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Biomedical subjects

D J Freeman

Publications and source records attributed to D J Freeman.

At least 55 records · Page 3Linked to original sources
PubMed1991

Tolerance to nicotinic acid flushing.

The mechanism of tolerance to nicotinic acid flushing was determined in subjects during a 5-day course of treatment. Objective measures of skin blood flow were used to confirm the development of tolerance. Plasma levels of nicotinic acid showed marked intraindividual variability but were not decreased with the development of tolerance. However plasma levels of 9-alpha 11-beta prostaglandin F2, a stable metabolite of prostaglandin D2, became undetectable in most subjects with the development of tolerance. Thus tolerance is not associated with decreased levels of nicotinic acid or development of tolerance to the prostaglandin mediator, but with decreased levels of the mediator.

Administration, Oral↗
PubMed1991

The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir.

The lips of 196 patients with a history of sun-induced herpes labialis were exposed to experimental ultraviolet radiation (UVR) and treated with acyclovir (ACV) or placebo at different times and by different routes. Of 98 placebo recipients, 39 (40%) developed 43 lesions inside or within 10 mm of the irradiated zone. The temporal distribution of lesions was bimodal. 11 (26%) occurring within 48 h (immediate) and 32 (72%) 2-7 days after UVR exposure (delayed). Prophylactic peroral ACV begun 7 days before or 5 min after UVR prevented the development of the delayed but not the immediate lesions (P less than .001). When peroral ACV was started 48 h after UVR, delayed lesions developed but were less severe (P = .01-.05). Prophylactic topical ACV begun 5 min after UVR did not reduce lesion frequency or severity. ACV therapy can be efficacious, but some rapidly developing lesions are unresponsive to treatment. This suggests that more than one process may contribute to the pathogenesis of herpes labialis.

Acyclovir↗
PubMed1991

The cyclosporin-erythromycin interaction: impaired first pass metabolism in the pig.

1. The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 2. Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days. 3. Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation. This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data. 4. The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 5. Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax. 6. The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.

Animals↗
PubMed1991

Ocular pharmacokinetics of subconjunctivally administered cyclosporine in the rabbit.

The authors assessed the ocular toxicity and pharmacokinetics of subconjunctivally and intravenously administered cyclosporine in New Zealand white rabbits. Fifteen rabbits received a subconjunctival injection of 5 (five animals), 10 (five animals) or 25 (five animals) mg of cyclosporine in 0.1 mL (intravenous solution of Sandimmune [50 mg/mL]); 5 mg was found to be the maximum tolerable dose. This dose was given as a bolus to 36 other rabbits either subconjunctivally (18 animals) or intravenously (18 animals). In both groups the cyclosporine concentrations in the ocular compartments, blood and urine were measured by means of high-pressure liquid chromatography at 0.5, 1, 2, 4, 8 and 12 hours, three animals being assessed at each interval. Subconjunctival administration resulted in peak cyclosporine concentrations of 718 ng/mL in the aqueous humour and 1078 ng/mL in the vitreous humour, compared with no detectable levels in the aqueous humour and a peak concentration of 292 ng/mL in the vitreous following intravenous administration. The peak blood cyclosporine levels were 10 times lower after subconjunctival injection than after intravenous injection. The results indicate that subconjunctival administration is superior to intravenous administration in enhancing the ocular absorption of cyclosporine while minimizing systemic exposure in the rabbit.

Animals↗
PubMed1990

Topical treatment of cutaneous herpes simplex virus infections.

Topical antiviral chemotherapy has a number of potential advantages over systemic drug delivery for the treatment of cutaneous herpes simplex virus infections, including convenience; higher target tissue drug levels and greater efficacy; and specific targeting of the drug to the site of infection, with reduced cost and reduced exposure of the remainder of the body to drug side effects. Realization of these possibilities has been slow in part because of the paucity of 'active' topical drug formulations with effective penetration-enhancing agents and a technical barrier-our failure as yet to measure drug levels in the epidermis, which could guide formulation development. Recent success with a topical treatment for herpes simplex labialis should stimulate continued laboratory and clinical research in this field.

Administration, Topical↗
PubMed1990

Polymorphisms in the gene coding for cholesteryl ester transfer protein are related to plasma high-density lipoprotein cholesterol and transfer protein activity.

1. Cholesteryl ester transfer protein activity may have a physiological effect on high-density lipoprotein levels. 2. We examined restriction fragment length polymorphisms associated with the cholesteryl ester transfer protein gene and the apolipoprotein AI gene in a group of 60 unrelated subjects selected from an initial survey of 5000 subjects on the basis of their high-density lipoprotein levels being high or low at the extremes of the distribution. The activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase (phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) were also determined. Analysis by selection of those with a low high-density lipoprotein cholesterol level (less than or equal to 1.1 for males, less than or equal to 1.2 for females) gave 32 individuals with 24% B2 alleles. Selection of subjects with a high-density lipoprotein cholesterol level (less than or equal to 2 mmol/l) gave 17 with 62% B2 alleles. 3. The group with low levels of high-density lipoprotein cholesterol had higher activity of cholesteryl ester transfer protein and significantly elevated triacylglycerol levels when compared with the group with high levels of high-density lipoprotein cholesterol. 4. A further significant finding was the correlation of the MspI restriction fragment length polymorphism detected by the apolipoprotein AI gene with lecithin:cholesterol acyltransferase activity.

Adult↗
PubMed1990

Treatment of recurrent herpes simplex labialis with oral acyclovir.

In a double-blind, randomized, patient-initiated clinical trial, 174 nonimmunocompromised patients with a history of virus-culture-confirmed herpes simplex labialis were treated with acyclovir capsules, 400 mg five times daily for 5 days, or placebo capsules. For 97% of the patients, treatment started within 1 h of the first sign or symptom of a recurrence. The frequency of positive lesion virus cultures was significantly lower among acyclovir-treated subjects (29/114, 25%) than among placebo-treated subjects (29/60, 48%; P = .004). Drug treatment did not affect the development of lesions, measured by the frequency of macular and papular (aborted) lesions and mean maximum lesion size. However, acyclovir hastened lesion resolution among the patients who could start treatment in the prodrome or erythema lesion stage. For this group, the mean duration of pain was reduced by 36% (P = .02) and the mean healing time to loss of crust by 27% (P = .03). Thus, oral acyclovir alleviated some of the clinical manifestations of herpes simplex labialis.

Acyclovir↗
PubMed1990

Early application of topical 15% idoxuridine in dimethyl sulfoxide shortens the course of herpes simplex labialis: a multicenter placebo-controlled trial.

In a double-blind, randomized, patient-initiated treatment study at five medical centers, 301 immunocompetent patients experiencing a recurrence of herpes labialis were treated with topical 15% idoxuridine (IDU) in dimethyl sulfoxide (DMSO), 80% DMSO control solution, or 2% DMSO control solution. IDU did not prevent the development of lesions but significantly accelerated lesion resolution in comparison with the combined control groups. For the total population, the mean duration of pain was reduced by 1.3 days (35%, P = .01) and the mean healing time to loss of crust by 1.7 days (21%, P = .004). Analysis of subpopulations revealed that the beneficial activity of the treatment was concentrated among the patients who began treatment in the prodrome or erythema lesion stage. For these patients, the mean duration of pain was reduced by 1.8 days (42%, P = .08) and the mean healing time to loss of crust by 3.3 days (38%, P less than .001). If only patients with classic herpes lesions (vesicle, ulcer, or crust formation) were considered, there was a greater drug effect on the duration of pain (reduction by 2.6 days, 49%; P = .03) and the mean healing time to normal skin was significantly shortened (reduction by 2.3 days, 23%; P = .004). Adverse reactions to the medication were minimal.

Administration, Topical↗
PubMed1990

Epidemiology of genital herpes in Pittsburgh: serologic, sexual, and racial correlates of apparent and inapparent herpes simplex infections.

Women attending family planning clinics in western Pennsylvania were enrolled into a prospective epidemiologic study of herpes simplex virus (HSV) infection. Detection of antibodies to HSV-1 and HSV-2 was based on an immunodot assay using type-specific glycoproteins gG-1 and gG-2. Serologic and historical data at enrollment were analyzed for 4527 subjects; the seroprevalence of HSV-2 was 21.6%. By multivariate analysis, HSV-2 infection as determined by seroprevalence was significantly and independently associated with age, years of sexual activity, race, one or more episodes of other genital infections, lower annual family income, and multiple sexual partners. The presence of antibody to HSV-1 was associated with a lower frequency of antibody to HSV-2, suggesting that developed immunity to HSV-1 protected against HSV-2 infection. Of 926 participants who had antibody to HSV-2, only 117 (12.6%) reported a history of genital herpes. Hence the vast majority of HSV-2 infections were inapparent. Although seroprevalence of HSV-2 was higher among black (35.4%) than white (18.5%) women, black women appeared to have significantly less symptomatic genital herpes than white women (7.7% vs. 14.7%, P less than .01).

Adolescent↗
PubMed1989

Synergistic adverse hemodynamic interaction between oral verapamil and propranolol.

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.

Administration, Oral↗
PubMed1989

New method for detecting slime production by coagulase negative staphylococci.

An alternative method for detecting the production of slime by coagulase negative staphylococci was compared with the routinely used Christensen method on 124 isolates of coagulase negative staphylococci from carriage sites, blood cultures, and infected peritoneal dialysis fluids. The alternative method requires the use of a specially prepared solid medium--brain heart infusion broth, supplemented with 5% sucrose, and Congo red stain. Of the 124 tests, there was complete agreement between methods in 107 and only one strain was clearly negative by Christensen's method while positive on Congo red agar. The Congo red method is rapid, sensitive, and reproducible and has the advantage that colonies remain viable on the medium. It is also not subject ot interbatch variation of media which sometimes affects the reproducibility of the Christensen method.

Bacteriological Techniques↗
PubMed1988

Mean apical concentration and duration in the comparative bioavailability of slowly absorbed and eliminated drug preparations.

Present criteria for comparing bioavailability are inadequate when the Cmax and tmax cannot be reliably identified in individual subjects. Drug formulations which are slowly absorbed and eliminated have concentration-time profiles with a broad apex, increasing the likelihood that samples taken at the apical region of the curve will have statistically indistinguishable concentrations. Using data from a study of three dosage forms of piroxicam, we propose an alternative approach which decreases the influence of sampling bias and analytical error on the identification of the apex of the concentration-time curve and provides a simple tool for describing the shape of the curve around the apex. An adequate frequency of sampling around the expected apex of the concentration-time curve and consideration of the coefficient of variation (CV) of the analytical assay when assessing the observed Cmax are used in defining new parameters. This approach may be useful for studying the relationship of onset and duration of maximal plasma concentration to the efficacy and toxicity of drugs and in developing standards for comparing the bioavailability of slow-release preparations, which is of increasing interest to pharmaceutical companies and regulatory agencies.

Absorption↗
PubMed1987

Recombinant human interferon-alpha A treatment of an experimental cutaneous herpes simplex virus type 1 infection of guinea pigs.

Recombinant human interferon-alpha A (rIFN-alpha A) was evaluated for therapeutic efficacy against an experimental dorsal cutaneous herpes simplex virus type 1 (HSV-1) infection of guinea pigs. Human IFN has activity in this species. Animals were treated either systemically (i.m.) or topically with different formulations of rIFN-alpha A. Therapy was initiated 24 h before (-24 h), 30 min after (+0.5 h), or 24 h following (+24 h) virus inoculation, and treatment was continued for 3-5 days. Efficacy was evaluated on day 4 following infection. Treatment with rIFN-alpha A given systemically beginning at -24 h was effective, reducing lesion number, total lesion area, and lesion virus titer by 64%, 85%, and 98% respectively (p less than 0.001). Efficacy diminished with delay in initiation of i.m. therapy. Topical rIFN-alpha A formulations were generally ineffective, showing only a marginal effect with therapy initiated -24 h or +0.5 h and no effect when treatment was delayed to +24 h. In summary, rIFN-alpha A is effective against cutaneous HSV-1 infection in this model if therapy is initiated prophylactically and if drug delivery is assured by systemic injection. Topical application of rIFN-alpha A showed little therapeutic effect. The large molecular weight of IFN likely retards its percutaneous delivery.

Administration, Topical↗
PubMed1987

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.

Adult↗
PubMed1986

Efficacy of topical treatment for herpes simplex virus infections: predictions from an index of drug characteristics in vitro.

Topical antiviral treatments for recurrent infection with herpes simplex virus in immunocompetent patients have been generally ineffective. We investigated whether in vitro drug measures could predict in vivo efficacy. Twelve topical antiviral formulations were evaluated in vitro by measuring inhibition of viral plaque formation in cell culture (ID50) and drug penetration through excised guinea pig skin. In vivo efficacy for each treatment was determined in an experimental cutaneous infection with herpes simplex virus type 1 in guinea pigs and expressed as the percent reduction in lesion number, lesion area, and virus titer in the lesions. The in vitro findings were correlated with the results in the animal model. ID50 was a poor predictor of in vivo efficacy, whereas stronger correlations were found between the degree of skin penetration and in vivo activity. The best correlation was noted by using a summary expression of the in vitro results as follows: the ratio of drug penetration through skin at 37 C to ID50 (r = .95, .94, and .92 for lesion number, area, and virus titer, respectively, P less than .0005). Determination of this in vitro index should be included in the preclinical evaluation of new topical antiviral formulations.

Acyclovir↗
PubMed1986

Failure of topical acyclovir in ointment to penetrate human skin.

Topical acyclovir (ACV) in polyethylene glycol (PEG) ointment has been disappointing in the treatment of recurrent herpes simplex virus infections in immunocompetent patients. To investigate the possible role of poor drug delivery from this formulation, we studied the penetration of ACV through excised human skin from three vehicles; PEG ointment, modified aqueous cream, and dimethyl sulfoxide. A second antiviral agent, idoxuridine, was studied in the same formulations, and drug delivery through excised guinea pig skin was also assessed for comparison. The delivery of ACV from PEG ointment was very slow for both human and guinea pig skin (drug flux, 0.055 and 0.047 microgram/cm2 per h, respectively). Formulation of ACV in modified aqueous cream and in dimethyl sulfoxide resulted in an 8- and 60-fold increase, respectively, in the flux of ACV through human skin. Idoxuridine behaved similarly to ACV in the three vehicles. The poor clinical results seen with topical use of ACV ointment may be due in part to retarded drug delivery from this formulation.

Acyclovir↗