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Biomedical subjects

M Barza

Publications and source records attributed to M Barza.

At least 91 records · Page 5Linked to original sources
PubMed1985

General principles of antibiotic tissue penetration.

It is well established that, at equilibrium, the concentrations of free drug on either side of a porous capillary are equal. However, the dynamic factors which operate on the way to achieving this equilibrium, while drug levels fluctuate in serum and extravascular sites, have been less well studied. This paper reviews some of the physical principles relating to diffusion through capillary pores and permeation through capillary membranes. Emphasis has been placed on the importance of the surface area-to-volume ratio in determining the time required to reach various stages of equilibrium. The effects of infection have been considered. At equilibrium, the AUC of free drug in serum and non-specialized extravascular compartments must be equal. Therefore, although the mode of administration (e.g. continuous infusion versus intermittent bolus) will affect the profile of the concentration-time curve in extravascular loci, it will not affect the overall AUC of drug in these sites. We have derived an equation to estimate the levels of drug within an abscess when bacteria are destroying the drug. Brief consideration has been given to transport in specialized sites with non-porous capillaries and with active transport systems. Throughout the analysis, we have focused on the application of these principles to in-vitro models and the potential use of in-vitro models to substantiate these principles.

Animals↗
PubMed1985

Imipenem: first of a new class of beta-lactam antibiotics.

Imipenem, the first of a new class of carbapenem antibiotics, has potent activity against most clinically important species of bacteria, including isolates resistant to other antibiotics. The drug is well distributed to most tissues and fluids after intravenous administration; however, levels in cerebrospinal fluid are modest. Most of the drug is eliminated in the urine, where it is metabolized by an enzyme on the brush border of the renal tubular cells; cilastatin is given simultaneously to inhibit this inactivation. Adverse effects include a syndrome of nausea and hypotension, especially after rapid intravenous infusion, and a predisposition to seizures in certain high-risk patients. Superinfections by resistant bacteria and fungi are infrequent. This new drug may be particularly useful in the treatment of infections caused by mixtures of bacteria for which a combination of antibiotics, often including an aminoglycoside, would otherwise be necessary. Examples include pulmonary, intra-abdominal, and soft-tissue infections.

Animals↗
PubMed1985

Acute bacterial meningitis in children and adults. A perspective.

Bacterial meningitis is an acute and serious illness associated with significant morbidity and mortality. Although methods to make the diagnosis are relatively simple and effective antimicrobial agents are available, bacterial meningitis accounts for more than 2000 reported deaths per year in the United States. The majority of cases and deaths occur in otherwise healthy individuals.

Adolescent↗
PubMed1985

Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits.

The ocular toxicity of liposome-intercalated amphotericin B and commercial amphotericin B were compared after intravitreal injection in healthy pigmented rabbits. Ophthalmoscopic observations over 5 weeks following a single intravitreal injection showed vitreal band formation and focal retinal damage after doses of commercial amphotericin B as low as 5 micrograms. Such lesions were not seen in animals given liposomal amphotericin B in doses up to 20 micrograms. Histopathologic examination showed areas of retinal atrophy or necrosis in five of 16 rabbits given commercial amphotericin B in doses of 5-20 micrograms but in none of 16 rabbits given the same doses of liposomal amphotericin B (P = 0.02). Small white vitreal bodies were seen clinically in virtually all animals given liposomal amphotericin B or "empty" (drug-free) liposomes but in only a few animals given commercial amphotericin B; these deposits may represent residual lipid. Concentrations of amphotericin B ranged from 0.4 to 1.0 micrograms per ml of vitreous humor 5 weeks after injection of 5-20 micrograms of either formulation. These studies indicate that liposome association markedly reduces the ocular toxicity of amphotericin B.

Amphotericin B↗
PubMed1984

Treatment of experimental cutaneous leishmaniasis with liposome-intercalated amphotericin B.

The therapeutic efficacy of a liposomal preparation of amphotericin B was evaluated in two murine models of cutaneous leishmaniasis. No significant decrease in tissue parasite density was observed in C57BL/6 mice after systemic treatment instituted seven days after footpad inoculation with Leishmania tropica; in contrast, BALB/c mice showed a modest response.

Amphotericin B↗
PubMed1984

Antimicrobial spectrum of Win 49375.

Win 49375 had excellent activity against members of the family Enterobacteriaceae and staphylococcal species. Its activity against Pseudomonas aeruginosa was equal to that of gentamicin. Win 49375 had moderate activity against clostridia but little against Bacteroides fragilis. The drug showed a marked inoculum effect at 10(8) CFU/ml and a slight decrease in potency at pH 5.

Anti-Bacterial Agents↗
PubMed1984

Efficacy of liposome-intercalated amphotericin B in the treatment of systemic candidiasis in mice.

We developed a liposome-intercalated preparation of amphotericin B by using small, unilamellar vesicles 0.06 to 0.1 micron in diameter. In contrast to previously described liposomal preparations of amphotericin B, these vesicles have the advantage that they are small enough to be filter sterilized. We compared the efficacy of liposomal amphotericin B with that of the commercial drug given as an intravenous bolus every other day for 13 days (seven doses) in mice with disseminated candidiasis. Survival rates were similar for the two preparations at each dosage of amphotericin B; however, the highest survival rates occurred at dosages of liposomal amphotericin B which would be lethal to these animals if administered as the commercial drug. Viable colony counts of fungi in various organs, particularly the kidneys, tended to be lower with increasing dosage of the drug. However, some organisms persisted even after 13 days. These studies indicate that liposomal formulations of amphotericin B merit further investigation because of their improved therapeutic margins.

Amphotericin B↗
PubMed1984

Pharmacokinetics of subconjunctival liposome-encapsulated gentamicin in normal rabbit eyes.

Subconjunctival injections of antibiotics produce very high corneal levels of drug that fall rapidly as the drug is dissipated. The authors studied the effects of liposome-encapsulation as a means of slowing release from the subconjunctival depot. Liposomes (0.1-1.0 micron) were made of phosphatidic acid, phosphatidylcholine, and alpha-tocopherol. The final suspension contained gentamicin 10 mg/ml with 60-70% encapsulated. Rabbits were given a single subconjunctival injection of liposome-encapsulated gentamicin, gentamicin with "empty" liposomes, or gentamicin alone. In each instance the dose of antibiotic was 5 mg. Gentamicin levels in the sclera and cornea, measured 3,9, and 24 hr after injection, were generally markedly higher with the liposome-encapsulated drug than with the other two preparations. The differences were 5- to 20-fold in the cornea at 24 hr and were statistically significant for temporal cornea. Liposome-encapsulation may be a useful means of extending the effects of a subconjunctival injection of antibiotic.

Animals↗
PubMed1983

An internally-standardized assay for amphotericin B in tissues and plasma.

A high-performance liquid chromatographic (HPLC) method with p-nitrophenol as internal standard is described for the rapid analysis of amphotericin B recovered by methanolic extraction from tissues and plasma. Programmed, gradient elution of the ODS column was used with detection by tungsten light at 388 nm. Standard curves were derived based on the peak height ratios. The lowest reproducible limit of the assay was 0.04 micrograms/ml with plasma. The extraction and chromatographic procedures recovered 53-71% of the amphotericin B from each of these sources. The coefficient of variation of the recovery ratios was less than 18% from plasma over a range of concentrations of amphotericin B from 0.08 to 10.0 micrograms/ml. Recovery from tissues, studied over a narrower concentration range, showed a similar degree of precision. Variations in precolumns apparently resulting in selective binding of the amphotericin B were found to have a systematic but important influence on recovery efficiency. No substances were detected which interfered with the assay procedures as described. By incorporating an internal standard we have enhanced the reliability and flexibility of the HPLC assay for amphotericin B especially for assay of tissues.

Amphotericin B↗
PubMed1983

Ocular infections.

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Adenovirus Infections, Human↗
PubMed1983

Topical vs subconjunctival treatment of bacterial corneal ulcers.

The efficacy of eye drops and subconjunctival injections in the treatment of bacterial corneal ulcers for each of the following combinations were compared: cefazolin for staphylococcal ulcers, gentamicin for staphylococcal ulcers, and gentamicin for pseudomonal ulcers. Topical and subconjunctival therapy were equally effective in reducing the numbers of viable bacteria in experimental corneal ulcers. Subconjunctival injections produced high but transient peaks followed by persistent low troughs. In contrast, eye drops produced moderate but sustained concentrations throughout the treatment period. Under the conditions of this study, it appears that transient high peaks are not needed to eliminate bacteria effectively from a corneal ulcer. Since eye drops and subconjunctival injections are equally effective, other factors should determine the preferred route or routes of therapy.

Administration, Topical↗
PubMed1983

Comparison of the effects of continuous and intermittent systemic administration on the penetration of gentamicin into infected rabbit eyes.

The effect of the mode of administration on the intraocular penetration of gentamicin in rabbits with bacterial endophthalmitis was examined. Animals were treated over a period of 12 hr either by intramuscular injection every 3 hr or by continuous intravenous infusion; both groups received the same total dose of drug. The mean peak and trough levels in serum with intramuscular injection were 11.4 and 1.6 micrograms/ml, respectively. Mean serum levels during continuous infusion were approximately 7 micrograms/ml. The area under the time-concentration curve for serum was approximately the same in both groups. Mean vitreous humor levels at the end of therapy were 2.8 micrograms/ml in the animals treated by repeated intramuscular injection and 2.6 micrograms/ml in those treated by continuous infusion (P greater than 0.2). In this model, the intraocular penetration of gentamicin was not influenced by the mode of systemic administration.

Animals↗
PubMed1983

Pharmacokinetics of aztreonam in rabbit eyes.

Subconjunctival injection of 100 mg of aztreonam in rabbits with Pseudomonas aeruginosa endophthalmitis produced transiently high antibiotic concentrations in most intraocular sites. Concentrations of approximately 2.5 micrograms/ml were achieved in the vitreous humor 15 min after injection and persisted for 6 h. Repeated intramuscular injections in dosages of 25 mg/kg every 4 h resulted in drug concentrations in the vitreous humor of 2.4 micrograms/ml in infected eyes. These levels might be adequate for the treatment of intraocular infections caused by highly susceptible organisms. Direct intravitreal injection of 100 micrograms of aztreonam in normal rabbit eyes produced an estimated peak concentration in the vitreous humor of 62 micrograms/ml, with a half-life of 7.5 h, which declined to 6 micrograms/ml by 48 h. The pharmacokinetic indices suggest that, like other beta-lactam antibiotics, aztreonam is eliminated from the vitreous humor by the retinal route. This novel antibiotic warrants further study of its efficacy and toxicity to determine whether it may be a useful alternative to the aminoglycosides for selected cases of ocular infection.

Animals↗
PubMed1983

Pharmacokinetics of intravitreal carbenicillin, cefazolin, and gentamicin in rhesus monkeys.

Although intravitreal injection of antibiotics is being used more widely in treatment of bacterial endophthalmitis, the pharmacokinetic principles that underlie such therapy have been derived exclusively from experiments in the rabbit. Therefore, we studied several representative antibiotics in normal eyes of rhesus monkeys. Carbenicillin (1,000 micrograms), cefazolin (1,000 micrograms), or gentamicin (100 micrograms) was injected intravitreally. Vitreous and aqueous humors were aspirated at intervals up to 96 hours after injection. The half-life values in the vitreous humor were: carbenicillin 10 hours, cefazolin 7 hours, and gentamicin 33 hours. Concomitant intraperitoneal administration of probenecid prolonged the vitreal half-life of carbenicillin to 20 hours and of cefazolin to 30 hours. The estimated vitreous volumes in these monkeys were approximately 3.0-4.0 ml. These results are consistent with the hypothesis that, in primates as in rabbits, beta-lactam antibiotics are eliminated via the retinal route and the aminoglycoside via the anterior route. This supports the applicability of the rabbit model to the treatment of endophthalmitis in humans.

Animals↗
PubMed1982

Systemic absorption of clindamycin hydrochloride after topical application.

Clindamycin has become a highly popular drug for the topical therapy of acne; however, the extent to which it is systemically absorbed from the skin has has not been established. We measured the serum level and urinary excretion of clindamycin on the third day and the twenty-seventh day of therapy in thirteen patients who were applying 1% clindamycin hydrochloride topically for acne. There was no detectable antibiotic in the serum of any subject (less than 0.4 microgram/ml); in contrast, clindamycin was found in the urine of ten of the thirteen patients. There was marked intersubject variation in the urinary excretion of the drug, ranging from less than 10 to 500 micrograms/day. However, there was a highly significant correlation (p less than 0.0001) for a given subject between excretion values on days 3 and 27. There was no correlation between urinary excretion of clindamycin and either racial pigmentation or severity of acne in this relatively small group of patients. After topical application of 1% clindamycin hydrochloride, an average of 4% to 5% of clindamycin appears to be absorbed systemically, but greater amounts are absorbed in some individuals.

Acne Vulgaris↗