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R Conklin

Publications and source records attributed to R Conklin.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models.

It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED25), ED50, ED75, and 1 log10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).

Amphotericin B↗
PubMed2004

Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis.

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to infinity values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R(2) = 83%; peak serum drug/MIC ratio R(2) = 85%; time that serum levels of posaconazole remained above the MIC R(2) = 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean +/- SD = 16.9 +/- 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.

Animals↗
PubMed2003

In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model.

In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (R(2) for AUC/MIC ratio = 82%, R(2) for peak level/MIC ratio = 63%, R(2) for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean +/- standard deviation, 24 +/- 17 [P = 0.45]). These AUC/MIC ratios observed for free drug are similar to those observed for other triazoles in this model.

Administration, Oral↗
PubMed2003

In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model.

In vivo pharmacokinetic/pharmacodynamic characterization for numerous antibacterial compounds has had a significant impact upon optimal dosing regimen design and the development of in vivo susceptibility breakpoints. More recently, similar characterization has been undertaken for antifungal drug classes. Very little is known of these pharmacodynamic relationships for the new echinocandin class of compounds. We utilized a neutropenic murine model of disseminated candidiasis to describe the time course antifungal activity of HMR 3270, a new glucan synthase inhibitor. Single-dose in vivo time kill studies with four 16-fold escalating doses demonstrated concentration-dependent killing when drug levels in serum were more than four times the MIC. Postantifungal effects were dose dependent, ranging from 8 to 80 h duration. Multiple dosing regimen studies utilized six total doses, four dosing intervals, and a treatment duration of 6 days. Shortening the dosing interval from every 144 h (q144h) to q36h resulted in a fourfold rise in the dose necessary to achieve a net fungistatic effect. The peak/MIC ratio most strongly correlated with treatment outcomes (peak/MIC ratio, R(2) = 98%; ratio of the area under the concentration-time curve from 0 to 24 h to the MIC, R(2) = 79%, percentage of time above the MIC, R(2) = 61%). Studies were also conducted with five additional Candida albicans isolates to determine if a similar peak/MIC ratio was associated with efficacy. In vivo concentration-dependent killing was similarly observed in studies with each of the additional isolates. The peak/MIC ratio necessary to produce efficacy was relatively similar among the strains studied (P = 0.42). The peak/MIC ratio (mean +/- standard deviation) necessary to achieve a fungistatic effect was 3.72 +/- 1.84, and the ratio necessary to achieve maximal killing was near 10.

Animals↗
PubMed2003

In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model.

In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for the AUC/MIC ratio as the PK/PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio, R(2) = 91%; peak/MIC ratio, R(2) = 85%; percent time above the MIC, R(2) = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean +/- SD = 20.3 +/- 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.

Animals↗
PubMed2001

Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model.

In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.

Amphotericin B↗
PubMed1995

A comparison of the effects of isoproterenol and forskolin on immunologic and nonimmunologic release of histamine from guinea-pig superfused trachea and dispersed tracheal cells.

This study has compared the abilities of isoproterenol and forskolin to inhibit immunologic- and nonimmunologic-induced histamine release from guinea-pig superfused trachea and enzymatically dispersed tracheal cells. Contraction was also measured in the former preparation. The potency of isoproterenol was similar for inhibition of all parameters associated with immunologic (ovalbumin) challenge in the two preparations. In contrast, forskolin appeared less potent in inhibiting ovalbumin-induced histamine release from dispersed tracheal cells. Histamine release by the nonimmunologic secretagogues d-tubocurarine and compound 48/80 was not altered by either substance. However, inhibition by isoproterenol and forskolin of tracheal contraction was evident when challenge was conducted with d-tubocurarine and compound 48/80. Inhibition of contraction appears to be a result of functional antagonism at the level of the smooth muscle. The superfused trachea is a useful preparation in which to explore the effects of substances that modulate mast cell mediator release.

Animals↗
PubMed1993

Pharmacologic modulation of the influence of the epithelium on immunologic- and nonimmunologic-induced histamine release and contraction in guinea pig superfused tracheal strips.

The influence of the epithelium on contractions and histamine release evoked by ovalbumin and d-tubocurarine has been examined in guinea pig superfused tracheal strips under several experimental conditions. Without drug pretreatment, removal of the epithelium resulted in larger (P < .05) total histamine released by ovalbumin, 10(-4) to 10(-1) mg/ml, and by d-tubocurarine, 3 x 10(-3) M. In the presence of indomethacin, 5 x 10(-6) M, epithelium removal resulted in elevated histamine release only at smaller ovalbumin concentrations, 10(-4) and 10(-3) mg/ml. Indomethacin did not change the influence of the epithelium on histamine release by d-tubocurarine. Indomethacin treatment abolished the influence of the epithelium on ovalbumin-induced tracheal contraction. With indomethacin, larger (P < .05) histamine release was seen with ovalbumin, 10(-1) and 1 mg/ml, when the epithelium was intact. The larger histamine release in response to ovalbumin, 10(-1) mg/ml, in the presence of the epithelium was unaltered by pyrilamine, 10(-6) M, cimetidine, 10(-4) M, and thioperamide, 10(-6) M, to block histamine H1, H2 and H3 receptors, respectively. Therefore, histamine released by ovalbumin does not stimulate histamine release through an action on these receptors when the epithelium is intact. In the presence, but not in the absence, of the epithelium, A64077, 10(-5) M, and ICI198615, 10(-8) and 10(-6) M, inhibitors of 5-lipoxygenase and LTD4/E4 receptors, respectively, inhibited histamine release by ovalbumin, 10(-1) mg/ml. Histamine release by ovalbumin, 10(-4) mg/ml, and d-tubocurarine, 3 x 10(-3) M, studied with or without epithelium was not altered by A64077 or ICI198615.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Studies of desensitization and cross-desensitization to immunologic and nonimmunologic stimuli that evoke contraction and histamine release in superfused guinea pig trachea.

This study examined the possibility that there is cross-desensitization between immunologic and nonimmunologic stimuli that evoke contraction and histamine release (HR) in the isolated guinea pig trachea. Compound 48/80 and D-tubocurarine were found to cause homologous and heterologous desensitization for both contraction and HR from superfused trachea. Specific antigen challenge of trachea obtained from animals sensitized with either IgG1 (ovalbumin [OA]) or IgE (oxazalone-human serum albumin [OX-HSA]) also resulted in homologous desensitization for both contraction and HR. However, in experiments with animals sensitized with both IgG1 and IgE antibodies, prechallenge with OA resulted in cross-desensitization to OX-HSA, whereas the reverse sequence was ineffective in eliciting this phenomenon. This may be related to the type of desensitization produced by each antigen (specific versus nonspecific) or to heterogeneity of mast cells in the tissue. Prechallenge of the trachea with compound 48/80 or D-tubocurarine failed to alter subsequent effects of antigen after active sensitization with OA or passive sensitization with either IgG1 or IgE antibodies. Small but statistically significant decreases in tracheal responses to D-tubocurarine were observed after antigen prechallenge to active both IgG1 and IgE antibodies. This is the first study to demonstrate a cross-desensitization between compound 48/80 and D-tubocurarine and the first to examine cross-desensitization with IgG1 and IgE antibodies in the guinea pig trachea. The overall conclusion is that there is no major overlap in the desensitization mechanisms between immunologic and nonimmunologic stimuli in the guinea pig trachea.

Animals↗
PubMed1990

Transplantation of adrenal medullary tissue to caudate nucleus using stereotactic techniques.

Stereotactic techniques were used to transplant adrenal medullary tissue to the head of the right caudate nucleus in 12 patients with Parkinson's disease. No significant lasting complications were seen. All patients had an initial improvement. 11 of the 12 patients remain improved over their preoperative condition after 6-18 months, 3 with good results and 9 with only modest improvement. At 6 months, the mean Schwab and England score had improved from 59.2 +/- 18.8 preoperatively to 75.8 +/- 15.1 (p less than or equal to 0.01) and the mean Hoehn and Yahr scale had improved from 3.42 +/- 0.90 to 2.92 +/- 0.63 (p less than or equal to 0.01).

Adrenal Medulla↗
PubMed1989

Flow cytometric analysis of megakaryocytes from patients with abnormal platelet counts.

Megakaryocytes (MKs) from 40 patients with quantitative platelet disorders and 19 normal volunteers were analyzed by flow cytometry for size, fine cell internal structure and granularity, membrane expression of the glycoprotein (GP) IIb/IIIa complex, and for ploidy distribution. Analysis was performed on unfractionated minimally manipulated marrows obtained from routine bone marrow aspirates. MKs were labeled with a fluorescent lineage-specific monoclonal antibody to the GPIIb/IIIa complex followed by DNA staining with propidium iodide. Eight hundred to 3,000 MKs were analyzed in each sample. The modal ploidy distribution in normals was 16N, comprising about half of the megakaryocytic population, with 22.6% of the cells less than or equal to 8N and 22.0% greater than or equal to 32N. Twelve thrombocytopenic patients with decreased marrow MKs on biopsy (mean platelet count [MPC] 44,600/microliters) showed an increase in low ploidy cells with 53.2% less than or equal to 8N (P less than .01); cell size was reduced in three patients when compared to normal cells of identical ploidy (P less than .05). Eight thrombocytopenic patients with enhanced platelet destruction (with normal or increased MKs on biopsy and shortened platelet survival; MPC 41,400/microliters) showed an increased proportion of high ploidy cells greater than or equal to 32N to 39.2% (P less than .01). Increased cell size and granularity were found in four of these patients (P less than .05). Six patients with thrombocytopenia secondary to multiple mechanisms affecting both platelet production and destruction (MPC 66,700/microliters) showed no shift in ploidy. Four patients with primary thrombocytosis (two with thrombocythemia and two with polycythemia vera; MPC 822,500/microliters) showed a marked shift toward high ploidy cells with 42.3% greater than or equal to 32N and 7.6% greater than or equal to 64N cells (P less than .01). The shift was accompanied by a marked increase in cell size and granularity in the patients with thrombocythemia. Ten patients with thrombocytosis secondary to chronic blood loss, malignant or inflammatory disorders (MPC 714,000/microliters), showed variable distributions with four patients exhibiting a shift in ploidy to the right similar to that found in the patients with increased platelet destruction. Based upon the present data, flow cytometric ploidy distribution may be diagnostically useful in thrombocytopenic patients by discriminating between disorders of platelet production and destruction. (ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow↗
PubMed1988

Renal function studies during intravenous acyclovir treatment of immune suppressed patients including renal transplantation.

We assessed the effect of acyclovir therapy on renal function during a course of therapy for herpesvirus disease. Renal function was assessed by measuring the clearances of inulin, albumin, and beta 2-microglobulin at the beginning and end of acyclovir therapy. Thirty-two patients had valid paired inulin clearances and 21 had valid paired albumin and beta 2-microglobulin clearances. No significant mean decrement of renal function was observed; however, 2 patients had a reversible renal dysfunction associated with acyclovir therapy which disappeared soon after discontinuation of the drug and was unassociated with a prior or recurrent renal dysfunction in short-term follow-up.

Acyclovir↗
PubMed1980

Rotavirus antibody in chickens as measured by enzyme-linked immunosorbent blocking assay.

The antibody titer of 202 chickens to SA-11 rotavirus was determined by enzyme-linked immunosorbent blocking assay. The chickens were from 15 separate flocks on six farms. The titer was detectable (1:18 or greater dilution) in 43% of the chickens. The wide variation in infection rate between flocks on individual farms (0% to 90%) indicated there is probably not significant transmission of the virus between flocks on the farm. Significant differences in numbers of serotest-positive birds were found between separate farms, possibly reflecting different management practices.

Animals↗