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3.3.1 Clinical Studies To date, there have been five clinical studies investigating P188-P in healthy volunteers or in patients with SCD. Various dosing regimens, involving both intravenous loading and maintenance dosing, have been evaluated. Study C97-1248 evaluated use of P188-P in SCD patients with acute vaso-occlusive crisis (VOC). Two hundred fifty-five

(255) patients with SCD-VOC were randomized Belnacasan to receive standard of care (hydration and analgesics for pain) and either P188-P (test) or volume-matched saline (control). The subjects had a serum creatinine level ≤1.0 mg/dL. Patients randomized to the test arm received P188-P intravenously at a loading dose of 100 mg/kg over 1 h, followed by a maintenance dose of 30 mg/kg/h over 47 h, corresponding to a total dose of 1.5 g/kg. Patients randomized to the control arm received a saline solution delivered at a volume and duration identical to those used for the active drug. Serum was periodically collected for creatinine testing both during the study and in the follow-up period (i.e., >48 h). The mean serum creatinine level and standard deviation for all study subjects over time are shown in Fig. 5. The mean values for serum creatinine were not clinically or statistically different between subjects treated with placebo and those treated with P188-P, and neither

group showed significant changes from baseline through follow-up. Fig. 5 Changes in serum click here creatinine levels following administration of purified poloxamer 188 (P188-P) or placebo to patients with sickle cell disease (SCD). Each bar represents the mean ± standard deviation for measurements conducted in the indicated group A summary table for serum creatinine elevations in subjects

enrolled in study C97-1248, stratified according to toxicity grade, is shown in Table 3. SSR128129E The National Cancer Institute Common Toxicity Criteria, Version 1, were used in this analysis [36]. Any Necrostatin-1 purchase instances of elevated creatinine values measured post-infusion were included in the table. Overall, the incidence of elevated creatinine levels for all grades was similar in both treatment groups. Table 3 Numbers of patients with elevated creatinine levels, stratified by toxicity grade and age, in study C97-1248 Toxicity gradea Subjects with elevated creatinine levels (n) Adults (aged ≥16 years; n = 176) Children (aged <16 years; n = 73) P188-P Placebo P188-P Placebo 1 46 49 18 14 2 12 9 5 3 3 1 0 0 1 4 0 0 0 0 P188-P purified poloxamer 188 a Toxicity grades according to the National Cancer Institute Common Toxicity Criteria, Version 1 [36] Study C97-1243 was an open-label trial evaluating the safety of varying doses of P188-P in pediatric and adult SCD subjects experiencing acute chest syndrome. Five different groups were intravenously administered a common loading dose of 200 mg/kg for 1 h, followed by maintenance doses for 23 h. The maintenance dose was different in each group and ranged from 20 to 120 mg/kg/h.

Materials and methods Animals Twenty-five female 6-month-old virgin Wistar rats (Harlan Laboratories, Torin 1 manufacturer Horst, The Netherlands) were allowed to acclimatize for 7 days before the start of the experiment. The rats were maintained with a cycle of 12 h light and 12 h darkness

and allowed to eat and drink ad libitum. The experiment was approved by the Animals Ethics Committee of the University of Maastricht, The Netherlands. The rats were see more divided into three groups (with equal weight distributions): control (n = 8), ovariectomy (OVX; n = 8), and OVX and PTH treatment (n = 9). All rats were ovariectomized at week 0 and the control MLN2238 solubility dmso group underwent a SHAM ovariectomy. Success of

OVX was confirmed at necropsy by determining atrophy of the uterine horns. Rats were left untreated for 8 weeks to allow for osteopenia to develop. After 8 weeks, rats in the PTH group received daily subcutaneous injections of PTH (60 μg/kg/day) for 6 weeks. This relatively high dose was chosen to maximize the possibility of trabecular tunneling to occur and lies within the dose range investigated in a dose-dependency study [18]. Synthetic human PTH (1–34; Bachem, Bubendorf, Switzerland) was dissolved in a vehicle of acidified saline (0.1 N) and 2% rat serum. Body weight was measured weekly, and the PTH dose adjusted accordingly. Rats were sacrificed at 14 weeks by cervical dislocation under deep

anesthesia after the final CT scan. Micro-CT scanning others Directly after the operation, a 6-mm micro CT-scan (70 kV, 114 μA, 1,000 projections per 180°, 261 ms integration time) with an isotropic resolution of 15 μm was made of the proximal tibia using an in vivo micro-CT scanner (vivaCT 40, Scanco Medical AG, Brütissellen, Switzerland). The CT scanner was calibrated and a beam-hardening correction algorithm was applied to all scans [34]. Another 3.15-mm micro-CT scan of the diaphysis was made with an isotropic resolution of 30 μm (70 kV, 114 μA, 250 projections per 180°, 350 ms integration time). Before this measurement, the most distal and proximal point of the tibia was located in a scout view to ensure that the exact middle of the diaphysis was scanned. Follow-up in vivo CT scans were made after 8, 10, 12, and 14 weeks to monitor bone structure. Every follow-up scan was registered with the first scan by using image registration software that registers two scans based on minimizing the correlation coefficient [35].