ABSTRACT
Forensic mental health services provide care to people in secure psychiatric hospitals and via specialised community teams. Such services are typically low volume and high cost, often highly restrictive and average duration of inpatient care prior to discharge is long. Measuring outcomes of care is important to safeguard patients and the public, monitor progress, inform treatment plans and assist in service evaluation and planning. We describe the development in England of a new outcome measure for forensic mental health services. Patient interviews and multistakeholder focus groups were held to elicit key concepts. Thematic analysis was used to develop an outcomes framework. Fifteen patients participated in the interviews and 48 stakeholders in the focus groups. Six domains were identified in thematic analysis: 'about me, my quality of life, my health, my safety and risk, my life skills and my progress'. Sixty-two stakeholders participated in the first round of the Delphi process, and 49 completed round two. Eight of the top fifteen outcomes were shared between patients/carers and professionals. Based on these results, a new outcome measure, the FORensic oUtcome Measure (FORUM), was developed including both a patient reported and clinician reported measure. Further assessment of the FORUM's use to track patients' progress over time, and facilitate shared decision-making and care planning, is required.
ABSTRACT
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.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Drug Discovery , Urea/chemistry , Urea/pharmacology , Anti-HIV Agents/chemistry , HIV-1/drug effectsABSTRACT
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.
Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Carboxylic Acids/pharmacokinetics , Amides/chemistry , Animals , Anti-HIV Agents/blood , Anti-HIV Agents/chemistry , Carboxylic Acids/blood , Carboxylic Acids/chemistry , Drug Discovery , RatsABSTRACT
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.
Subject(s)
Anti-HIV Agents/chemical synthesis , Drug Resistance, Viral , HIV Reverse Transcriptase/chemistry , Quinolones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzoxazines , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclopropanes , Drug Design , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Humans , Models, Molecular , Molecular Structure , Mutation , Oxazines/chemistry , Quinolones/chemistry , Quinolones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
GW4511, GW4751, and GW3011 showed IC50 values < or =2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.
Subject(s)
Anti-HIV Agents/chemical synthesis , Benzophenones/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzophenones/chemistry , Benzophenones/pharmacology , Cell Line , Crystallography, X-Ray , Drug Resistance, Viral , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , HIV-1/genetics , Humans , Inhibitory Concentration 50 , Mutation , Protein Binding , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
M-tropic HIV strains gain access to their host cell via interaction of the viral envelope protein gp120 with the CCR5 coreceptor and CD4 located on the host cell. Inhibition of this event has been shown to reduce viral fusion and entry into cells in vitro. In the present study we describe the development of a novel cell/cell fusion assay that both mimics the viral/cell fusion process and allows quantification of this event. The assay has been characterized both biochemically, using selective antibodies, and pharmacologically, using selective CCR5 antagonists, and has been shown to be selective for examining the interaction of viral gp120 with hCCR5/hCD4. In addition, compound pIC50 data obtained from this cell/cell fusion assay correlates well (r2 = 0.7274) with data obtained from an HIV-1 replication assay. Furthermore, this assay has the added ability to simultaneously determine compound toxicity, thus allowing rapid determination of active, non-toxic compounds. In conclusion, the cell/cell fusion assay developed has been demonstrated to be a suitable surrogate assay that can be used to assess the effects of compounds on gp120/CCR5/CD4 mediated viral fusion into host cells.
