Vision impairment and health.
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Blood Chemical Analysis↗
Biomedical subjects
R Griffith
Publications and source records attributed to R Griffith.
Ligand design for alpha(1) adrenoceptors.
An area of continuing interest in medicinal chemistry is the design, synthesis and pharmacological evaluation of ligands which bind at adrenoceptor subtypes, which include alpha(1A), alpha(1B), alpha(1D); alpha(2A), alpha(2B), alpha(2C); beta(1), beta(2), beta(3) and possibly beta(4) subtypes. The selective blockade or stimulation of these receptor subtypes is of on-going pharmacological and medicinal interest. However, the design principles for ligand differentiation at these subtypes still need further development. This review focuses on alpha(1) adrenoceptors with a concentration on literature over the past five years. Structural, physiological and therapeutic aspects of the alpha(1A), alpha(1B) and alpha(1D) subtypes are discussed together with ligands binding to these receptor subtypes. Approaches to alpha(1) adrenoceptor ligand design based on known ligands and on receptor docking are evaluated. A new combined approach using pharmacophores and receptor docking affords possibilities for deeper insights into achieving small molecule binding selectivity.
Adrenergic alpha-Agonists↗
(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.
Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.
Acetylcholine↗
Regulation of microglial tyrosine phosphorylation in response to neuronal injury.
The regulation and substrate specificity of microglial phosphotyrosine (ptyr) increases accompanying motor neuron degeneration in the rat spinal cord induced by injection of the cytotoxic lectin, ricin, into sciatic nerve were examined using specific enzyme inhibitors, immunohistochemistry, and Western blot analyses. Optical density measurements of immunostained sections show that microglial ptyr levels are elevated at 3 days postinjection. This period coincides with initial stages of neuronal degeneration, and ptyr levels are maximal at 7 days. We next asked whether this increase is due to increased tyrosine kinase or decreased tyrosine phosphatase activities by assaying ptyr immunostaining in animals that received osmotic pump infusion of the nonreceptor tyrosine kinase inhibitor, herbimycin A, for the 7-day survival period. When compared to the control ventral horn, microglial ptyr on the experimental side was attenuated by at least 45% in the presence of herbimycin A. In order to identify microglial substrates undergoing increased tyrosine phosphorylation, Western blot analysis was performed on hemicord and punch biopsy samples from control and experimental sides following ricin injection. A subset of two proteins was identified whose increased ptyr was almost completely attenuated in the herbimycin-A-treated animals. We conclude that the data support earlier indications that upregulation of microglial tyrosine phosphorylation is a key early event in response to neuronal injury. Further, this upregulation is due to turning on tyrosine kinase activities, particularly nonreceptor kinases, and the end product is phosphorylation of a very limited number of substrates. This suggests the activation of specific tyrosine phosphorylation pathways, which may represent critical therapeutic intervention points, rather than a global response. The results are discussed in terms of recent cell culture models of microglial activation and earlier data demonstrating elevated microglial ptyr in neurodegenerative disease.
Animals↗
Ligand design for alpha1 adrenoceptor subtype selective antagonists.
Alpha1 adrenoceptors have three subtypes and drugs interacting selectively with these subtypes could be useful in the treatment of a variety of diseases. In order to gain an insight into the structural principles governing subtype selectivity, ligand based drug design (pharmacophore development) methods have been used to design a novel 1,2,3-thiadiazole ring D analogue of the aporphine system. Synthesis and testing of this compound as a ligand on cloned and expressed human alpha1 adrenoceptors is described. Low binding affinity was found, possibly due to an unfavourable electrostatic potential distribution. Pharmacophore models for antagonists at the three adrenoceptor sites (alpha1A, alpha1B, alpha1D) were generated from a number of different training sets and their value for the design of new selective antagonists discussed. The first preliminary antagonist pharmacophore model for the alpha1D adrenoceptor subtype is also reported.
Adrenergic alpha-1 Receptor Antagonists↗
Development of computational and graphical tools for analysis of movement and flexibility in large molecules.
We developed a computer program for the calculation and display of the difference distance matrices (DDMs) of macromolecules that has the ability to compare multiple structures simultaneously. To demonstrate its use, a data set of atoms for superimposition of the HIV-1 reverse transcriptase enzyme was defined using the coordinates for the 21 available crystal structures of this enzyme and its complexes. The DDM technique for superimposition data set generation allows selection of atoms that are invariant in all structures, is free from user bias, and represents the most accurate and precise method of producing such subsets. Comparison of this technique was made against other published methods of generating superimposition data sets, and it was found that significant differences in magnitude and trends of atom movements are observed depending on which data set was used.
Computer Graphics↗
Use and cost of hospital and community service provision for children with HIV infection at an English HIV referral centre.
OBJECTIVE: To describe the use of hospital and community services for children infected with HIV and estimate the cost per patient-year by stage of HIV infection during the era of antiretroviral monotherapy. DESIGN: Data on the use of hospital services were collected from case notes; the use of statutory and nonstatutory community services was recorded through diaries and interviews. Total cost estimates were calculated from unit costs from relevant hospital departments and community organisations. SETTING: Children managed at St. Mary's Hospital (London, England) between 1 January 1986 and 31 December 1994, some of whom used statutory and nonstatutory community services in South East England between 1 November 1994 and 31 May 1996. PATIENTS AND PARTICIPANTS: 118 children with positive HIV antibody status. MAIN OUTCOME MEASURES AND RESULTS: Mean inpatient days, outpatient visits, tests and procedures performed, drugs prescribed, community services used, associated unit costs and average cost estimates per patient-year by stage of HIV infection (1995/1996 values), and lifetime costs. Service provision during the study period was predominantly hospital-based. The use of services increased for different stages of HIV infection and increased with increasing severity of HIV infection. A shift from an inpatient-based to an outpatient-based service was seen between the periods 1986 to 1991 and 1992 to 1994. As symptoms evolved, children used more hospital inpatient services, with an accompanying shift in the use of community services from general services, such as schooling, to increased use of nurses, social care and home help. The estimated total cost of hospital and community care was 18,600 Pounds per symptomatic non-AIDS patient per year and 46,600 Pounds per AIDS patient per year. Similar estimates for children with indeterminate HIV infection and asymptomatic infection amounted to 8300 Pounds and 4800 Pounds per patient-year, respectively. Nondiscounted lifetime costs for hospital care amounted to 152,400 Pounds (44,300 Pounds to 266,800 Pounds) compared with discounted lifetime costs of 122,700 Pounds (42,000 Pounds to 182,200 Pounds); nondiscounted lifetime costs for community care amounted to 24,300 Pounds (7900 Pounds to 41,600 Pounds) compared with discounted lifetime costs of 21,000 Pounds (6800 Pounds to 32,000 Pounds). CONCLUSIONS: The continued emphasis on the use of hospital services may be due to the small number of children infected with HIV, most of whom lived in the London metropolitan area where specialist care was concentrated in a few centres. A shift from an inpatient- to an outpatient-based service was observed over time; the advent of the use of combination antiretroviral therapy in this population may further facilitate a shift in service provision and promote shared care between specialist centres, local hospital and community-based services.
Anti-HIV Agents↗
A new technique for intraoperative graft angiography utilizing the radial artery stump.
BACKGROUND: Angiographic visualization is the gold standard in evaluating the patency of newly constructed bypass grafts. With the growth of beating heart bypass grafting procedures, there is a need to confirm patency and document the success of the operative techniques. METHODS: We have developed a new technique for performing intraoperative graft angiography following off-pump coronary artery bypass grafting (OPCABG) when utilizing the left radial artery as a free graft. Once the radial artery is removed, the proximal radial artery stump is cannulated using a standard femoral introducer sheath passed over an appropriately sized guide wire. The introducer is secured by simple ligature and the arm remains abducted during the construction of the grafts. Prior to heparin reversal, standard coronary angiographic catheters are introduced through the sheath and intraoperative images of the grafts obtained. RESULTS: Transsternal OPCAB was performed in 7 patients using the left radial artery as a free graft followed by transradial artery completion angiography. A total of 18 grafts (2.5 per patient) were examined with an immediate patency rate of 100% and TIMI grade 3 flow in all grafts. Mean fluoroscopy time was 8.21 minutes. No angiographic or surgical complications occurred in this group. CONCLUSIONS: Beating heart coronary bypass grafting is evolving as a new standard that competes with the traditional technique of cardiopulmonary bypass and elective cardiac arrest. With newer digital portable fluoroscopy systems, excellent imaging of newly constructed grafts can be obtained prior to completion of the procedure using a transradial approach. Verification of graft patency is the essential element in protecting the quality of surgical coronary artery reconstruction in the new era of beating heart surgery.
Aged↗
Use and cost of hospital services by HIV-infected children during the era of antiretroviral monotherapy.
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Acquired Immunodeficiency Syndrome↗
Identification of glutathionyl-3-hydroxykynurenine glucoside as a novel fluorophore associated with aging of the human lens.
A novel fluorophore was isolated from human lenses using high performance liquid chromatography (HPLC). The new fluorophore was well separated from 3-hydroxykynurenine glucoside (3-OHKG) and its deaminated isoform, 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid O-glucoside, which are known UV filter compounds. The new compound exhibited UV absorbance maxima at 260 and 365 nm, was fluorescent (Ex(360 nm)/Em(500 nm)), and increased in concentration with age. Further analysis of the purified compound by microbore HPLC with in-line electrospray ionization mass spectrometry revealed a molecular mass of 676 Da. This mass corresponds to that of an adduct of GSH with a deaminated form of 3-OHKG. This adduct was synthesized using 3-OHKG and GSH as starting materials. The synthetic glutathionyl-3-hydroxykynurenine glucoside (GSH-3-OHKG) adduct had the same HPLC elution time, thin-layer chromatography R(F) value, UV absorbance maxima, fluorescence characteristics, and mass spectrum as the lens-derived fluorophore. Furthermore, the (1)H and (13)C NMR spectra of the synthetic adduct were entirely consistent with the proposed structure of GSH-3-OHKG. These data indicate that GSH-3-OHKG is present as a novel fluorophore in aged human lenses. The GSH-3-OHKG adduct was found to be less reactive with beta-glucosidase compared with 3-OHKG, and this could be due to a folded conformation of the adduct that was suggested by molecular modeling.
Aging↗
Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase.
Docking experiments were undertaken using a number of published crystal structures of HIV-1 reverse transcriptase complexes with various non-nucleoside inhibitors. The docking method was validated by successfully docking each ligand, in the conformation found in the crystal structure of the complex with the enzyme, back into its binding pocket in the right orientation and position. Each ligand was then subjected to conformational searching and a database of unique low-energy conformations of all ligands established. Docking this database into each of the reverse transcriptase binding pockets showed that all inhibitors could be fitted into each different pocket, without alteration of the pocket geometry. This contradicts findings from earlier docking investigations and implies that the conformation of the binding pocket in each different complex is conserved sufficiently to allow particular uniform ligand binding modes. The inhibitor conformations selected by this docking process are mostly the same as the one the ligand adopts in its own pocket and the selected conformations and orientations exhibit an impressive degree of similarity in the arrangement of their steric and electronic features. A correlation has also been observed between inhibitor flexibility and tightness of fit into the pockets with the more flexible inhibitors achieving a tighter fit and thus fewer favourable orientations upon docking.
Binding Sites↗
Modelling of adrenoceptor ligand targets based on novel medium- or macro-sized fused nitrogen heterocyclic systems.
Novel medium- and macro-sized heterocyclic compounds were assessed for their potential as subtype-selective adrenergic ligands. Their conformational flexibilities were investigated and their geometric shapes were compared to rigid lead compounds of known selectivity. In the case of alpha 1A selective antagonists, interesting potential targets for synthesis and evaluation were identified by 'opening up' various rings of the fused-ring lead compound 1 by shared-bond cleavage. For alpha 2 selective ligands, compound 6 was the lead compound and the possibility of mimicking the fused-ring system via intramolecular hydrogen bonding was investigated. None of the potential targets were closely enough related in this case to the lead compound to warrant synthesis.
Heterocyclic Compounds↗
Patient satisfaction with HIV service provision in NPMS hospitals: the development of a standard satisfaction questionnaire. NPMS Steering Group.
A self-completion satisfaction questionnaire evaluating the standard of care of HIV outpatient services was developed as part of the National Prospective Monitoring System on the Use, Cost and Outcome of HIV Service Provision in English Hospitals (NPMS). The questionnaire was designed in conjunction with service users and health care professionals, and piloted in three London and three non-London HIV clinics. In addition to testing alternative methods of administering the questionnaire, the pilot provided satisfaction scores on a variety of aspects of service provision for participating clinics. The questionnaire was completed by 548 respondents and was most effectively collected using a sealed box in the clinic waiting area. Mean satisfaction scores for the attitude and skills of staff members was 4.7 (95% CI 4.6-4.7) but satisfaction scores were significantly lower for the clinic environment with a mean of 4.1 (95% CI 4.1-4.2). Satisfaction scores did not differ significantly by gender, age, sexual orientation, ethnic group, employment status or severity of symptoms. London respondents were more satisfied with the clinic environment and seeing preferred members of staff than their non-London counterparts, however there were no other differences between clinics. The questionnaire functioned well in practice and provided meaningful and useful information for individual clinics as well as at aggregate level.
Acquired Immunodeficiency Syndrome↗
What is the cost of getting the price wrong?
BACKGROUND: The objective of this study was to compare differences in cost estimates for paediatric HIV hospital service provision based on hospital prices with cost estimates obtained through a research-based service-specific costing exercise. METHODS: Activity data on the use of hospital services of children by stage of HIV infection were collected from case-notes for 118 HIV antibody positive children, managed at St Mary's Hospital NHS Trust, London, 1 January 1986-31 December 1994. Hospital unit prices were obtained from the Hospital Trust Finance Department; unit cost estimates were obtained from relevant hospital departments through a research-based service-specific costing exercise. Financial data related to the 1993-1994 financial year, and were indexed to 1995-1996 prices. The main outcome measures were cost estimates per patient-year by stage of HIV infection. Three cost scenarios were calculated: first by linking activity data with hospital prices (Trust Prices); second by linking activity data with routinely available hospital prices plus units costs from the costing exercise where no relevant hospital prices existed (Supplemented Trust Prices); third, by linking activity data exclusively with unit costs from the hospital-specific costing exercise (Unit Costs). RESULTS: There were substantial differences between unit cost estimates per patient-year based on Trust Prices and Supplemented Trust Prices compared with those based on Unit Costs. Differences increased with more intense use of services. The deficit based on Trust Prices compared with Unit Costs ranged from Pound Sterling 432 per patient-year for HIV negative children, Pound Sterling 574 for asymptomatic HIV-infected children, Pound Sterling 1288 for indeterminate children, Pound Sterling 1814 for children with symptomatic non-AIDS to Pound Sterling 7418 per patient-year for children with AIDS. CONCLUSIONS: In this hospital, reliance on generic hospital prices to derive cost estimates for paediatric HIV services produced considerable underestimates of the cost of service provision compared with data derived through the costing exercise. If this occurs across all or most areas of service provision, this can lead to substantial financial deficits, which in turn may mean that the needs of specific client populations may not be met.
Bias↗
Intramuscular rocuronium in infants and children: a multicenter study to evaluate tracheal intubating conditions, onset, and duration of action.
BACKGROUND: This multicenter, assessor-blinded, randomized study was done to confirm and extend a pilot study showing that intramuscular rocuronium can provide adequate tracheal intubating conditions in infants (2.5 min) and children (3 min) during halothane anesthesia. METHODS: Thirty-eight infants (age range, 3-12 months) and 38 children (age range, 1 to 5 yr) classified as American Society of Anesthesiologists physical status 1 and 2 were evaluated at four investigational sites. Anesthesia was maintained with halothane and oxygen (1% end-tidal concentration if <2.5 yr; 0.80% end-tidal concentration if >2.5 yr) for 5 min. One half of the patients received 0.45 mg/kg intravenous rocuronium. The others received 1 mg/kg (infants) or 1.8 mg/kg (children) of intramuscular rocuronium into the deltoid muscle. Intubating conditions and mechanomyographic responses to ulnar nerve stimulation were assessed. RESULTS: The conditions for tracheal intubation at 2.5 and 3 min in infants and children, respectively, were inadequate in a high percentage of patients in the intramuscular group. Nine of 16 infants and 10 of 17 children had adequate or better intubating conditions at 3.5 and 4 min, respectively, after intramuscular rocuronium. Better-than-adequate intubating conditions were achieved in 14 of 15 infants and 16 of 17 children given intravenous rocuronium. Intramuscular rocuronium provided > or =98% blockade in 7.4+/-3.4 min (in infants) and 8+/-6.3 min (in children). Twenty-five percent recovery occurred in 79+/-26 min (in infants) and in 86+/-22 min (in children). CONCLUSIONS: Intramuscular rocuronium, in the doses and conditions tested, does not consistently provide satisfactory tracheal intubating conditions in infants and children and is not an adequate alternative to intramuscular succinylcholine when rapid intubation is necessary.
Androstanols↗
A quantitative investigation of the transannular amine-ketone (N...C=O) interaction in medium-sized heterocycles.
The transannular N...C=O interaction in several medium-sized heterocycles has been investigated by force-field methods. Conformational searching has been performed at the molecular mechanics level using different methods and the conformers so generated have been reoptimized at RHF/6-31G(d). For selected conformers, N...C distances are reported, together with transannular bond orders and atomic charges. Good agreement with available X-ray crystallographic data is obtained for the transannular bond distance in cryptopine. Changes in the partial atomic charges derived from the electrostatic potential provide good support for the donor-acceptor model of transannular interactions. Partial charges derived with other methods do not give satisfactory results. Some force fields do not reproduce the transannular interaction very well. This is demonstrated and rationalized, and modifications are suggested and tested for these force fields with good results when comparing diagnostic geometric features with X-ray data.
Alkaloids↗
Reactive astrocyte formation in vivo is regulated by noradrenergic axons.
Beta adrenergic receptor antagonists greatly reduce reactive astrocyte formation induced by neuronal degeneration. To test the hypothesis that the density of noradrenergic innervation is a factor in the regulation of astrocytosis, we measured glial fibrillary acidic protein (GFAP) optical density after neuronal injury in central nervous system (CNS) regions with permanent noradrenergic sprouting or norepinephrine (NE) depletion. The injury model employs the injection of Ricinus communis lectin into a cranial or peripheral nerve to destroy CNS neurons without the blood-brain barrier disruption and lymphocyte infiltration associated with contusive or surgical lesions. We took advantage of the lack of an NE transporter in the terminals of certain classes of noradrenergic axons to produce noradrenergic sprouting in the trigeminal motor nucleus (MoV) with neonatal 6-hydroxydopamine (6-OHDA) treatment and to produce depletion of NE in the spinal cord dorsal horn with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) administration. In each of these regions, GFAP optical density in the region of reactive astrocytes on the Ricin lectin-treated side was compared with the untreated contralateral (control) side in animals with NE hyperinnervation or NE depletion. GFAP density was increased about 55% in the injured NE-hyperinnervated MoV and was decreased about 35% in the injured NE-depleted dorsal horn. The degree of reactive astrocyte formation to injury is known to vary in different regions of the CNS, and our results suggest that differences in noradrenergic innervation may contribute to this variation. Along with earlier findings that beta-adrenergic receptor blockade reduces reactive astrocyte formation, these data indicate that the noradrenergic innervation is a factor in the degree of astrocyte reactivity following injury.
Analysis of Variance↗
Pharmacophore development for antagonists at alpha 1 adrenergic receptor subtypes.
Many receptors, including alpha 1 adrenergic receptors, have a range of subtypes. This offers possibilities for the development of highly selective antagonists with potentially fewer detrimental effects. Antagonists developed for alpha 1A receptors, for example, would have potential in the treatment of benign prostatic hyperplasia. As part of the molecular design process, structural features necessary for the selective affinity for alpha 1A and alpha 1B adrenergic receptors have been investigated. The molecular modelling software (particularly the Apex module) of Molecular Simulations, Inc. was used to develop pharmacophore models for these two subtypes. Low-energy conformations of a set of known antagonists were used as input, together with a classification of the receptor affinity data. The biophores proposed by the program were evaluated and pharmacophores were proposed. The pharmacophore models were validated by testing the fit of known antagonists, not included in the training set. The critical structural feature for selectivity between the alpha 1A and alpha 1B adrenergic receptor sites is the distance between the basic nitrogen atom and the centre of an aromatic ring system. This will be exploited in the design and synthesis of structurally new selective antagonists for these sites.
Adrenergic alpha-1 Receptor Antagonists↗