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Biomedical subjects

E G Maderazo

Publications and source records attributed to E G Maderazo.

At least 19 recordsLinked to original sources
PubMed1992

Simplification of antibiotic dose adjustments in renal insufficiency: the DREM system.

Many clinicians, unassisted by reference books, are unable to make the required dose adjustment of antibiotics needed when a patient has renal insufficiency. We describe the DREM (dosing in renopathy by easy-to-use multipliers) system, which simplifies the understanding and the process of dose adjustment. DREM is a two-step process: Cockcroft and Gault estimation of creatinine clearance (CLcr) from age, sex, and serum creatinine and calculation of the adjusted dose or dosing interval by multipliers. If the normal dose is multiplied by the dose multiplier (CLcr/100) and the dosing interval by the interval multiplier (100/CLcr), the adjusted dose and interval, respectively, are obtained. Theoretical trough concentrations calculated with the DREM system correlated closely (r = 0.9) with actual concentrations obtained from doses calculated by the Hull and Sarubbi method in 23 patients. With DREM, gentamicin or tobramycin trough concentrations above 2 micrograms/ml were less likely to occur. The DREM system is a simple and easily remembered method for dose adjustments of certain anti-infective agents in renal insufficiency. Dose estimates with this method are reasonably accurate and compare favourably with other standard methods of correction.

Anti-Bacterial Agents↗
PubMed1992

Lomefloxacin concentrations in bone after a single oral dose.

We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 micrograms/mL at 2 hours post-dose and 3.0 micrograms/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still greater than 1.0 microgram/mL. Two hours after dosing the average bone-to-plasma ratio was greater than 0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.

Administration, Oral↗
PubMed1992

Characterization of a direct effect of phorbol myristate acetate on human neutrophil cell membrane using 31D8 monoclonal antibody.

We found that 4-beta-phorbol 12-myristate 13-acetate (PMA) caused decreased expression of the polymorphonuclear neutrophil (PMN) surface antigen 31D8. In contrast to the rapid initiation of the oxidative burst caused by PMA, the effect was slow to start but increased during incubation periods up to 50 min. To study this apparent protein kinase C-independent late effect of PMA, we measured 31D8 expression in PMNs after incubation with various concentrations of PMA. The maximum PMA-induced inhibition was 76 +/- 2%, with an ID50 of 3.9 +/- 0.4 ng/ml. Oxidants and prooxidants (hydrogen peroxide, hypochlorite, taurine-chloramine, and ferrous iron, with or without H2O2) had no direct effect on 31D8 antigen expression. The following substances were not protective against the inhibitory affect of PMA: (1) antioxidants (superoxide dismutase, catalase, azide, dimethyl sulfoxide, Desferal, and ascorbate, with the exception of alpha-tocopherol), (2) inhibitors of protein kinase C (H7 and W7), (3) inhibitors of 5-lipoxygenase (A-63162, MK886, and high-dose indomethacin) and (4) inhibitors of cyclooxygenase (low-dose indomethacin). Myeloperoxidase-deficient PMNs had normal 31D8 antigen expression and a decrease of 31D8 antigen expression by PMA, as did normal PMNs. The inactive analog of PMA, 4-alpha-phorbol didecanoate, had no effect on 31D8 antigen expression. alpha-Tocopherol (50 micrograms/ml) and betamethasone (150 micrograms/ml) protected against the PMA effect by 30.5 +/- 7.3 (P less than .0005) and 52 +/- 15 (P less than 0.004) channels, respectively. These results indicate that PMA has a protein kinase C-independent late effect on human neutrophils, which can be prevented by pretreatment with alpha-tocopherol or the steroid betamethasone. These compounds probably exert their protective effect by membrane stabilization.

Acetamides↗
PubMed1991

Characteristics of ceftriaxone binding to immunoglobulin G and potential clinical significance.

The interaction between immunoglobulin G (IgG) and ceftriaxone was studied. Using an ultrafiltration method, we performed dose ranging studies at a ceftriaxone concentration range of 1 to 720 micrograms/ml in the presence of various concentrations of human IgG, human serum albumin (HSA), and combinations of IgG and HSA at pH 7.4 and 37 degrees C. The results showed that ceftriaxone binding to IgG was nonlinear and was consistent with the presence of two binding sites that possess different binding capacities and affinities. Except for increased peak percent binding as the IgG concentration increased, the binding characteristics did not change with IgG concentration. Binding to HSA was consistent, with the presence of only one high-affinity binding site. A mathematical model based on the observed data was constructed; this model was used to predict protein binding at various concentrations of drug, IgG, HSA, or combinations of IgG and HSA in buffer and in plasma medium. Correlations between the observed versus the predicted values were excellent in both media. Simulations with the model indicated that patients with hypergammaglobulinemia have an increased potential of being exposed to prolonged subinhibitory concentrations of ceftriaxone if the drug is given once every 24 h.

Ceftriaxone↗
PubMed1991

Modulation of neonatal neutrophil function by pentoxifylline.

Immunomodulating agents are being investigated for treatment of infection in newborn infants where morbidity and mortality remain high despite the continued development of new antibiotics. We studied the effect of the methylxanthine pentoxifylline on polymorphonuclear leukocyte (PMN) chemotaxis, F-actin content, and phagocytic activity as measured by nitroblue tetrazolium reduction and H2O2 production in neonates and adults to determine whether pentoxifylline might be useful in augmenting PMN function. The drug was found to have a dose-dependent effect on both neonatal and adult PMN function with enhancement at lower concentrations and suppression at higher concentrations. PMN chemotaxis increased 42% (p less than 0.01) in neonates and 16% (p less than 0.05) in adults at 100 micrograms/mL of pentoxifylline and it decreased 4 and 25%, respectively, at 4000 micrograms/mL. PMN nitroblue tetrazolium reduction increased by 34% in neonates and 23% (p less than 0.05) in adults at 100 micrograms/mL of pentoxifylline and decreased by 52 (p less than 0.01) and 74% (p less than 0.01), respectively, at 2000 micrograms/mL. Similar dose-dependent responses were noted with F-actin content and H2O2 production. These and other observations support the hypothesis that pentoxifylline has a broad range of effects on PMN but that a primary effect is alteration of PMN deformability. Pentoxifylline has potential clinical use as an immunomodulator in augmenting impaired PMN function in neonates and other immunocompromised hosts or in suppressing excessive PMN activity in certain disease processes.

Actins↗
PubMed1991

A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma.

Studies in patients with serious trauma indicate that the observed neutrophil (PMN) locomotory dysfunction is partly the result of auto-oxidation as shown by evidence of preactivation, diminished reducing capacity, and low serum and cellular ascorbic acid and alpha-tocopherol. To investigate whether replacement of the antioxidant vitamins ascorbic acid and alpha-tocopherol can improve the PMN locomotory defect, ascorbic acid, alpha-tocopherol, ascorbic acid and alpha-tocopherol, or placebo was administered to a total of 46 victims of blunt trauma. PMN locomotion was quantitated using a micropore filter assay. Locomotion data were analyzed by repeated measures analysis with a split plot design and data for days 2-6 after injury were compared. Compared with placebo, the antioxidants improved PMN locomotion. The mean differences in distance migrated (treated minus placebo) were ascorbic acid and alpha-tocopherol = 11.3 +/- 3.0 microns (one-tailed p = 0.001) (mean +/- SE); ascorbic acid = 4.7 +/- 3.4 microns (p = 0.19); and alpha-tocopherol = 3.3 +/- 2.9 microns (p = 0.27). Although both antioxidants given together produced the best results, a plot of the 95% confidence intervals indicates that ascorbic acid and alpha-tocopherol, either given alone, were also better than placebo. We conclude that antioxidant replacement therapy significantly improves the PMN locomotory abnormality in blunt trauma.

Adult↗
PubMed1990

The role of cellular maturation in neutrophil heterogeneity.

Previous studies have shown that many neutrophil (PMN) characteristics are heterogeneous but the origin of PMN heterogeneity is unknown. It is unclear if PMN functional heterogeneity is secondary to maturational differences or due to distinct subpopulations of cells that possess different functional capacities. The PMN 31D8 antigen is a useful probe for evaluation of PMN subpopulations. The majority of PMNs (approximately 85%) exhibit a high intensity fluorescence after 31D8 monoclonal antibody (MoAb) labeling (31D8 enriched or "bright" PMNs) as determined by flow cytometric analysis. These cells are more functional than cells with low intensity fluorescence (31D8 diminished or "dull" PMNs). Various immunologic, clonogenic and functional techniques were used to study the expression of the 31D8 antigen in HL-60 cells and myeloid cells in order to evaluate antigenic and functional heterogeneity during morphologic maturation. The results of this study indicate that the percentage of 31D8 antigen positive (31D8 antigen enriched and diminished) bone marrow cells increases from 20 +/- 11% in myeloblast cells to 68 +/- 10% in promyelocytes, 93 +/- 2% in myelocytes and 99 +/- 1% in bands and PMNs. 31D8 antigen enriched cells first appear at the myelocyte stage (32 +/- 10%) and increase in bands (52 +/- 13%), marrow PMNs (62 +/- 13%) and peripheral blood PMNs (88 +/- 4%). These data indicate that the heterogeneous expression of 31D8 antigen in PMNs is due, at least in part, to maturational differences within the PMN population and raise the possibility that other heterogeneously expressed PMN characteristics are also maturationally derived. They also suggest that 31D8 antigenic expression may be a more precise indicator of myeloid functional maturation than maturation as identified by cellular morphology.

Antigens, Surface↗
PubMed1990

Additional evidence of autoxidation as a possible mechanism of neutrophil locomotory dysfunction in blunt trauma.

Previous studies in victims of blunt injury suggest that the observed neutrophil (PMN) locomotory dysfunction is, in part, due to autoxidation. To further clarify the occurrence and significance of autoxidation, we studied changes in levels of glutathione in PMN and of ascorbic acid and alpha-tocopherol in serum and blood cells of postsurgical and blunt trauma patients. Levels of total, reduced, and oxidized glutathione in PMN from trauma patients were similar to normal controls. Serum and cellular ascorbic acid and alpha-tocopherol levels dropped significantly after injury and remained below normal control levels during the 7 to 8-day study period. Low serum alpha-tocopherol was partially explainable on the basis of changes in serum lipids. When serum samples of trauma patients were thawed unprotected without pyrogallol, there was significant loss of recoverable alpha-tocopherol, whereas no significant losses occurred with unprotected thawed normal sera. Less total reducing capacity was observed in PMN of trauma patients compared with normal controls. These findings indicate that synthesis and regeneration capacity of glutathione are intact but that the levels of the consumable antioxidants, ascorbic acid, and alpha-tocopherol are compromised after injury. These results add further support to the hypothesis that autoxidation occurs in trauma.

Adolescent↗
PubMed1990

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections.

Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10(8) Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PTX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug. PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).

Animals↗
PubMed1989

Pitfalls in testing drug uptake by leukocytes using radiolabeled drugs and an explanation of conflicting results with clindamycin.

Although studies of drug uptake by leukocytes use similar methods, the results reported are sometimes vastly different. To determine the possible reasons for this, we studied neutrophil uptake of [3H]-clindamycin using the most frequently used density gradient centrifugation method and the volume probes 3H2O and [3H]-polyethylene glycol. We found that the [3H]-clindamycin available to investigators had undergone radiolytic decomposition; thus, its microbiologic activity was only 20% of its original potency. By thin-layer chromatography and autoradiography, four extra label-bearing regions were observed with [3H]-clindamycin. Results of neutrophil uptake studies have shown a drop of cellular:extracellular concentration ratios from 40:1 in 1981 to 10:1 in 1982 and 1987.

Chromatography, Thin Layer↗
PubMed1988

Indomethacin-associated sepsis in very-low-birth-weight infants.

Indomethacin sodium promotes closure of the patent ductus arteriosus in premature infants. In addition to renal and gastrointestinal side effects, indomethacin may predispose to infection because of inhibition of polymorphonuclear leukocyte (PMN) function. We retrospectively assessed the incidence of sepsis in a group of 58 premature infants with patent ductus arteriosus who received either oral indomethacin, surgery, or usual medical management. A significant increase in the incidence of sepsis was observed in the indomethacin-treated group compared with patients treated with surgery or usual medical management (seven of 31 vs one of 27). All episodes of sepsis occurred within one week of therapy. Patients in the indomethacin group who developed sepsis were less mature, had more gastrointestinal symptoms, and were less likely to survive than nonseptic indomethacin-treated patients. Nine patients studied prospectively showed no difference in PMN chemotaxis and adherence before and after indomethacin administration. Neither adult nor neonatal cord PMN chemotaxis was inhibited following in vitro incubation with concentrations of indomethacin ranging from 1 to 1000 mg/L. Bactericidal activity of neonatal cord neutrophils was also unaffected by concentrations of indomethacin from 1 to 200 mg/L. These results suggest that oral indomethacin administration may predispose the very-low-birth-weight infant to the development of sepsis shortly after therapy is begun although the mechanism remains unclear.

Bacterial Infections↗
PubMed1988

The inhibitory effect of parenteral nutrition on recovery of neutrophil locomotory function in blunt trauma.

Twenty patients were investigated to determine whether total parenteral nutrition (TPN) influences the recovery of neutrophil (PMN) locomotory dysfunction in blunt trauma. Half were given TPN consisting of amino acids, glucose, electrolytes, and trace minerals, and half were given intravenous (I.V.) fluids consisting of 5% glucose in water or saline, electrolytes, and trace minerals. PMN locomotion was assayed using micropore filters. Analysis of the data by general linear modeling showed that PMN locomotion in TPN patients was significantly slower during the first 3 to 4 days postinjury. By sequential analysis, improved PMN function in the group not given TPN (NO TPN) occurred less than 95% of the time. TPN with amino acids and glucose may worsen and delay the recovery of PMN locomotory responses in blunt trauma, but the preference ratio of NO TPN:TPN for better PMN function was less than 95:5.

Adolescent↗
PubMed1988

High teicoplanin uptake by human neutrophils.

The cellular/extracellular (C/E) concentration ratio of teicoplanin in polymorphonuclear leukocytes (PMNs) increased rapidly with time (C/E 60 +/- 13 at 20 min). The C/E ratio was time- and concentration-dependent. At 20 min and an initial concentration of 75 +/- 16 micrograms/ml the cellular drug concentration was 4,700 +/- 1,300 micrograms/ml. The mechanism of drug uptake was by an active process and transported (cellular) drug retained its antimicrobial activity. Washing removed 42% of cellular drug. Teicoplanin inhibited PMN chemotaxis at very high concentrations and PMN microbicidal activity at lower concentrations.

Biological Transport, Active↗
PubMed1988

The influence of various factors on the accuracy of gallium-67 imaging for occult infection.

To examine whether the results and interpretation of gallium-67 citrate imaging may be adversely influenced by factors present in compromised patients, we reviewed our 1-year experience in 69 patients in intensive care units, renal transplants, and those on hemodialysis. Our results indicate that it is an inappropriate diagnostic procedure for acute pancreatitis since seven of nine had false-negative results. Using loglinear modeling and chi-square analysis we found that treatment with antiinflammatory steroids, severe liver disease, end-stage renal disease, and renal transplantation with immunosuppressive therapy did not interfere with gallium-67 uptake. Increased rate of true-negative results in patients with end-stage renal disease was due to a greater and earlier use of the test in the febrile transplant patient and in hemodialysis patients with infections not amenable to diagnosis with gallium-67 scan (transient bacteremia and bacteriuria). We conclude that gallium-67 imaging is a useful diagnostic tool that, with the exception of acute pancreatitis, has very few false-negative results.

Abdomen↗
PubMed1988

Late infections of total joint prostheses. A review and recommendations for prevention.

The incidence of late infection of total joint prostheses is 0.6%. Because this incidence has increased from 0.08% in 1978, the authors reviewed their experience and the literature in search of pathogenetic and preventative measures. The most common pathogen responsible for late prosthetic joint infections was staphylococcus (54%; both Staphylococcus aureus and Staphylococcus epidermidis), even when infection was of dental origin. The three most common origins of infection were skin and soft tissue (46%), dental (15%), and urinary (13%). Escherichia coli was the most common pathogen when the source was the urinary tract. Mortality and cost calculations indicate that chemoprophylaxis is justified for dental procedures and probably also for other surgical procedures in organs containing microflora. Prophylaxis must include antistaphylococcal drugs. The first generation cephalosporin antibiotics are recommended.

Adult↗