericin B (335 mg) and flucytosine (nine days) followed by prolonged therapy with oral fluconazole (400 mg daily for 72 days). Three years post treatment she had no evidence of relapse, and normal renal graft function.

Purpose To evaluate the efficacy of the addition of palifosfamide to carboplatin and etoposide in extensive stage (ES) small-cell lung cancer (SCLC). Patients and Methods MATISSE was a randomized, open-label, adaptive phase III study. Previously untreated patients with ES SCLC were randomly assigned in a 1:1 fashion to receive carboplatin at area under the serum concentration-time curve 5 on day 1 plus etoposide 100 mg/m 2 per day on days 1 to 3 every 21 days (CE) or carboplatin at area under the serum concentration-time curve 4 on day 1 plus etoposide 100 mg/m 2 per day plus palifosfamide 130 mg/m 2 per day on days 1 to 3 every 21 days (PaCE). The primary end point was overall survival. Results In all, 188 patients were enrolled; 94 patients received CE and 94 patients received PaCE. The median age on both arms was 61 years. Six cycles of chemotherapy were completed on both arms of the study by approximately 50% of the patients. Serious adverse events were documented and did not differ significantly between patients receiving PaCE and those receiving CE. Median overall survival was similar between both arms with 10.03 months on PaCE and 10.37 months on CE ( P = .096). Conclusion The addition of palifosfamide to CE failed to improve survival in ES SCLC.

Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m 2 intravenously day 1 plus palifosfamide 150 mg/m 2 /d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.