Checking for correct endotracheal tube placement.
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Carbon Dioxide↗
Biomedical subjects
G Phillips
Publications and source records attributed to G Phillips.
Intramuscular ketorolac.
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Acute Kidney Injury↗
Teaching interviewing and interpersonal skills.
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Education, Medical↗
Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.
The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary. The cis racemate (+/-)-3a, was found to be a selective and potent 5-HT1A receptor agonist with the activity residing in the cis-(3aR)-enantiomer, (-)-3a. The cis-(3aS)-enantiomer (+)-3a and trans-(3aR)-enantiomer (-)-3b displayed partial 5-HT1A agonist activity whereas the other trans-(3aS)-enantiomer (+)-3b showed no activity. The enantiomer (-)-3a was found to be selective in both in vitro and in vivo biochemical/behavioral assays. This compound potently reduced rectal temperature in mice, decreased the firing rate of rat midbrain serotonergic neurons, and suppressed rat brain 5-HT synthesis. This compound also reduced sympathetic nerve discharge and blood pressure in the anesthetized cat and showed activity in the forced swim assay in mice. It exhibited good oral activity in behavioral and biochemical assays and, in fact, had a 46% oral availability in the rat when comparing blood levels of parent drug after iv and po administration. This compound has demonstrated a potential for anxiolytic and antidepressant activity and is currently undergoing clinical evaluation.
Administration, Oral↗
Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives.
The conformationally restricted linear tricyclic analogs of 5- and 8-hydroxy-2-(di-n-propylamino)-tetralins were investigated for their serotonergic and dopaminergic properties. These cis and trans analogs of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (3), where a five-membered ring is fused between the nitrogen and C-3 carbon of 2-aminotetralin, were synthesized from 5-methoxy- and 8-methoxytetralones. The enantiomers of trans-5-methoxy-N-n-propyl and -N-allyl analogs were obtained via fractional recrystallization of their di-p-toluoyl-L (or D) tartaric acid salts. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. In the 5-substituted series (R1 in 3), the trans isomers were found to possess higher levels of pharmacological activity then the corresponding cis isomers. The trans-5-methoxy analogs showed selective 5-HT1A receptor activity in vitro but displayed mixed 5-HT1A and D2 agonist properties in vivo. The corresponding trans-5-hydroxy analogs were found to be potent D2 agonists with full intrinsic activity. An examination of nitrogen substitution (R2 in 3) revealed that analogs with either an allyl or an n-propyl group displayed equipotent activities. Substitution with a cyclopropylmethyl or benzyl group resulted in reduced activity. Among the resolved analogs tested, the activity was found to reside exclusively in the (3aS)-(-)-enantiomers. In the 8-substituted series (R1 in 3), only 8-methoxy-N-allyl analogs were synthesized and evaluated. In this case, both cis and trans isomers showed equally weak in vitro 5-HT1A receptor agonist activity devoid of dopaminergic effects. The presence of an additional methyl group at the C-2 position (R3 in 3) of the cis-(+/-)-8-methoxy-N-n-propyl analog resulted in enhancement of in vitro 5-HT1A receptor binding affinity, with the (2 beta,3a alpha,9a alpha)-(+/-)-isomer displaying potency 35 times greater than the (2 alpha,3a alpha,9a alpha)-(+/-)-isomer.
Animals↗
Managing urinary tract infections.
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Female↗
Physiological consequence of expression of soluble and active hen egg white lysozyme in Escherichia coli.
Hen egg white lysozyme was expressed as a protein fusion with the OmpA signal sequence and an octapeptide linker in Escherichia coli. The expression yielded soluble and enzymatically active lysozyme. Lysozyme activity was detected in the periplasmic space, in the cytosol and in the insoluble cytosolic fraction of E. coli. The results indicate that the environmental conditions in both the cytosol and the periplasmic space of E. coli were sufficient for correct protein folding and disulphide bond formation of eukaryotic recombinant lysozyme. However, the expression of active enzyme in E. coli consequently led to bacterial cell lysis due to hydrolysis of the peptidoglucan.
Animals↗
Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement.
Several experiments investigated the involvement of D1 and D2 dopamine receptors in the ventral striatum in the control over behaviour by a conditioned reinforcer using an acquisition of new response procedure. Intra-accumbens infusion of either the D1 receptor antagonist, SCH 23390, or the D2 receptor antagonist, raclopride, completely blocked the potentiative effects of intra-accumbens d-amphetamine on responding with conditioned reinforcement and reduced responding to control levels. SCH 23390 was more potent than raclopride. At higher doses in the absence of d-amphetamine, both antagonists also blocked the preference for responding on the lever producing the conditioned reinforcer. Intra-accumbens infusions of either the D1 receptor agonist, SKF 38393, or the D2/3 receptor agonist, LY 171555 (quinpirole), selectively potentiated responding on the lever producing the conditioned reinforcer. Various combined infusions of the D1 and D2 agonists in specific low doses had additive, but not synergistic, effects on responding with conditioned reinforcement. None of the drugs affected the drinking of water in deprived subjects when infused intra-accumbens. These results suggest that both D1 and D2 receptors in the nucleus accumbens are involved in mediating the effects of dopamine in potentiating the control over behaviour by conditioned reinforcers.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Taurolin for the prevention of parenteral nutrition related infection: antimicrobial activity and long-term use.
A case is described in which bis (1, 1 dioxoperhydro-1, 2, 4-thiadiazinyl-4-) methane (Taurolin) has saferly been administered on a long term basis to prevent recurrent sepsis in a patient receiving parenteral nutrition. A 26-year-old male with Crohn's disease receiving parenteral nutrition suffered repeated episodes of sepsis and developed an infected intra-atrial thrombus despite repeated courses of antimicrobial chemotherapy and surgical intervention. Continued parenteral nutrition was essential du5e to intestinal failure. Taurolin was administered in the parenteral feed, as a 0.3% solution, to prevent recrudescent and recurrent infection. This concentration was shown, in vitro, to be bactericidal to a variety of pathogenic organisms. No recurrence of sepsis, nor any evidence of side effects was observed throughout the 12 month period of Taurolin administration. After 12 months the taurolin was discontinued and within 2 weeks the patient was re-admitted with recurrent septicaemia. Following re-introduction of Taurolin the infection was controlled and the patient remains well. In our experience the addition of taurolin to the nutritive feeds of a patient at risk of sepsis is a safe and effective method of preventing recurrent sepsis.
Journal Article↗
Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients.
Deoxygenation of erythrocytes from sickle cell anemia (SCA) patients alters membrane phospholipid distribution with increased exposure of phosphatidylethanolamine (PE) and phosphatidylserine (PS) on the outer leaflet. This study investigated whether altered membrane phospholipid exposure on sickle erythrocytes results in complement activation. In vitro deoxygenation of sickle but not normal erythrocytes resulted in complement activation measured by C3 binding. Additional evidence indicated that this activation was the result of the alterations in membrane phospholipids. First, complement was activated by normal erythrocytes after incubation with sodium tetrathionate, which produces similar phospholipid changes. Second, antibody was not required for complement activation by sickle or tetrathionate-treated erythrocytes. Third, the membrane regulatory proteins, decay-accelerating factor (CD55) and the C3b/C4b receptor (CD35), were normal on sickle and tetrathionate-treated erythrocytes. Finally, insertion of PE or PS into normal erythrocytes induced alternative pathway activation. SCA patients in crisis exhibited increased plasma factor Bb levels compared with baseline, and erythrocytes isolated from hospitalized SCA patients had increased levels of bound C3, indicating that alternative pathway activation occurs in vivo. Activation of complement may be a contributing factor in sickle crisis episodes, shortening the life span of erythrocytes and decreasing host defense against infections.
Anemia, Sickle Cell↗
Uterine activity in spontaneous labour and maternal peripheral plasma prostaglandin E2 and F2 alpha metabolites.
The relationship between maternal peripheral plasma concentrations of prostaglandin E2 and prostaglandin F2 alpha metabolites (bicyclo-PGEM and PGFM respectively) and the level of uterine activity in spontaneous labour was studied in 10 nulliparous and 10 multiparous women. Plasma prostaglandin metabolites were measured by radioimmunoassay. Uterine activity was quantified by computer analysis of changes in intrauterine pressure and expressed as mean active pressure (MAP). As labour progressed, both parity groups showed a significant rise in MAP which was associated with a significant increase in the levels of PGFM. However, the percentage rise in PGFM did not significantly correlate with the percentage rise in MAP. At all stages in labour PGFM and MAP levels were higher in the nulliparous group compared with the multiparous group. Bicyclo-PGEM levels showed no significant change in the nulliparous group but rose in late first stage/second stage in the multiparous group. Our observations support a role for prostaglandin F2 alpha in the generation of uterine activity in spontaneous labour. However, further study is required to elucidate the mechanisms controlling prostaglandin production by the fetal membranes and decidua in vivo, and how this relates to maternal peripheral plasma prostaglandin metabolite concentrations and the level of uterine activity.
Dinoprost↗
Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.
Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.
Adult↗
Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme.
BACKGROUND: Nephropathy may develop in patients with sickle cell disease. We determined the prevalence of proteinuria and renal insufficiency in a group of patients with sickle cell disease and investigated the renal pathologic changes and the effects of an angiotensin-converting-enzyme inhibitor (enalapril) on protein excretion in patients found to have nephropathy. METHODS: We prospectively screened 381 patients with sickle cell disease for the presence of proteinuria and renal insufficiency. Renal biopsy and measurements of glomerular filtration rate, effective renal plasma flow, and urinary protein excretion were performed in 10 patients with mild nephropathy before and after the administration of enalapril, and again two to three weeks after its discontinuation. RESULTS: Of the 381 patients with sickle cell disease, 26 (7 percent) had serum creatinine concentrations above the normal range and 101 (26 percent) had proteinuria of at least 1+. The renal lesions in the 10 patients who had biopsies consisted of glomerular enlargement and perihilar focal segmental glomerulosclerosis. The mean (+/- SD) glomerular area in these patients was 28.7 +/- 4.1 x 10(3) micron 2, as compared with 15.8 +/- 4.3 x 10(3) micron 2 in 10 control patients without renal disease who had died of trauma (P less than 0.0001). During the administration of enalapril, the mean 24-hour urinary protein excretion decreased 57 percent (range, 23 to 79 percent) below the base-line value (P less than 0.001), and it increased to 25 percent below the base-line value after enalapril was discontinued. The glomerular filtration rate and effective renal plasma flow did not change significantly. CONCLUSIONS: Approximately 25 percent of patients with sickle cell disease have proteinuria. Treatment with enalapril reduces the degree of proteinuria in these patients, suggesting that glomerular capillary hypertension may be a pathogenic factor in sickle cell nephropathy.
Adult↗
The complex CD44 transcriptional unit; alternative splicing of three internal exons generates the epithelial form of CD44.
We have utilized the polymerase chain reaction (PCR) to isolate a 3.5 kilobase pair (kb) genomic fragment that encodes the additional extracellular domain unique to the epithelial isoform of CD44 (CD44E). Nucleotide sequence was determined for this complete region and sequence comparison to our previously determined CD44R1 and CD44R2 cDNA sequences revealed the R region to be comprised of three exons of 102 bp, 90 bp, and 204 bp. Northern blot analysis of CD44 expressing cell lines confirmed the presence of CD44R1 transcripts and indicates that the epithelial domain may be inserted through alternative splicing into all CD44 transcript classes. Southern blot analysis of the CD44E genomic fragments is consistent with a single copy per human haploid genome. The data presented here further supports our model of the human CD44 transcriptional unit as a single gene complex that utilizes an invariant 5' initiation site, alternative internal and 3' end splicing, and multiple poly (A) sites to generate through RNA processing a diverse number of human CD44 isoforms.
Amino Acid Sequence↗
Vancomycin and teicoplanin: something old, something new.
OBJECTIVE: To compare and contrast the pharmacology, activity and clinical efficacy of two glycopeptide antibiotics, vancomycin and teicoplanin. DATA SOURCES: English language literature search using MEDLINE, Index Medicus, relevant textbooks and product information literature. STUDY SELECTION: Over 200 publications were examined extending back to the period of initial Phase I trials with vancomycin. DATA EXTRACTION AND SYNTHESIS: Many publications covered similar ground and came to the same conclusions. In these instances one or two of the best pieces were chosen as cited reference material. Conflicting results and conclusions are discussed and an attempt is made to interpret the findings. CONCLUSION: Vancomycin and teicoplanin show differences in activity both in vitro and in vivo. Vancomycin is superior against coagulase-negative staphylococci and reliable dosage regimens are available. Teicoplanin, however, needs to be given in significantly larger doses than initially thought necessary to maximise clinical efficacy. Teicoplanin has a lower incidence of side effects but in clinical practice this advantage is small. Vancomycin remains the glycopeptide of choice for the treatment of infections due to Gram-positive bacteria.
Anti-Bacterial Agents↗
Relationship of plasma alpha tocopherol to index of clinical severity in individuals with sickle cell anemia.
Several parameters of micronutrition related to antioxidant activity are reduced in individuals with sickle cell anemia (SCA). The data presented here suggest that vitamin E, specifically alpha tocopherol, has a significant correlation (r = -0.38, P < 0.04) with a retrospective survey of clinical events and a significant correlation with a prospective survey of clinical events (r = -0.42, P < 0.03). The survey of clinical events score takes into account important vaso-occlusive manifestations in SCA. Differences in plasma vitamin E levels explained about 15% of the variability in the clinical manifestations of SCA in the population studied. Previously reported data from our lab suggests that the differences in alpha tocopherol levels are not related to dietary intake. Vitamin E may play an important role in modulating the ability of sickle hemoglobin containing erythrocytes to produce vaso-occlusion. Alternatively, it may simply be a marker of disease activity. Studies are ongoing at our center to determine if the relationship of alpha tocopherol to clinical events is causal.
Adult↗
Adult sexual orientation in relation to memories of childhood gender conforming and gender nonconforming behaviors.
Heterosexual, bisexual, and homosexual men recalled the extent to which they had engaged in gender conforming (masculine) and gender nonconforming (feminine) behaviors as a child. Adult sexual orientation was predicted as accurately by memories of childhood gender conforming behaviors as by memories of childhood gender nonconforming behaviors. However, childhood scripts as recalled by homosexual men were considerably more diverse. Twenty-two of 61 homosexual men reported having experienced few, if any, of the gender conforming behaviors and most, if not all, of the gender nonconforming behaviors. Another 18 homosexual men had the same profile of recalled childhood experiences as heterosexual men (high probability of masculine behaviors and low probability of feminine behaviors). Such diversity has implications not only for commentaries on the basis for homosexuality but for issues to be addressed in future research.
Adolescent↗
Pseudotumoral paraesophageal varices.
We report a case of paraesophageal varices presenting as a posterior mediastinal mass in a patient with long-standing portal hypertension. These collaterals were present, despite multiple previous sclerotherapies for submucosal esophageal varices and no endoscopic evidence of their recurrence.
Adult↗