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Biomedical subjects

P Davis

Publications and source records attributed to P Davis.

At least 217 records · Page 12Linked to original sources
PubMed1995

Surfactant treatment at birth reduces lung vascular injury and edema in preterm lambs.

To study the effect of surfactant administration on fluid balance in the premature lung, we measured pulmonary vascular pressures, lung lymph and pleural liquid flow, and concentrations of protein in lymph, pleural liquid, and plasma before and after birth in 12 chronically catheterized preterm lambs (127-128 d gestation) treated with either placebo or surfactant just before surgical delivery. Eight lambs received intrapulmonary saline (placebo), and four lambs received surfactant; all lambs were mechanically ventilated with O2 for 8 h after birth. In control lambs, lung lymph and pleural liquid flow increased from 2.7 +/- 0.4 mL/h during the 2-4 h before birth to 9.2 +/- 2.1 mL/h by 6-8 h after birth; lymph and pleural space protein drainage increased from 58 +/- 7 mg/h during the 2-4 h before birth to 134 +/- 25 mg/h by 6-8 h after birth. In lambs treated with surfactant, there was no significant increase in lymph and pleural liquid flow after birth (before birth, 2.3 +/- 0.3 mL/h; 6-8 h after birth, 3.4 +/- 0.9 mL/h); likewise, lymph and pleural space protein drainage did not change after birth (before birth, 54 +/- 6 mg/h; 6-8 h after birth, 50 +/- 8 mg/h). Postmortem extravascular lung water was significantly less in lambs treated with surfactant compared with control lambs (control, 6.5 +/- 0.3 g/g dry lung; surfactant-treated, 5.0 +/- 0.2 g/g dry lung).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Projective personality tests of children with inflammatory bowel disease.

15 children with inflammatory bowel disease were given projective tests after initial diagnosis. Analysis of responses suggested affective constriction, abandonment anxiety, and depression. The children were of good intelligence with good object relationships and psychosexual differentiation for their ages. Severe psychopathology and bizarre slippage were absent.

Adolescent↗
PubMed1995

Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: molecular rationale and early clinical results.

The three most active types of agents in the treatment of cancer of the ovary are platinum compounds (cisplatin or carboplatin), bifunctional alkylating agents (cyclophosphamide, melphalan, etc), and the recently developed natural product paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). In an effort to improve long-term disease-free survival in patients with advanced disease, we have developed a three-drug regimen consisting of cisplatin, paclitaxel, and cyclophosphamide. Granulocyte-colony stimulating factor is given as bone marrow support using a flexible dosing approach. The molecular basis for this approach is founded in the positive molecular interactions between cisplatin and bifunctional alkylating agents and between paclitaxel and DNA-damaging agents. Cisplatin and cyclophosphamide damage DNA by two very different mechanisms; the respective importance of DNA strand "kinking" versus DNA strand "cross-linking" may explain the positive cell kill interaction between these two drugs. Paclitaxel appears to markedly slow the repair of DNA lesions caused by DNA-damaging agents, which may include radiation-induced lesions, cisplatin adducts, and cyclophosphamide cross-links. Clinical data to date from several different groups strongly suggest that these molecular interactions translate into positive clinical benefit in human ovarian cancer. Preliminary data from our clinical trial show that these three agents are well tolerated in the doses administered and that this combination shows exceptional promise as a possible therapeutic advance in this disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist.

The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective delta agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The delta selective antagonist ICI 174,864 (1 microM) and the mu selective antagonist CTAP (1 microM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (delta receptors) rather than against those labeled by [3H]DAMGO (mu receptors) or [3H]U69, 593 kappa receptors) in mouse whole-brain assays. The ratios of the calculated Ki values for SNC 80 at mu/delta and kappa/delta sites were 495- and 248-fold, respectively, which indicates a significant degree of delta selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95% C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95% C.I.) of 91.9 (60.3-140.0) nmol.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1995

An assessment of the needs of family physicians for a rheumatology Continuing Medical Educational program: results of a pilot project.

OBJECTIVE: To assess the needs and determine the effect of a Continuing Medical Education (CME) program designed for primary care physicians on the management of osteoarthritis (OA). METHODS: The needs of potential CME consumers were determined using a standardized case recall questionnaire on the management of OA. A CME program was designed to specifically address identified needs, and the effect of the program was determined by repeat questionnaire by participants at 3 mo followup. RESULTS: Primary care physicians had a high rate of use of nonsteroidal antiinflammatory drugs (NSAID) and a proportionately low rate of use of analgesics. Physiotherapeutic modalities and local steroid injections were underused. There was a relatively low appreciation of potential side effects of therapeutic choices and possible risk factors for toxicity. After participating in the CME program, attendees demonstrated change in their therapeutic practices with an increased awareness of relative risks/benefits of NSAID vs analgesics. CONCLUSION: A case recall questionnaire format is a simple and inexpensive means of determining the need for developing a specific program for, and determining the effect of a CME program applicable to rheumatology CME activities for primary care physicians.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

A multicenter study of nabumetone and diclofenac SR in patients with osteoarthritis.

OBJECTIVE: To conduct the first Canadian study of the comparative efficacy and safety of nabumetone and diclofenac SR in patients with primary osteoarthritis (OA) of the hip, knee and shoulder. METHODS: Nabumetone 1000-1500 mg po daily was compared to diclofenac SR 100-150 mg po daily in a 6-month, double blind, randomized, controlled, multicenter, parallel trial. Initial starting doses were nabumetone 1000 mg daily and diclofenac SR 100 mg daily, with optional subsequent one-level dose titration permitted after 2 weeks on lower dose up to 1500 mg nabumetone and 150 mg diclofenac SR. The primary outcome measures were overall pain and disease activity as assessed by physician and patient. Secondary efficacy measures included tenderness, swelling, limitation of motion, duration of morning stiffness, acetaminophen consumption, physician and patient global assessment, and patient evaluation of efficacy and tolerability. Following an initial screening visit and a 2 to 7 day nonsteroidal antiinflammatory drug free washout period (i.e., randomization), patients were assessed at Weeks 2, 8, 14, 20, and 26. RESULTS: In all, 382 patients [nabumetone (n = 192), diclofenac SR (n = 190)] participated in the trial. Improvement in all efficacy variables was noted, but there was no statistically significant difference between drugs. Significantly fewer (p = 0.01) patients reported upper gastrointestinal (GI) adverse experiences in the nabumetone group. Significantly fewer (p < 0.04) patients withdrew from the study for adverse experiences in the nabumetone (14%) than the diclofenac SR (23%) group, particularly from upper abdominal pain (p < 0.04) and dyspepsia (p = 0.02). Three patients treated with diclofenac SR and none with nabumetone developed upper GI ulcers or bleeds. The number of patients experiencing clinically important elevations in transaminases (p < 0.04) or BUN/creatinine (p < 0.03) was significantly lower in the nabumetone group. CONCLUSION: Nabumetone is efficacious and well tolerated in patients with OA of the hip, knee or shoulder. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac SR.

Adult↗
PubMed1994

Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).

The in vitro pharmacological properties and conformational features of analogs of the delta opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of beta-methylphenylalanine (beta-MePhe) were investigated. Both analogs in which the alpha carbon of the Phe3 replacement has L-stereochemistry display high affinity for delta receptors with the (2S,3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S,3R)-MePhe3 diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe3 analog, also displays high affinity for the delta receptor and is extraordinarily selective for this receptor. All analogs were agonists in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle bioassays, displaying MVD and GPI potencies consistent with their delta and mu opioid receptor affinities, respectively. The use of beta-MePhe as a replacement for Phe3 was based upon the desire to reduce the conformational flexibility of the Phe3 side chain by imposing a steric rotational constraint in the form of the beta-methyl substituent and to thus deduce the residue 3 side chain orientation in the delta receptor-bound conformation from the correlation between delta receptor binding affinities and conformational preferences. Molecular mechanics computations revealed, however, that the conformational constraints imposed by the beta-methyl group in the (2S,3S)-MePhe3 and (2S,3R)-MePhe3 analogs were too modest to allow unequivocal determination of delta receptor-bound residue 3 side chain conformation. However, analysis of the high-affinity (2R,3R)-MePhe3 analog revealed a strong preference for a single side chain conformer (chi 1 approximately 60 degrees). Low-energy conformers of this analog could only be effectively superimposed with low-energy conformers of the parent peptide in which the Phe3 side chain conformation was limited to chi 1 approximately -60 degrees. This observation eliminates the last remaining uncertainty regarding conformational features of the pharmacophore elements in the delta receptor-bound state, allowing the proposal of a complete model.

Amino Acid Sequence↗
PubMed1994

Design, synthesis, and biological properties of highly potent cyclic dynorphin A analogues. Analogues cyclized between positions 5 and 11.

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the kappa and mu receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5,D-Cys11] Dyn A1-11-NH2, c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.

Amino Acid Sequence↗
PubMed1994

The Waikato Medical Care (WaiMedCa) Survey 1991-1992.

Objective. The main objective of this study is to provide a comprehensive description of general practice in the Waikato, an area which represents many aspects of New Zealand. Accurate, detailed and up to date information in this area is needed for future planning of medical education and the provision of health services. Survey method. The survey was conducted over one year, from September 1991 to August 1992. Participating general practitioners and practice nurses recorded details of a sample of patient encounters in the surgery or on home visits. Each participant was assigned four single weeks for data gathering over the course of the year. A one in five sub-sample of patients was also given questionnaires to complete immediately and two weeks after the consultations. This component of the study was reported elsewhere. Participants. A list of all active general practitioners working within the area covered by the Waikato Area Health board was constructed. All were contacted during May and June 1991 and asked to contribute to the study. During this initial, recruiting stage the practitioners and their practice nurses were asked to provide details of their professional background and to outline the structure, functions and size of their practices. Data collection. The variables studied included: provider characteristics (age, gender, qualifications, type of practice and services offered); patient attributes (age, gender, ethnicity, benefit category and occupation); patient reasons for encounter (up to four per encounter); doctor diagnoses (again up to four per encounter); drugs prescribed and or other treatments provided; tests and investigations ordered and referrals made; planned follow up and subjective view on the encounter. Data were centrally coded by trained staff. Patient reasons for encounter were coded according to NAMCS, practitioner diagnoses were classified into OXMIS, and drugs prescribed were allocated into the ATC classification system. Participation rate. 87% of practitioners (182/209), 89% of practices (95/107), and 80% of practice nurses (150/189) completed the initial recruitment survey. The participation rate at the first phase of the encounter survey was 80.5% (169/210), but this had dropped to 65.7% (136/207) by the fourth collection week. An overall response rate of 68.6% was achieved, representing successful collection of encounter data in 562 of 819 potential doctor recording weeks. On average, general practitioners recorded 109 encounters per week, from which they selected on average a sample of 23 patients for the survey. They described 141 problems per 100 encounters, of which 49 were new. On average general practitioners made less than three home visits per 100 encounters.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1994

Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier.

Most peptides have not proved useful as neuroactive drugs because they are blocked by the blood-brain barrier and do not reach their receptors within the brain. Intraperitoneally administered L-serinyl beta-D-glucoside analogues of [Met5]enkephalin (glycopeptides) have been shown to be transported across the blood-brain barrier to bind with targeted mu- and delta-opioid receptors in the mouse brain. The opioid nature of the binding has been demonstrated with intracerebroventricularly administered naloxone. Paradoxically, glucosylation decreases the lipophilicity of the peptides while promoting transport across the lipophilic endothelial layer. It is suggested that glucose transporter GLUT-1 is responsible for the transport of the peptide message. Profound and long-lasting analgesia has been observed in mice (tail-flick and hot-plate assays) with two of the glycopeptide analogues when administered intraperitoneally.

Amino Acid Sequence↗
PubMed1994

Newly discovered stereochemical requirements in the side-chain conformation of delta opioid agonists for recognizing opioid delta receptors.

Topographic design of peptide ligands using specialized topographically constrained amino acids can provide new insights into the stereochemical requirements for delta opioid receptors. A highly constrained tyrosine derivative, (2S,3S)-beta-methyl-2',6'-dimethyltyrosine [(2S,3S)-TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen2,D-Pen5] enkephalin (delta 1) and Deltorphin I (delta 2). The results of binding assays and bioassays showed that the two analogues (3 and 4) acted very differently at delta opioid receptors. Further pharmacological evaluations suggested that they actually interact primarily with the delta 1 and delta 2 receptor subtypes, respectively. These results, and conformational studies using NMR and computer-assisted modeling, provided insights into the different stereochemical requirements for these two delta opioid ligands to recognize the delta opioid receptor and its subtypes.

Amino Acid Sequence↗
PubMed1994

[L-Ala3]DPDPE: a new enkephalin analog with a unique opioid receptor activity profile. Further evidence of delta-opioid receptor multiplicity.

To investigate delta-opioid receptor topography near the 3-position of [D-Pen2,D-Pen5]enkephalin (DPDPE), a series of small-group 3-position analogs of DPDPE have been synthesized and assayed for binding potencies and in vitro biological activities. L-Amino acid substitutions at this position are highly favored over D-amino acid substitutions, with the smallest, [L-Ala3]DPDPE (DPADPE), being the most favored in the series investigated. [L-Ala3]DPDPE is nearly as delta-potent and more delta-selective in both rat brain binding (18 nM vs [3H] [p-ClPhe4]DPDPE and mu/delta = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, mu/delta = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [L-Ala3]DPDPE is only a weak analgesic. However, [L-Ala3]DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent (pA2 = 5.7) and selective fashion in vivo. Thus, [L-Ala3]DPDPE is a fairly potent agonist at peripheral delta receptors and is a moderately potent (mixed) antagonist of delta 1 receptors in the brain. It appears that [L-Ala3]DPDPE does not interact in any significant manner with delta 2 or mu receptors in the brain.

Amino Acid Sequence↗
PubMed1994

Design of cyclic deltorphins and dermenkephalins with a disulfide bridge leads to analogues with high selectivity for delta-opioid receptors.

We earlier suggested that the low receptor selectivity observed for previously synthesized constrained analogues of deltorphin I (DT I) was the result of a reduction in the lipophilic surface of the C-terminal of the peptide. To confirm this prediction and to further test a previously proposed conformational model for bioactivity at delta opioid receptors, we have synthesized several new cyclic analogues with the general structure [D-Xaa2,Yaa5]deltorphin I and II in which Xaa2 is D-cysteine or D-penicillamine (D-Pen), and Yaa5 is an L- or D-penicillamine residue. Additional substitutions at positions 4, 6, and 7 also were examined. The analogues were tested for binding to mu- and delta-opioid receptors and in mouse vas deferens and guinea pig ileum biological assays. The introduction of a lipophilic L-Pen in position 5 and D-Cys or D-Pen in position 2 resulted in a highly delta-selective series of analogues, which fully confirmed our prediction. The cyclic analogues formula; see text: DT I are among the most delta-selective analogues described thus far.

Amino Acid Sequence↗
PubMed1994

Cyclic enkephalin analogs with exceptional potency at peripheral delta opioid receptors.

A series of super potent and delta-opioid-receptor-selective cyclic hexapeptides of the general formula [formula: see text] (where X is hydrogen or halogen) has been synthesized. The unsubstituted hexapeptide formula; see text: [Phe6]DPLCE) has extremely high potency at peripheral delta opioid receptors (IC50 value in the MVD assay is 0.016 nM) and in bioassays is the most selective compound in this series. The introduction of halogens in the phenyl ring of phenylalanine at position 4 led to significant changes in the selectivity and affinities at peripheral and central opioid receptors. In the binding studies, the most potent compound is the p-fluoro analog, whereas the most selective analog is the p-iodo-substituted peptide.

Amino Acid Sequence↗