Ultrasonography-Guided Procedures in the Intensive Care Setting.

Ultrasonography guidance can help make procedures safer and more effective, particularly in the intensive care setting. This article discusses techniques to optimize periprocedural ultrasonography and reviews common intensive care procedures for which ultrasonography can be used: vascular access procedures, paracentesis, thoracentesis, and pericardiocentesis.

Pain Outcomes in Patients Undergoing CT-Guided Celiac Plexus Neurolysis for Intractable Abdominal Visceral Pain.

The purpose of this study was to assess outcomes in patients who have undergone celiac plexus neurolysis (CPN) as treatment for refractory abdominal visceral pain at a tertiary care medical center. This study involved retrospective analysis of all patients who had undergone computed tomography (CT)-guided CPN over a 7-year period, as identified in the medical record. Cases were categorized into 1 of 3 groups-group 1: patients getting at least moderate improvement in pain but with improvements subsiding within 2 days; group 2: patients with some sustained pain relief but still requiring heavy doses of narcotics; group 3: patients with major or complete sustained reduction in pain where the narcotic dose was able to be reduced. One hundred thirty-eight cases were identified, 51 of which had no or insufficient follow-up, leaving 87 cases for analysis. Of the 87 cases, 31 (36%) were categorized as group 1, 21 (24%) as group 2, and 35 (40%) as group 3. There were no statistical differences in outcomes based on patient age, gender, time since diagnosis, or type of cancer. Documented postoperative complications were diarrhea (11 cases) and 1 case each of obtundation, hypotension, and presyncopal event. We conclude that patients undergoing CT-guided CPN for abdominal visceral pain achieve moderate or major short-term pain relief in a majority of cases. The procedure is safe with minimal complications.

Pain prevalence and trajectories following pediatric spinal fusion surgery.

UNLABELLED: Factors contributing to pain following surgery are poorly understood, with previous research largely focused on adults. With approximately 6 million children undergoing surgery each year, there is a need to study pediatric persistent postsurgical pain. The present study includes patients with adolescent idiopathic scoliosis undergoing spinal fusion surgery enrolled in a prospective, multicentered registry examining postsurgical outcomes. The Scoliosis Research Society Questionnaire-Version 30, which includes pain, activity, mental health, and self-image subscales, was administered to 190 patients prior to surgery and at 1 and 2 years postsurgery. A subset (n = 77) completed 5-year postsurgery data. Pain prevalence at each time point and longitudinal trajectories of pain outcomes derived from SAS PROC TRAJ were examined using analyses of variance and post hoc pairwise analyses across groups. Thirty-five percent of patients reported pain in the moderate to severe range presurgery. One year postoperation, 11% reported pain in this range, whereas 15% reported pain at 2 years postsurgery. At 5 years postsurgery, 15% of patients reported pain in the moderate to severe range. Among the 5 empirically derived pain trajectories, there were significant differences on self-image, mental health, and age. Identifying predictors of poor long-term outcomes in children with postsurgical pain may prevent the development of chronic pain into adulthood. PERSPECTIVE: This investigation explores the prevalence of pediatric pain following surgery, up to 5 years after spinal fusion surgery. Five pain trajectories were identified and were distinguishable on presurgical characteristics of age, mental health, and self-image. This is the largest study to examine longitudinal pediatric pain trajectories after surgery.

Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.

Discovery of a novel series of cyclic urea as potent CCR5 antagonists.

A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.

Discovery of novel pyridyl carboxamides as potent CCR5 antagonists and optimization of their pharmacokinetic profile in rats.

A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.

Synthesis and evaluation of 2-phenyl-1,4-butanediamine-based CCR5 antagonists for the treatment of HIV-1.

We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): optimization of the amine portion.

Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (II): modification of the acyl portion.

Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.

Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist.

GSK812397 is a potent entry inhibitor of X4-tropic strains of HIV-1, as demonstrated in multiple in vitro cellular assays (e.g., in peripheral blood mononuclear cells [PBMCs] and a viral human osteosarcoma [HOS] assay, mean 50% inhibitory concentrations [IC50s]+/-standard errors of the means were 4.60+/-1.23 nM and 1.50+/-0.21 nM, respectively). The primary in vitro potency of GSK812397 was not significantly altered by the addition of serum proteins (2.55 [+/-0.12]-fold shift in the presence of human serum albumin and alpha-acid glycoprotein in the PBMC assay). Pharmacological characterization of GSK812397 in cell-based functional assays revealed it to be a noncompetitive antagonist of the CXCR4 receptor, with GSK812397 producing a concentration-dependent decrease in both an SDF-1-mediated chemotaxis and intracellular calcium release (IC50s were 0.34+/-0.01 nM and 2.41+/-0.50 nM, respectively). With respect to the antiviral activity of GSK812397, it was effective against a broad range of X4- and X4R5-utilizing clinical isolates. The potency and efficacy of GSK812397 were dependent on the individual isolate, with complete inhibition of infection observed with 24 of 30 isolates. GSK812397 did not show any detectable in vitro cytotoxicity and was highly selective for CXCR4, as determined using a wide range of receptors, enzymes, and transporters. Moreover, GSK812397 demonstrated acceptable pharmacokinetic properties and bioavailability across species. The data demonstrate that GSK812397 has antiviral activity against a broad range of X4-utilizing strains of HIV-1 via a noncompetitive antagonism of the CXCR4 receptor.

The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property?

Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science 307: 1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog.

Acute myelogenous leukemia (AML) is a heterogeneous disease consisting of a variety of different leukemic subtypes. While acute promyelocytic leukemia displays marked sensitivity to the differentiating effects of trans-retinoic acid (tRA), other subtypes of AML display resistance. We now describe a novel compound (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) that induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1, and HL-60R, and in tRA-resistant patient leukemic blasts. The 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations that inhibit committed human bone marrow stem cell proliferation, that is, granulocyte/macrophage colony-forming units (CFU-GMs) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly(adenosine diphosphate) (poly(ADP)) ribose polymerase. While activation of the extracellular signal-regulated kinase (ERK) and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires c-Jun N-terminal kinase (JNK) activation. The 3-Cl-AHPC-mediated cleavage of the antiapoptotic B-cell leukemia XL (Bcl-XL) protein to a proapoptotic 18-kDa product is found in both the M07e cell line and patient leukemic blasts. The 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. While 3-Cl-AHPC does not activate retinoic nuclear receptors, it is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease.

Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog.

We have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) that induces apoptosis in a number of malignant cell types. We now describe our studies examining the effects of CD437 and a nonretinoidal analog (MM002) on the in vitro proliferation of the ALL-REH cell line, the in vitro and in vivo growth of a novel Epstein-Barr virus-negative (EBV(-)) B-cell chronic lymphocytic leukemia (B-CLL) cell line (WSU-CLL), and primary cultures of human B-CLL and acute lymphoblastic leukemia (ALL) cells. CD437 and MM002 induce apoptosis in both cell lines, as indicated by the activation of caspase-2 and caspase-3, cleavage of poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase, increase in annexin V binding, and subsequent nuclear fragmentation. CD437-mediated apoptosis was not associated with the modulation of Bcl-2, Bax, or Mcl-1 levels, but was associated with the cleavage of the antiapoptotic protein Bcl-X(L) to a proapoptotic 18-kD form. This cleavage of Bcl-X(L) was dependent on caspase-3 activation since Bcl-X(L) cleavage and apoptosis were inhibited by the caspase-3 inhibitor Z-DVED-fmk. CD437 markedly inhibited the growth of WSU-CLL cells in severe combined immunodeficiency (SCID) mice. Tumor growth inhibition, growth delay, and log cell kill were 85.7%, 21 days, and 2.1, respectively, in the treated mice. Moreover, 1 of the 5 treated mice was tumor-free longer than 150 days and thus was considered cured. Exposure of primary cultures of both B-CLL and ALL cells obtained from patients to CD437 and MM002 resulted in their apoptosis. These results suggest that CD437 and MM002 analogs may have a potential role in the treatment of B-CLL and ALL.