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Biomedical subjects

V A Johnson

Publications and source records attributed to V A Johnson.

At least 55 records · Page 3Linked to original sources
PubMed1994

Combination therapy: more effective control of HIV type 1?

The rationale for combining anti-HIV-1 agents is to provide more complete viral suppression, to limit the emergence of drug resistance during chronic viral replication, and to provide more effective antiretroviral treatment even when mixtures of drug-resistant and drug-sensitive strains are present. In vitro experiments reveal increased suppression with multiple-drug therapy, but viral breakthrough occurs after prolonged time in culture even during triple-drug therapy. Clinical results available to date indicate that drugs should be given simultaneously for optimal benefit. There appears to be a rationale for early initiation of combination therapy before the onset of increased viral burden and the emergence of syncytium-inducing viral variants. The results of ACTG protocol 155 revealed benefit of zidovudine and zalcitabine over monotherapy with either agent in patients with CD4+ cell counts > or = 150 cells/mm3. However, further clinical studies will be necessary before firm recommendations can be made about the indications for combination antiretroviral therapy in HIV-1-infected individuals at different stages of disease. Ultimately, we need better drugs, in combination, which significantly impact on HIV-1 burden to achieve more complete viral suppression and to reduce selection of drug-resistant viral variants.

Antiviral Agents↗
PubMed1994

Fetal pulse oximetry: a new method of monitoring the fetus.

Experimental pulse oximetry devices, similar to the existing systems used in adult and neonatal monitoring, can be used on the fetus to provide safe, and rapid information about oxygenation. They have been calibrated using fetal lambs and validated in human cross-sectional studies. Experiments have shown that fetal oxygen saturation decreases during normal labour, and drops after a uterine contraction especially with oxytocin-induced tachysystole. When the mother is given oxygen the fetal oxygen saturation increases. Readings are effected by caput and movement, and trends seem to be more meaningful than absolute values. Pulse oximetry can predict fetal outcome and a normal oxygen saturation result is specific for a good outcome perhaps even if the CTG is abnormal. However the technique is still experimental and there is insufficient data to support its use as a replacement for fetal blood sampling or a discriminator for an abnormal fetal heart trace.

Animals↗
PubMed1993

Decision analysis for best management of mildly dyskaryotic smear.

Should a woman with a mildly dyskaryotic cervical smear be referred for colposcopy or should the smear be repeated? One way to answer this question is to use decision analysis and compare the expected mortality and cost of each policy. Data for each component of the question were obtained from published work worldwide and were supplemented with an audit of mildly dyskaryotic smears in West Yorkshire, UK. 2 out of 1000 women with an initial mildly dyskaryotic smear will develop cancer if a conservative repeat smear policy is adopted in association with five-yearly cervical screening. This number can be reduced to 1.6 per 1000 if cervical screening is offered every three years. A policy of immediate referral for colposcopy is also associated with a subsequent cancer rate of 1.6 per 1000. Therefore, repeating the smear is almost as effective as an immediate referral to a colposcopy unit. Even if a five-yearly cervical screening programme is adopted, 2500 women with a mildly dyskaryotic smear will need to be referred for immediate colposcopy to save 1 additional cancer. A conservative policy is not financially cheaper: an average of six additional smears is required to save each colposcopy referral. Sensitivity analysis shows that the excess cost of the conservative policy increases exponentially as the risk of a subsequent cytological abnormality exceeds 60%. Local cytopathology laboratories should audit their recurrent dyskaryosis rate associated with borderline, mild, and moderate dyskaryosis before accepting the U-turn in the national recommendations.

Colposcopy↗
PubMed1993

Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group.

A standardized antiviral drug susceptibility assay for clinical human immunodeficiency virus type 1 (HIV-1) isolates has been developed for use in clinical trials. The protocol is a two-step procedure that first involves cocultivation of patient infected peripheral blood mononuclear cells (PBMC) with seronegative phytohemagglutinin-stimulated donor PBMC to obtain an HIV-1 stock. The virus stock is titrated for viral infectivity (50% tissue culture infective dose) by use of serial fourfold virus dilutions in donor PBMC. A standardized inoculum of 1,000 50% tissue culture infective doses per 10(6) cells is used in the second step of the procedure to acutely infect seronegative donor PBMC in a 7-day microtiter plate assay with triplicate wells containing zidovudine (ZDV) concentrations ranging from 0 to 5.0 microM. The ZDV 50% inhibitory concentrations (IC50) for reference ZDV-susceptible and ZDV-resistant HIV-1 isolates ranged from 0.002 to 0.113 microM and from 0.15 to > 5.0 microM, respectively. Use of this consensus protocol reduced interlaboratory variability for ZDV IC50 determinations with reference HIV-1 isolates. Among eight laboratories, the coefficient of variation ranged from 0.85 to 1.25 with different PBMC protocols and was reduced to 0.39 to 0.98 with the standardized assay. Among the clinical HIV-1 isolates assayed by the standardized drug susceptibility assay, the median ZDV IC50 increased gradually with more ZDV therapy. This protocol provides an efficient and reproducible means to assess the in vitro susceptibility to antiretroviral agents of virtually all clinical HIV-1 isolates.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Microanalytical high-performance liquid chromatographic assay for cefpirome in human milk and urine.

To permit the characterization of cefpirome disposition in lactating females, a previously published high-performance liquid chromatographic (HPLC) method for determining the drug in serum was adapted for use with milk and urine. This automated, microanalytical technique requires 50 microliters of biological matrix, which is subjected to an isopropanol extraction. Chromatography was accomplished using a microbore HPLC system, a reversed-phase C18 column and a mobile phase of 0.3% triethylamine in water (pH 5.1). Cefpirome and the internal standard (beta-hydroxypropyltheophylline) were monitored using UV detection at 240 nm and had retention times of 2.84 and 5.05 min, respectively. The method was linear up to 500 mg/l for both matrices and had a limit of detection of 0.6 mg/l. The interday variation (relative standard deviation) at concentrations of 5.0, 50.0 and 500.0 mg/l was consistently less than 5% in both urine and breast milk. The method was found to be free from interference by other commonly administered medications and readily adaptable for use in clinical investigations. The ease of sample preparation, small sample volume requirement, short chromatographic time, apparent lack of interferences, analytical sensitivity and high precision and accuracy make this method ideal for use in pharmacokinetic investigations involving the determination of cefpirome in human milk and urine.

Cephalosporins↗
PubMed1992

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.

Acetaminophen↗
PubMed1992

Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro.

Protease inhibitor Ro 31-8959, a compound that interrupts human immunodeficiency virus (HIV)-specific formation of infectious virions, was evaluated in two-drug combined regimens with zidovudine, 2',3'-dideoxycytidine (ddC), or recombinant interferon-alpha A (rIFN-alpha A) against HIV-1 replication in vitro. By using peripheral blood mononuclear cells infected with HIV-1, drug interactions were evaluated by the median-effect principle and the isobologram technique. A zidovudine-sensitive and -resistant HIV-1 isolate pair was studied. Additive to synergistic anti-HIV-1 interactions were seen with 7.5-30 nM Ro 31-8959 and 0.005-0.02 microM zidovudine (for the zidovudine-sensitive HIV-1 isolate), 0.25-1.0 microM zidovudine (for the zidovudine-resistant HIV-1 isolate), 0.025-0.1 microM ddC, and 8-32 units/mL rIFN-alpha A, without additive toxicity. Phase I/II clinical trials of Ro 31-8959 for therapy of HIV-1 infection are in progress. If results are favorable, combined regimens including Ro 31-8959 deserve consideration for future clinical trials.

Cells, Cultured↗
PubMed1992

Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro.

The combination of zidovudine (AZT) and 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro with AZT-sensitive and AZT-resistant clinical isolates and HIV-1IIIB. Synergy was determined by the median-effect principle and isobologram techniques. Cytotoxicity of the agents was not observed. Clinical trials are ongoing to define the combination's role in HIV-1 therapy.

Drug Combinations↗
PubMed1991

Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children.

Ibuprofen was evaluated as an antipyretic agent in 178 children (aged 3 months to 12 years) to compare dosage (5 vs 10 mg/kg), establish absolute efficacy (with a placebo control group), determine relative efficacy (ibuprofen vs acetaminophen), evaluate maximum efficacy, and identify potential confounding variables. Ibuprofen 5 mg/kg was minimally effective in children less than 6 years of age who had an initial temperature of at least 38.8 degrees C (101.9 degrees F). Ibuprofen 10 mg/kg was more effective for febrile children. The area under the curve for temperature (or change in temperature) captured the net effect of each drug and provided the best estimate for efficacy comparison during a defined period. A linear correlation between initial temperature and measures of efficacy was observed. A twofold increase in efficacy was observed for children with an initial temperature less than 38.8 degrees C. A similar effect was noted for each treatment group. Age was also found to have confounding effects on antipyretic response. A complex interaction between antipyretic response, initial temperature, and age raises questions about the pharmacodynamics of the antipyretic response. We conclude that the most important variable in antipyretic study design is initial temperature. The influence of initial temperature on the magnitude of the response to an antipyretic drug is a previously unappreciated finding with potential impact on pharmacodynamic investigations of antipyretic medications. We describe this finding as nonlinear pharmacodynamics.

Acetaminophen↗
PubMed1991

Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro.

Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of anti-HIV-1 agents. Zidovudine (AZT, 3'-azido-3'-deoxythymidine), didanosine (ddI, 2',3'-dideoxyinosine), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in two-drug regimens against replication of AZT-resistant HIV-1 in vitro. AZT-sensitive and AZT-resistant isolate pairs derived from two individuals before and after extended AZT monotherapy were studied. Drug interactions using peripheral blood mononuclear cells infected with HIV-1 were evaluated mathematically. Synergistic interactions were seen among AZT, ddI, and rIFN-alpha A in two-drug regimens against AZT-resistant HIV-1 in vitro, even when AZT was included in the treatment regimen. Mixtures of wild-type and mutant reverse transcriptase genes were found in one of the late-AZT therapy isolates, suggesting that the mechanism of synergy of AZT-containing regimens may involve inhibition of AZT-sensitive viruses in the viral pool. These studies suggest that AZT may be useful in drug combination regimens, even when AZT-resistant viruses are isolated in vitro.

Base Sequence↗
PubMed1991

Fetal monitoring with pulse oximetry.

Continuous fetal monitoring was achieved with a fetal scalp pulse oximetry sensor in 86 labours. The average recorded fetal oxygen saturation in early labour (cervical dilatation less than 5 cm) was 68% (SD 13%). At the end of labour (cervical dilatation greater than or equal to 9 cm) the recorded mean oxygen saturation was 58% (SD 17%). The largest range of readings during a single labour was 81%-11% but this drop was associated with cord compression. The average SD during 1 h of normal labour was 10%. A second group of 40 fetuses was monitored during induction of labour before and after elective amniotomy. Oxygen saturation did not appear to change after amniotomy (mean change -0.4%, SD 1.2%) and there was no difference between mean antenatal or early intrapartum readings. We excluded the amniochorionic membranes as a possible source of data corruption by measuring their in vitro absorption spectra and confirming that they do not preferentially absorb light of either 660 or 940 nm wavelength. Non-invasive pulse oximetry can be used to monitor the fetus before and during labour.

Amnion↗
PubMed1991

The accuracy of fetal pulse oximetry in the second stage of labour.

The aim of this study is to assess the accuracy of fetal monitoring with pulse oximetry at delivery. The pulse oximetry reading from the fetus at delivery was compared to fetal condition at birth. There is poor correlation between fetal scalp oximetry readings at delivery and fetal condition (Apgar scores), umbilical venous or arterial blood gas analysis or pH. Although there are good theoretical reasons why the correlation should not be perfect, the wide deviation from expected values suggest that readings taken during delivery are particularly prone to errors. Examination of the unprocessed photodetector signal during the second stage of labour reveals considerable movement interference. The signal may also be affected by congestion and transmitted venous pulsation in the scalp as the head crowns. The current generation of reflectance pulse oximeters can predict fetal hypoxemia during labour but a single reading during delivery is subject to too much movement interference to produce useful data.

Cardiotocography↗
PubMed1990

Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A.

Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of agents that attack different targets in the viral replicative cycle. Zidovudine (AZT), recombinant soluble CD4 (rsCD4), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in 2- and 3-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells and a CD4+ T cell line (H9) were studied using multiple HIV-1 replicative end points. Drug interactions were evaluated by the median-effect principle and the isobologram technique. AZT, rsCD4, and rIFN-alpha A inhibited HIV-1 synergistically in 2- and 3-drug combinations. The 3-drug regimen provided more complete virus suppression than the 2-drug regimens. In H9 cells, single-drug regimens lost effectiveness at 10-14 days and 2-drug regimens lost effectiveness at 14-18 days. In contrast, the 3-drug regimen showed nearly complete suppression over 28 days in culture without toxicity. Clinical trials of these 3 drugs in combination should be considered.

CD4 Antigens↗
PubMed1990

The effect of caput succedaneum on oxygen saturation measurements.

Advances in oximetry have allowed the obstetrician to measure oxygen saturation in the fetus with non-invasive transcutaneous techniques. The influence of caput succedaneum formation on the oxygen saturation results obtained with a pulse oximeter was studied in 30 newborn infants. Caput was associated with a reduced oxygen saturation reading (mean reduction of 15%; P less than 0.001). This effect is partly due to a true drop in local tissue oxygenation but is exacerbated by a systematic error intrinsic to the physics of spectrophotometry. If continuous intrapartum oximetry is ever to become a part of routine obstetric monitoring then probes that pass through the cervix beyond the caput of the presenting part will be required if erroneously low readings are to be avoided.

Edema↗