Biomedical subjects
P Davis
Publications and source records attributed to P Davis.
Coming full circle: a history of the 168th medical detachment (VS).
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Exploring the structure-activity relationships of [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective delta-opioid receptor nonpeptide agonist ligand.
SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the delta-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation.(6) To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH(2)-O-CH(2)-Ph; b = Me; c = CH(2)Ph; d = CH(2)OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the delta-receptor was observed for 15c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.
Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic delta opioid receptor ligands.
We recently reported (+)-4-¿(alphaR)-alpha-¿(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl¿-3-methoxybenzyl-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic delta receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that delta binding activities and selectivity showed little change when the 3-methoxy group in 1b was removed or replaced by the other substituents, whereas the N, N-diethylbenzamide group is important for interaction with the delta receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N, N-diethyl(alpha-piperazinylbenzyl)benzamides (2, 3a-e), N, N-diethyl(alpha-piperidinyl or piperidinylidenebenzyl)benzamides (4a, 5a-c, 6a-b), and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly bound to the delta receptor with K(i) values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were negligible, indicating excellent delta opioid receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the delta receptor. Nitrogen N(4) appears to be an important structural element and is essential for electrostatic interaction, while N(1) seems to be unnecessary for recognition at the delta receptor.
Synthesis and biological activities of position one and three transposed analogs of the opioid peptide YKFA.
Tyr-c[D-Lys-Phe-Ala], YKFA, is a potent opioid peptide analog with subnanomolar IC50s toward mu and delta receptors. Transposing Phe and Tyr, a modification found to promote mu antagonist activity in opioid/somatostatin hybrids, gave surprisingly high mu agonist activities for several related analogs, considering the lack of a 1-position hydroxyl function.
4-Pyridin-5-yl-2-(3,4,5-trimethoxyphenylamino)pyrimidines: potent and selective inhibitors of ZAP 70.
Activation of the tyrosine kinase ZAP 70 has been shown to be crucial to the transduction of the T-cell receptor signalling pathway, which leads ultimately to proliferation, cytokine gene expression and T-cell effector functions. A series of 2-phenylaminopyrimidines have been identified as potent and selective inhibitors of ZAP 70.
Biological activity of fragments and analogues of the potent dimeric opioid peptide, biphalin.
The synthesis and biological activity of two fragments of the very potent opioid peptide biphalin, showed that Tyr-D-Ala-Gly-Phe-NH-NH<-Phe is the minimal fragment necessary to express equal affinities and the same biological activity profile as the parent biphalin. The replacement of N'-Phe with other L- or D- lipophilic amino acids showed the possibility of modification of receptor efficacy of the analogues.
Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans.
A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid delta, mu, and kappa receptors with K(i) values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and GPI with K(e) values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and delta receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative delta address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4'-position of 6a or the equivalent 6'-position of 7a led to dramatic reduction in binding potencies at all the three opioid receptors, indicating the existence of a somewhat similar steric constraint at the ligand binding sites of delta, mu, and kappa receptors. In contrast, the introduction of a phenyl group at the 5'-position of 6a did not cause any reduction in the binding affinity at the delta receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in mu/delta and kappa/delta binding selectivity ratios as well as in the delta antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in delta antagonist potency in the MVD but also shifted the intrinsic activity profile of 6c from an antagonist to that of a mu agonist in the GPI. Compound 6d thus possesses the characteristics of a nonpeptide mu agonist/delta antagonist ligand with high affinity at the delta receptor (K(i) = 2.2 nM), high antagonist potency in the MVD (K(e) = 0.66 nM), and moderate agonist potency in the GPI (IC(50) = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 degrees C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A(50) = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icv injections of an A(90) dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent delta antagonist component of this mixed mu agonist/delta antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays.
Crystal structure of a ternary complex between human chorionic gonadotropin (hCG) and two Fv fragments specific for the alpha and beta-subunits.
Human chorionic gonadotropin (hCG), is a placental hormone which exerts its major effect by stimulating progesterone production, crucially sustaining the early weeks of pregnancy. Detection of hCG with specific monoclonal antibodies (mAbs) has become the chosen means for pregnancy diagnosis. We have used antibody Fv fragments derived from two high-affinity mAbs, one against the alpha and the other against the beta-hCG subunit to enable the crystallisation of intact or desialylated hCG. Crystals of a ternary complex composed of Fv anti-alpha/hCG/Fv anti-beta were found to diffract to 3.5 A resolution, and the structure was solved by molecular replacement. In the crystal, the two Fvs keep hCG as in a molecular cage, providing good protein-protein contacts and leaving enough space for the saccharides to be accommodated in the cell solvent. The two Fvs were found not to interact directly through their complementary-determining regions with the hCG saccharides, but only with the protein. The hCG structure in the ternary complex was very close to that of the HF partially deglycosylated hormone, thus indicating that neither the saccharides nor the Fvs had any substantial influence on hormone structure.
delta Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole.
To investigate the effect of the introduction of a 4-phenolic substituent on the delta opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (mu, kappa, delta), 17-cyclopropylmethyl-6, 7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan (13) was an exception, displaying excellent delta binding selectivity (delta Ki = 7 nM, mu/delta = 1900, mu/kappa = 1130). GTP-gamma-S functional assays showed 13 to be a selective delta antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce mu activity, to obtain increased delta selectivity.
Comparison of physical chemical properties of llama VHH antibody fragments and mouse monoclonal antibodies.
Antigen specific llama VHH antibody fragments were compared to antigen specific mouse monoclonal antibodies with respect to specificity, affinity and stability. The llama VHH antibody fragments and the mouse monoclonal antibodies investigated were shown to be highly specific for the protein antigen hCG or the hapten antigen RR-6. The affinity of the interaction between monovalent llama VHH antibody fragments and their antigen is close to the nanomolar range, similar to the bivalent mouse monoclonal antibodies studied. Llama VHH antibody fragments are similar to mouse monoclonal antibodies with respect to antigen binding in the presence of ammonium thiocyanate and ethanol. The results show that relative to antigen specific mouse monoclonal antibodies, antigen specific llama VHH fragments are extremely temperature stable. Two out of six llama VHHs are able to bind antigen specifically at temperatures as high as 90 degrees C, whereas four out of four mouse monoclonal antibodies are not functional at this temperature. Together with the finding that llama VHH fragments can be produced at high yield in Saccharomyces cerevisiae, these findings indicate that in the near future antigen specific llama VHH fragments can be used in for antibodies unexpected products and processes.
Practice nurses in the Waikato, 1991-1992, I: Occupational profile.
AIMS: To describe the personal characteristics, working conditions, clinical activities and professional development of a representative sample of practice nurses in the Waikato during the period 1991-1992. METHODS: The data are from a survey of practice nurses drawn from a larger study of general practice carried out in the Waikato (the WaiMedCa Study). Eighty-nine percent of the 107 practices in the region participated in the study. The practice nurse survey was carried out on the 189 nurses working in these practices. Of these 149 replied, representing a response rate of 79%. RESULTS: On average, there was one nurse for each solo practice and two in most other practices. Only two practices--both solo--did not employ a nurse. Practice nurses were female and aged between 30 and 50. While only one-third had received a postgraduate qualification, two-thirds had been to recent professional development courses. The majority had worked as a practice nurse for between one and ten years. Nurses averaged just under 15 telephone contacts a day and 28 face-to-face contacts a week. Nurses' workload comprised general measurements and assessments, monitoring and surveillance procedures (such as diabetes, asthma and child development), and counselling and women's health activities. CONCLUSION: Practice nurses are an accepted and essential part of primary health care in New Zealand. However, their potential is probably underdeveloped and they could be more fully utilised for a wider range of nursing functions.
Increased carriage of resistant non-pneumococcal alpha-hemolytic streptococci after antibiotic therapy.
OBJECTIVE: We compared colonization and resistance rates of non-pneumococcal alpha-hemolytic streptococci (AHS) and Streptococcus pneumoniae in children receiving antibiotic therapy for acute otitis media. STUDY DESIGN: Between December 1997 and September 1998, children 6 months to 6 years of age, diagnosed with acute otitis media were randomly assigned to receive amoxicillin/clavulanate (Augmentin) 45 mg/kg/d in 2 divided doses for 10 days or azithromycin (Zithromax), 10 mg/kg, once on the first day, followed by 5 mg/kg daily for 4 days. Nasopharyngeal swabs for culture were obtained before and at 2 weeks and 2 months after the start of therapy. Streptococci were identified by species, and antibiotic susceptibility was determined by the epsilometric test. RESULTS: One hundred six children completed the 2-week follow-up and 2-month follow-up, respectively. The nasopharyngeal carriage rate of non-pneumococcal AHS increased from 14% before treatment to 32% at the 2-week follow-up (P =.02) and was similar in both treatment groups. In contrast, the carriage of S pneumoniae decreased from 51% before therapy to 27% at the 2-week follow-up (P =.002). The carriage of penicillin-resistant AHS strains (minimum inhibitory concentration > 1 microg/mL) increased from 9% before treatment to 26% at 2 weeks and 36% at 2 months. CONCLUSIONS: Amoxicillin/clavulanate and azithromycin therapy resulted in increased isolation of nasopharyngeal non-pneumococcal AHS, many of which were multidrug-resistant, in contrast to a decrease in pneumococcal carriage. This suggests that the competitive balance between these 2 groups of organisms was disturbed as a result of differential antibiotic susceptibility. The importance of drug-resistant AHS as a reservoir for resistance genes for S pneumoniae warrants further investigation.
Epidemiology of complementary and alternative practices in rheumatology.
The increasing prevalence of complementary and alternative medicine usage by the general population and rheumatic patients worldwide is reviewed. The many potential concerns about this type of therapy are addressed, ranging from toxicity issues to changes in behavioral attitudes. Finally, the authors speculate on some major socioeconomic outcomes associated with these therapies.
Evaluation of cytotoxicity and absorption enhancing effects of melittin - a novel absorption enhancer.
Melittin is the major active ingredient in bee venom and has been widely studied for its membrane-fusion property. We have explored the possibility of determining a concentration range of melittin where it is relatively safe to be used as an adsorption enhancer. Melittin's potential use as an adsorption enhancer for mannitol was determined using Caco-2 cells as the model epithelial membrane. The results indicated that at concentrations below 2.4 (M melittin is safe. Using a melittin concentration of 1.5 (M there was 3.5 times increased transepithelial transport of mannitol across Caco-2 cell monolayers.
Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case with prolonged disease-free survival.
Despite the known association of these malignancies, the incidence of a synchronous presentation of breast and ovarian cancer is low, and the current literature does not address an approach to this clinical problem directly. We report a greater than 2.5 year disease-free survival in a patient treated for synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial ovarian cancer. The prolonged disease-free survival in our case may provide some guidance in this unusual clinical situation.
Cyclic enkephalin analogs that are hybrids of DPDPE-related peptides and metenkephalin-Arg-Gly-Leu: prohormone analogs that retain good potency and selectivity for delta opioid receptors.
We report here on the binding affinity and bioassay results of cyclic enkephalin analogs comprising a cyclic moiety and C-terminal fragment of MERGL, where ME denotes methionine enkephalin. MERGL (YGGFMRGL) has been suggested to be cleaved enzymatically by membrane-bound enkephalinase 24.11 to leave ME and the tripeptide RGL. In our study we have synthesized hybrids of DPDPE or DPLCE and the C-terminal tripeptide RGL in order to mimic a prohormone able to cross the blood-brain barrier. The study has shown that of the homologs presented here, analogs of DPLCE often are more potent at delta opioid receptors both in binding affinity and in bioactivity at the MVD, than DPDPE. Our hypothesis that hybrids (consisting of the drug and the spacer for the carrier) could be designed which would either have no opioid activity or, alternatively, be by themselves very active, has been verified.
Changing mortality and causes of death in infants 23-27 weeks' gestational age.
OBJECTIVE: To contrast the mortality rates and changes in the causes of death of very preterm infants (23-27 weeks), before and after the introduction of exogenous surfactant in 1991, and to identify any preventable causes of death remaining in the 1990s. METHODOLOGY: This was a cohort study on consecutive preterm infants of 23-27 weeks' gestational age born in the Royal Women's Hospital, Melbourne, a level III perinatal centre. The infants were livebirths free of lethal anomalies from two distinct eras, 1983-90, and 1992-96, inclusive. The main outcome measures were mortality during the primary hospitalization and the causes of death before and after the introduction of exogenous surfactant in 1991. RESULTS: In 1983-90, 261 of 508 livebirths (51.4%) of 23-27 weeks' gestational age died, a significantly higher proportion than the 109 of 384 (28.4%) livebirths who died in the period 1992-96. The mortality rate fell significantly with increasing gestational age and was lower at each week of gestational age in 1992-96. More infants who died in 1992-96 were treated intensively in the neonatal intensive care unit (NICU). Of the group of infants who died or who were treated intensively in NICU, respiratory causes of death predominated. However, the causes of death changed over time. In 1992-96 proportionally fewer infants died from respiratory causes (1983-90, 82.5%; 1992-96, 60.0%; odds ratio (OR) 0.31, 95%; confidence interval (CI) 0.16-0.57), but more from septic causes (1983-90, 14.3%; 1992-96, 43.8%; OR 4.9, 95%; CI 2.6-9.2). CONCLUSIONS: As the mortality rate has fallen over time, respiratory causes of death have diminished, but septic causes of death have increased. Further advances in the use of exogenous surfactant and respiratory support may reduce respiratory deaths. Effective strategies to reduce nosocomial infections are urgently required.