Search PubMed⌕ Search

Biomedical subjects

M L Moore

Publications and source records attributed to M L Moore.

At least 55 records · Page 3Linked to original sources
PubMed1990

Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues.

The gag and pol genes of the human immunodeficiency virus type 1 (HIV-1) (ref. 1) are translated as two polyproteins, Pr55gag and Pr160gag-pol (refs 2-6), which are subsequently cleaved by the action of a virus-encoded protease into the four structural gag proteins of the virion core (p17, p24, p7 and p6) and the pol-encoded enzymes essential for retrovirus replication (protease, reverse transcriptase, ribonuclease H, and endonuclease). Mutational inactivation of the proteases of HIV-1 and other retroviruses results in immature, non-infectious virions, indicating that exogenous inhibition of the protease may represent an attractive approach to anti-AIDS therapy. Here we demonstrate that synthetic peptide analogues, which are potent inhibitors of purified HIV-1 protease, inhibit the processing of the viral polyproteins in cultures of HIV-1-infected T lymphocytes and attenuate viral infectivity.

Amino Acid Sequence↗
PubMed1990

Disseminated prostatic carcinoma presenting with acute interstitial nephritis and microangiopathic haemolytic anaemia.

A 74-year-old man with metastatic prostatic carcinoma developed acute oliguric renal failure, a microangiopathic haemolytic anaemia and thrombocytopaenia. A renal biopsy showed an acute interstitial nephritis but no changes suggestive of the haemolytic uraemic syndrome. He recovered normal renal function after treatment with haemodialysis and prednisone 20 mg daily for five days. Previous assumptions about the renal lesion in patients with malignancy-associated microangiopathic haemolytic anaemia may need review.

Acute Disease↗
PubMed1989

Hyperkalaemia in patients in hospital.

A survey of all laboratory blood specimens with a plasma potassium concentration greater than or equal to 5.5 mmol/L was conducted over a three month period. Of 331 specimens with hyperkalaemia, 71 were excluded because the specimens was haemolysed, old or contaminated. The laboratory served a population of 348,561 and during this time measured the plasma potassium on 25,016 occasions. Sixty-six outpatients and 20 neonates were not evaluated. The survey was undertaken on 86 of 102 inpatients (46 males), 48 of whom were over 66 years of age. Fifty-seven patients were admitted under a medical service and 29 under a surgical service. Fifty-nine had a single episode of hyperkalaemia. Thirty-two underwent a surgical procedure. The commonest contributing factor was impaired renal function which was present in 71 (83%) patients. Although a definitive causative role for drugs could be identified in only five patients, in 52 (60%) patients drugs were a contributing factor (potassium supplements 24, ACE inhibitors 16, nonsteroidal antiinflammatory drugs 12). Thirty-five of the 86 (41%) patients died during their hospital admission. Nineteen of the 35 deaths occurred within three days of the hyperkalaemia being recorded. A normal plasma potassium was eventually documented in 50 of the 86 patients. Of the remaining 36 patients, 25 (69%) subsequently died. In general the treatment of patients with hyperkalaemia focused on identifying and treating the underlying cause. Hyperkalaemia must always be considered seriously and regard given to the overall clinical status of the patient, with particular attention to drug therapy, renal and cardiac function, acid base status and the possibility of sepsis.

Adolescent↗
PubMed1989

Peptide substrates and inhibitors of the HIV-1 protease.

Oligopeptides containing the consensus retroviral protease cleavage sequence Ser/Thr-X-Y-Tyr/Phe-Pro are substrates for purified recombinant HIV-1 protease with Km's in the millimolar range. The minimum sequence containing the consensus pentapeptide which serves as a good substrate is a heptapeptide spanning the P4-P3' residues. Substitution of reduced Phe-Pro or Tyr-Pro dipeptide isosteres or the statine analog 3-hydroxy-4-amino-5-phenylpentanoic acid for the scissile dipeptide afforded inhibitors of HIV-1 protease with Ki values in the micromolar range, three orders of magnitude better in affinity than the corresponding substrates. Inhibitors of HIV-1 protease may provide a novel and potentially useful therapeutic approach to the treatment of acquired immune deficiency syndrome (AIDS).

Amino Acid Sequence↗
PubMed1989

Vasopressin receptor antagonism in rhesus monkey and man: stereochemical requirements.

The vasopressin antidiuretic (V2) antagonist activity of the position 6 stereoisomers of four vasopressin analogs were tested for water diuretic activity in the rhesus monkey and for activity to inhibit vasopressin-stimulated adenylate cyclase activity in rhesus monkey and human renomedullary tissue in vitro. Replacement of the mercapto groups of the cysteine residues with methylene groups resulted in compounds having similar in vitro potencies to their disulfide analogs; however, these 'dicarba' compounds demonstrated more potent aquaretic activity. Position 6 D enantiomers were associated with less vasopressin antagonist activity in vitro in both species. Based upon these studies, the most potent aquaretic structure identified was the dicarba analog SK & F 105494.

Adenylyl Cyclase Inhibitors↗
PubMed1989

A prospective randomised trial comparing individualised pharmacokinetic dosage prediction for aminoglycosides with prediction based on estimated creatinine clearance in critically ill patients.

A prospective randomised trial was conducted in critically ill patients to evaluate a computer aided pharmacokinetic method of aminoglycoside dose prediction based on 3 measured plasma concentrations following the loading dose. The ability of this method to achieve therapeutic plasma aminoglycoside concentrations early in the course of treatment was compared with that of a nomogram approach based on creatinine clearance estimated using the formula of Cockroft and Gault. Ninety-two percent of patients in the computer group achieved peak plasma concentrations within the optimum range of 6-10 mg/l at 48-72 h compared with 21% of control group patients (p = 0.0009). The mean peak plasma concentration of 7.45 mg/l at 48-72 h in the computer group was closer to the target concentration of 8 mg/l than was the 5.14 mg/l in the control group (p = 0.0004). There was no significant difference between the groups in measured indices of renal function, both groups showing an improvement in mean estimated creatinine clearance from the beginning to the end of the course of treatment. Dosing based on individualised pharmacokinetic data is therefore a more reliable method of achieving therapeutic blood concentrations early in the course of treatment than is nomogram based dosing. Other studies suggest that this should be associated with a reduction in mortality in severe infections.

Adult↗
PubMed1989

Cyclic enkephalin analogues containing alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid at positions 2 or 5.

Analogues of the highly potent and delta-receptor-selective enkephalins 1-4 were prepared with alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid (Apmp) replacing the beta,beta-dimethylcysteine (Pen) at positions 2 or 5. The peptides 5-8 were prepared by employing D,L-Apmp and, following oxidative cyclization, the resulting diastereomeric peptides were separated and purified by preparative high performance liquid chromatography. Compounds 7 and 8, with D- or L-Apmp substituted at position 5 are approximately 5 orders of magnitude more potent in the MVD assay than analogues 5 or 6 with D- or L-Apmp at position 2. While displaying less delta-receptor selectivity than the corresponding Pen-containing compounds, 7 and 8 are an order of magnitude more potent. All the analogues showed diminished delta-receptor selectivity in the rat brain binding assay. Compounds 7 and 8 displayed delta-receptor affinity comparable to the corresponding Pen-containing analogues.

Amino Acids, Sulfur↗
PubMed1989

Structure-activity relationships of novel vasopressin antagonists containing C-terminal diaminoalkanes and (aminoalkyl)guanidines.

We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)nNH2] or (aminoalkyl)guanidine [NH(CH2)nNHC(= NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an "optimal" distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.

Animals↗
PubMed1989

A minor modification of residue 1 in potent vasopressin antagonists dramatically reduces agonist activity.

[1-(beta,beta-Pentamethylene-beta-mercaptopropionic acid),2-(O-ethyl)-D- tyrosine,4-valine,9-desglycine]arginine-vasopressin (SK&F 101926, 1), a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and shown to be a full antidiuretic agonist. A new animal model for vasopressin activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK&F 101926. In this model we have discovered that substitution of a cis-4'-methyl group on the Pmp moiety at residue 1 of vasopressin antagonists results in substantially reduced agonist activity compared to the unsubstituted molecule (SK&F 101926). The corresponding analogue with a trans-4'-methyl group exhibits more agonist activity than the cis molecule. These findings can be explained by viewing the biological activities of compounds such as 1 as the interaction of the vasopressin receptor with a number of discrete molecular entities, conformers of 1, which present different pharmacophores. Models have been developed to assist in the understanding of these results.

Adenylyl Cyclase Inhibitors↗
PubMed1989

Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.

Inhibitors of the protease from human immunodeficiency virus 1 (HIV-1) were designed, synthesized, and kinetically characterized. Analogues of a heptapeptide substrate of HIV-1 protease with sequence similar to the p17-p24 cleavage site in the natural substrate, Pr55gag, were synthesized in which the scissile dipeptide bond was replaced with bonds from six categories of stable mimics of an aspartic proteolysis transition state or intermediate. These mimics included an analogue of statine, hydroxyethylene isosteres, two categories of phosphinic acids, a reduced amide isostere, and an alpha,alpha-difluoroketone. The resulting peptide analogues were linear competitive inhibitors of purified recombinant HIV-1 protease with inhibition constants ranging from 18 nM to 40 microM depending on the type of inhibitor. A truncated inhibitor, an analogue of a hexapeptide, retained full inhibitory potency. The most potent inhibitors, containing the hydroxyethylene isostere, effectively blocked the proteolytic processing of a recombinant form of Pr55gag by HIV-1 protease in a cell-free assay.

Amino Acid Sequence↗
PubMed1989

Human immunodeficiency virus 1 protease expressed in Escherichia coli behaves as a dimeric aspartic protease.

Recombinant human immunodeficiency virus 1 (HIV-1) protease, purified from a bacterial expression system, processed a recombinant form of its natural substrate, Pr55gag, into protein fragments that possess molecular weights commensurate with those of the virion gag proteins. Molecular weights of the protease obtained under denaturing and nondenaturing conditions (11,000 and 22,000, respectively) and chemical crosslinking studies were consistent with a dimeric structure for the active enzyme. The protease appropriately cleaved the nonapeptide Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2 between the tyrosine and proline residues. HIV-1 protease was sensitive to inactivators of the aspartic proteases. The aspartic protease inactivator 1,2-epoxy-3-(4-nitrophenoxy)propane produced irreversible, time-dependent inactivation of the protease. The pH-dependent kinetics of this inactivator were consistent with the requirement of an unprotonated carboxyl group in the active site of the enzyme, suggesting that HIV-1 protease is also an aspartic protease.

Aspartic Acid Endopeptidases↗
PubMed1989

The effect of a preterm birth prevention program in 17 rural and three urban counties in northwest North Carolina.

The results of a program of low birthweight prevention in 17 rural (20,727 births) and three urban counties (15,561 births) for calendar years 1985 and 1986 are described. Records for women in the program were matched with birth certificate data by computer. Rural and urban women in and out of the program were compared by race on the following risk factors: age less than 18 years, unmarried, education less than 12 years, Medicaid recipient, not WIC recipient, inadequate prenatal care, and previous fetal or live born death. Adjusting for these risk factors, logistic regression was used to estimate program effects on low birthweight (LBW), very low birthweight (VLBW), and preterm low birthweight (PLBW) among rural women. There was a statistically significant difference (p less than or equal to 0.01) favoring women in the program for very low birthweight and preterm low birthweight in white women, and low birthweight and preterm low birthweight in nonwhite women. The differences in rural areas exceed those in urban areas for all but one mean, very low birthweight births among white women.

Adolescent↗
PubMed1989

Vaginal pH: a marker of preterm premature rupture of the membranes.

Preterm premature rupture of the membranes (PROM) is a common predecessor of preterm or low birth weight (LBW) birth, yet the risk of preterm PROM is presently unpredictable. Numerous infectious organisms that change the normal vaginal milieu have been associated with preterm PROM. Because these organisms alter vaginal pH, the use of pH was evaluated as a potential marker for women at increased risk for preterm PROM. Among 115 women at high risk for an LBW birth, those with a mean vaginal pH above 4.5 had a threefold increased risk of preterm PROM as compared with those with a mean pH of 4.5 or lower. Vaginal pH may be a useful marker to predict a woman's risk for preterm PROM.

Female↗
PubMed1988

Identification of women at high risk for preterm-low-birthweight births.

Preterm-low-birthweight births comprise a subset of extremely high-risk low-birthweight infants. While numerous studies have evaluated risk factors to predict an individual's chance of a high-risk pregnancy, few have identified risk factors specifically related to preterm-low-birthweight births. Risk factors for preterm-low-birthweight births were analyzed in a sample of 11,623 women from northwest North Carolina enrolled in a low-birth-weight prevention program. Significant risk factors for preterm-low-birthweight births in this population were identified, and weights were assigned to each factor. Application of the weighting system to each patient's specific risk factors identifies women at high risk for a preterm-low-birthweight birth and assists in the determination of appropriate intervention. These data make use of all current information in the low-birthweight births prevention project. Prospective assessment of the scoring system as the project continues should improve the ability to identify and intervene with women at highest risk for a preterm-low-birthweight birth.

Adult↗
PubMed1988

Design, synthesis, and biological activity of a peptide mimic of vasopressin.

Our molecular modeling studies suggested that the conformational effects of the "cystine-line" residue Pmp1-Cys6 on the cyclohexapeptide ring of the vasopressin antagonist [Pmp1,D-Phe2,Val4]AVP might be mimicked by substitution of D-aminoadipic acid at position 6 and cyclization of its side-chain carboxyl to the alpha-amine of residue 2. The peptide was prepared with DL-aminoadipic acid, and following cyclization, the two diastereomeric peptides were separated and purified by preparative high-performance liquid chromatography. The structure of each was confirmed by amino acid analysis and fast atom bombardment mass spectrometry. The chirality of the aminoadipic acid residue of each peptide was determined by chiral gas chromatography. The circular dichroism spectrum of each peptide was run and compared with the appropriate agonist and antagonist peptide standards. These peptides demonstrated in vitro poor V2-receptor affinity and an inability to inhibit or stimulate vasopressin-induced adenylate cyclase formation, suggesting that they lack one or more key features of the agonist/antagonist pharmacophore.

Adenylyl Cyclase Inhibitors↗
PubMed1988

A comparison of women in and out of a prematurity prevention project in a North Carolina perinatal care region.

We assessed a prematurity prevention project in a North Carolina region with 21,000 annual births in terms of its impact on low birthweight. Project records were matched to birth certificates in order to compare characteristics of women in and out of the program who received prenatal care from private providers. A logistic regression analysis, in which the effects of race, marital status, age, and other risk factors for low birthweight were statistically controlled, showed that women not in the project were 1.32 times (95% Confidence Interval 1.14, 1.54) as likely as project participants to have a birth under 2500 grams. The relative risk for non-participants for a birth under 1500 grams was 1.87 (95% CI 1.25, 2.80). Strengths and limitations of the study are discussed. The results are consistent with previous work examining the etiologies of low birthweight in private versus public patients.

Adolescent↗
PubMed1987

Causes of low birth weight births in public and private patients.

This examination of the cause of low birth weight births in two model populations, one of public and one of private patients, finds significant differences in the reasons for low birth weight births in the two groups. Idiopathic premature labor was related to 47.1% of private low birth weight births, but only 24.8% of public births; low birth weight term (26.7%) and premature rupture of fetal membranes (33.7%) were more common in public low birth weight births than in private births (13.8% and 23.0%, respectively). Medical problems were related to 16.1% of private and 14.9% of public low birth weight births. Since current prematurity prevention methods are most likely to prevent low birth weight births related to idiopathic premature labor, the relative success of such programs in reducing the rate of low birth weight births is likely to depend on the characteristics of the patient population to which the programs are directed.

Ethnicity↗