Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin (CPT) is an alkaloid that displays considerable antitumour activity, but clinical use has been limited by its poor water solubility and the instability of the lactone moiety (active form) in physiological media. We have therefore formulated the drug into nanocarrier systems in an attempt to improve its therapeutic properties. This study evaluates the effect of intraperitoneally administered stealth and non-stealth nanocapsules containing CPT on lung metastatic spread in mice inoculated with B16-F10 melanoma cells, and on the cytotoxic activity against B16-F10 melanoma cells in-vitro. Poly (D,L-lactide) PLA (non-stealth) and methoxy polyethylene glycol-(D,L-lactide) (PLA-PEG) (stealth) nanocapsules (49 and 66.6 kDa) were prepared by interfacial deposition of preformed polymer. CPT, as free drug or as drug-loaded nanocapsules, was administrated at a dose of 0.5 mg kg(-1) at 3-day intervals for 17 days. Free drug and CPT-loaded nanocapsules reduced the number of metastatic nodules by 45.09-91.76% (P < 0.05 vs positive control). However, only CPT-loaded PLA-PEG 49 kD nanocapsules significantly decreased the number of lung metastases when compared with free drug (P < 0.05). The administration of CPT-loaded nanocapsules and free drug did not result in neutropenia at the administered dose. The improved effectiveness of pegylated nanocapsules was attributed to protection of the drug by nanoencapsulation and to reduced uptake of particles by macrophages located in the lymph nodes. This assumption was supported by the in-vitro study, in which both PLA and 49 kDa PLA-PEG nanocapsules containing CPT were more cytotoxic than the free drug against B16-F10 melanoma cells.
 ...
PMID:Stealth and non-stealth nanocapsules containing camptothecin: in-vitro and in-vivo activity on B16-F10 melanoma. 1791 Aug 10

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.
 ...
PMID:An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors. 2679 87

Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants (n = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4+ T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4+ T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV+ subjects indicating promise as an adjuvant for HIV therapeutic vaccines. Trial Registration: www.ClinicalTrials.gov, identifier: NCT02071095.
 ...
PMID:Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial. 3102 57