Showing papers in "Chemotherapy in 1982"

Combination Therapy of Experimental Candidiasis, Cryptococcosis and Aspergillosis in Mice

Abstract: Combination pairs of the major systematic antimycotic drugs, amphotericin B (AmphB), 5-fluorocytosine (5-FC) and ketoconazole (Ktz) were administered to mice with experimental candidiasis, cryptococcosis and aspergillosis at a variety of combination ratios. The 3 mycoses were produced with 3 strains each of Candida albicans, Cryptococcusneoformans, and Aspergillus jumigatus, respectively, which were preselected to represent 3 different degrees of 5-FC sensitivity (‘normally sensitive’, ‘moderately resistant’, and ‘definitely resistant’). The life-prolonging effect of the combinations was compared with the effect of each partner administered alone at the same and at the double dosage. Using the U test of Mann and Whitney and setting limits which on the whole were more rigorous than those of the isobole methods commonly applied to the study of drug interactions, the effects of the concentrations were classified as ‘synergistic’, ‘additive’, ‘indifferent’ or ‘antagonistic’. The combination AmphB plus 5-FC was definitely synergistic or definitely additive in all 3 candidiasis models, the most pronounced synergism occurring in the infection with the ‘definitely 5-FC-resistant’ C. albicans strain; in cryptococcosis produced by any of the 3 C. neoformans strains the effect was definitely additive, but only slightly additive or indifferent in the 3 aspergillosis models. The combination AmphBplus Ktz was slightly synergistic in candidiasis produced by one C. albicans strain, but definitely antagonistic in this mycosis produced by the remaining 2 strains of the same species; the combination was definitely additive or, even, slightly synergistic in the 3 cryptococcus models, but, again, antagonistic in aspergillosis produced by all 3 strains of A. fumigatus. 5-FC plus Ktz was additive or indifferent in the 3 candidiasis models, but throughout indifferent in cryptococcosis and aspergillosis.

Single dose kinetics of mefloquine in man. Plasma levels of the unchanged drug and of one of its metabolites.

Abstract: Oral single dose kinetics of mefloquine was investigated in 16 male volunteers, 3 Caucasians and 13 African natives. Unchanged mefloquine (= M) and one of its metabolites (= MM) were measured in the plasma. The apparent half-life of absorption of M ranged from 0.36 to 2.0 h, its terminal half-life of elimination from 15 to 33 days. Assuming complete systemic availability, an apparent volume of distribution of 14-29 liters x kg-1 and a total clearance of 18-39 ml x min-1 were derived. MM given orally to mice or rats showed at equal dose the same tolerance as mefloquine. Following oral administration of M to man, plasma levels of MM surpassed those of M, resulting in a 2.4-5.1 larger AUC. However, because of its much smaller apparent volume of distribution, MM may be anticipated to represent only a small percentage of the dose and therefore to contribute only to a minor extent towards the unwanted side effects of the drug.

In vivo anti-cancer activity of RC-18: a plant isolate from Rubia cordifolia, Linn. against a spectrum of experimental tumour models.

Abstract: Anti-tumour activity of RC-18, a pure isolate from Rubia cordifolia was repeatedly tested in different sets of experiments on a spectrum of experimental murine tumours, viz. P388, L1210, L5178Y, B16 melanoma, Lewis lung carcinoma and sarcoma-180. RC-18 exhibited significant increase in life span of ascites leukaemia P388, L1210, L5178Y and a solid tumour B16 melanoma. However, it failed to show any inhibitory effect on solid tumours, Lewis lung carcinoma and sarcoma 180. Promising results against a spectrum of experimental tumours suggest that RC-18 may lead to the development of a potential anti-cancer agent.

Dose dependence of piperacillin pharmacokinetics.

Abstract: Pharmacokinetics were evaluated for piperacillin given as doses of 15, 30 and 60 mg/kg body weight to 12 healthy volunteers subdivided into three groups which were each given different dosage levels.

Pharmacokinetic fundamentals of vaginal treatment with clotrimazole.

Abstract: Absorption of clotrimazole after vaginal application was estimated to be between 3 and 10%. In order to investigate the fate of clotrimazole reaching systemic circulation, pharmacokinetic studies following oral and intravenous administration were carried out. The concentrations of clotrimazole in vaginal fluid and in blood plasma after vaginal application of 200 and 500 mg were determined using a specific assay by quantitative thin-layer chromatography. Fungicidal concentrations of clotrimazole in vaginal fluid up to 3 days after application of one vaginal tablet containing 500 mg were found. In contrast, clotrimazole plasma levels were lower than 0.01 µg/ml, demonstrating that clotrimazole is rapidly metabolized.

In vitro susceptibility of mycobacteria species other than Mycobacterium tuberculosis to amikacin, cephalosporins and cefoxitin.

Abstract: The susceptibility of different species of mycobacteria, other than M. tuberculosis, to a range of cephalosporins and to amikacin was studied. Susceptibility patterns varied with species. M. fortuitum, M. marinum and M. szulgai were the most susceptible species to amikacin and to cefoxitin, whereas M. kansasii, M. scrojulaceum and MAIS complex the most resistant. Cefoxitin appears to be much more active against mycobacteria than the other cephalosporins used in this study. Most of the cefoxitin-sensitive mycobacteria were inhibited by concentrations which can be easily attained in serum on standard dosage schedules.

Further evidence for sequential action of amphotericin B and 5-fluorocytosine against Candida albicans.

Abstract: Experiments were designed to determine the nature of amphotericin B (AMB)– 5-fluorocytosine (5-FC) synergism against strains of Candida albicans susceptible to either drug alone. AM

Treatment of Experimental Ascending Escherichia coli Pyelonephritis with Ceftriaxone Alone and in Combination with Gentamicin

Abstract: We have tested the effectiveness of several antibiotic regimens, using a rat model of Escherichia coli experimental pyelonephritis that mimics the conditions of severe renal infecti

Demonstration of typical features of individual Candida albicans strains as a means of studying sources of infection.

Abstract: For research into sources of infection it is very important to distinguish one strain of an infective agent from other strains of the same species by characteristics peculiar to it alone. The relatively unvarying properties which are used to differentiate species (e.g. typical fermentation and assimilation patterns) are not suitable for this purpose. Different authors have utilized for this purpose either morphological features or enzymatic and also, most recently, resistance characteristics vis-a-vis certain fungicidal agents. The so-called Resistogram method of Warnock and a combination test set by Odds have proved especially useful. Like these 2 authors, we, too, addressed ourselves once again to the question whether vaginal reinfections are frequently due to associated intestinal colonization by Candida albicans and infection of the vagina from this reservoir. Initial studies by Warnock seemed to refute this hypothesis. However, our own data and later studies by Warnock did confirm the above assumption.

Evaluation of ribavirin in the treatment of acute hepatitis.

Abstract: In this double-blind, placebo-controlled study, treatment of 60 acute hepatitis patients with ribavirin resulted in a more rapid reduction of abnormal laboratory values when compared with the placebo group. Moreover, improved clinical status as reflected by increased appetite with resultant weight gain was noted to be significantly greater in the ribavirin-treated patients. Ribavirin was well tolerated. With this dosage regimen, there were no side effects or changes in laboratory values that could be associated with drug-related toxicity. Since hepatitis A is one of the most common viral infections afflicting the Indian population, the use of a safe and effective therapeutic agent, such as ribavirin, will be necessary to treat these cases.

Comparison of the Conventional Methods and High-Performance Liquid Chromatography for the Determination of Trimethoprim, Sulfamethoxazole and Its Metabolite in Serum

Abstract: A modified high-performance liquid chromatographic (HPLC) method for sensitive and rapid determination of trimethoprim, sulfamethoxazole and its metabolite N4-acetylsulfamethoxazole has been compared with the bioassay for trimethoprim and a colorimetric procedure for sulfonamides. The sensitivity of the (HPLC) method has been increased by ultrafiltration of the sample. Thus, the sample dilution was markedly reduced compared to the values obtained with precipitation procedures. The recovery was 102.7 +/- 6.1% for trimethoprim, 93 +/- 5.4% for sulfamethoxazole and 90.2 +/- 7.9% for N4-acetylsulfamethoxazole. The between-day reproducibility was 5% (n = 5). The coefficients of correlation for HPLC and reference methods were 0.993 (bioassay) and 0.995 (colorimetric assay).

In vitro activity and beta-lactamase stability of N-formimidoyl thienamycin compared to that of second and third generation cephalosporins.

Abstract: N-Formimidoyl thienamycin (MK0787) was found to be active against 21 gram-negative isolates, selected for their beta-lactamase production. None of the crude beta-lactamases could hydrolyze MK0787 or cefoxitin, in contrast to cefotaxime which was moderately attacked by a number of enzymes. MK0787 behaved as a moderate inhibitor of most beta-lactamases, whereas cefoxitin and cefotaxime were strong inhibitors of cephalosporinases but not of broad-spectrum enzymes. The new compound had good penetration characteristics in a strain of Enterobacter cloacae, in contrast to cefoxitin. Against a number of trained cefamandole- and cefoxitin-resistant variants, MK0787 was clearly the most active of the compounds tested.

Simultaneous simulation of the serum profiles of two antibiotics and analysis of the combined effect against a culture of Pseudomonas aeruginosa.

Abstract: The serum profiles of ceftriaxone (CEF) and netilmicin (NET) were produced in a liquid culture of Pseudomonas aeruginosa, and the change in viable count recorded. Synergism was detectable between CEF and NET despite of the widely disparate serum halflife times of NET and CEF.

Investigations into the pathoaetiology and diagnosis of vaginal mycoses.

Abstract: Clear microscopic evidence of yeasts together with a detailed case history and results of the clinical examination are adequate for a definite diagnosis of vaginal mycoses. In principle, vaginal mycoses can only be ruled out by culture studies. This must be taken into account particularly when assessing the efficacy of antimycotics. Yeasts, in particular Candida albicans, are often detected on the mucosa and morphologically similar areas in man and animals without any symptoms being present. They are also occasionally found elsewhere, for example on fruit, foodstuffs, etc. This has led to the organisms being termed ‘facultative pathogenic saprophytes’ and to them being evaluated as relatively harmless. The term ‘facultative pathogenic opportunists’ is certainly more relevant. The problems in determining the pathogenicity of yeasts are similar to those encountered in the past with various bacteria. The pathogenic significance of yeast contamination is also linked to the interaction between organism- and host-related factors. In the case of organism-related factors, viable count and rate of proliferation are important as well as the different biochemical properties of the individual yeast strains, such as endo- and exotoxin formation and proteolytic activity. Endocrine disturbances, such as diabetes mellitus, hypothyroidism and hypoparathyroid-ism are accompanied by an increase in yeast infestation and a corresponding increase in the incidence of infection. The transition from yeast contamination to yeast infection largely depends upon the tolerance of the host or host tissue. This is lowered by a general reduction in resistance, antibody deficiency syndrome, avitaminosis, serum iron deficiency, etc. The well-known enhancing effect of various chemotherapeutic agents on the virulence of yeasts or responsiveness of the host organism is assessed in different ways; the threshold for the transition from contamination to infection is difficult to define, and the pathophysiological mechanism of yeast-related diseases is also unclear. Yeasts produce endo- and exotoxins only on a small scale, a purely toxic genesis is therefore improbable. Their interpretation as an allergic reaction, which is possible in gynaecological observations of acute mycotic vulvitis, is questionable since inflammatory reactions have also been observed in neonates with immature immunological systems during the first days of life and very occasionally even during intrauterine life. More information about the infectious process is expected from additional immunological and histochemical investigations. The following report deals with experimental investigations which provide an answer to some current problems.

Dose-Dependent Pharmacokinetics of Azlocillin Compared to Mezlocillin

Abstract: The pharmacokinetics of azlocillin at intravenous doses of 1.0, 2.0 and 5.0 g and of 2.0 g mezlocillin were studied in a cross-over study on 10 healthy volunteers. The serum concentrations and total area under the serum curves for azlocillin increased more than expected from the multiples of the dose size. Likewise, the percentage of urinary excretion of an antibacterially active agent increased steadily with higher doses. The same applied to the serum half-life (t 1/2), whereas the total body clearance was reduced. All these characteristics are indicative of dose-dependent, i.e. capacity-limited pharmacokinetics. The t 1/2 was 0.89, 0.98, and 1.53 h for each dose. For 2.0 g mezlocillin, the serum values, urinary recovery, and t 1/2 were lower than the values after the same dose of azlocillin. The t 1/2 was 0.64 h. The total body clearance was 12,0, 9.2, and 6.4 liters/h for the three doses of azlocillin and 14.4 liters/h for 2. g mezlocillin. Dose dependence appears to be more pronounced with azlocillin than found previously with mezlocillin. Unchanged azlocillin and its biotransformation products are excreted more slowly than mezlocillin and its metabolites.

Effect of Ceftriaxone on Pseudomonas aeruginosa and Staphylococcus aureus in Broth, Serum, and in Combination with Human Polymorphonuclear Leukocytes

Abstract: We investigated the antibacterial activity of ceftriaxone at concentrations of ¼ × minimum inhibition concentration (MIC), 1 × MIC and 4 × MIC against a serum-resistant Pseudomonas aeruginosa

Pharmacokinetics of phenoxymethylpenicillin in volunteers.

Abstract: Pharmacokinetics of phenoxymethylpenicillin was studied in 12 healthy volunteers. They received four different single oral dose sizes. At all dose levels (0.4, 1, 2 and 3 g) phenoxymethylpenicillin was rapidly absorbed, usually with serum peaks within 0.75 h. The mean maximal serum peaks (+/- SD) were 6.1 +/- 2.0, 15.0 +/- 4.3, 26.3 +/- 10.0 and 35.5 +/- 10.8 mg/l after 0.4, 1, 2 and 3 g, respectively. The relationship between the mean peak serum concentrations and the doses was nonlinear (p less than 0.001). The mean areas under the serum concentrations vs. time curve (AUC) increased almost linearly with increasing doses, and the deviation from linearity was not significant (p less than 0.05). Very low penicillin concentrations were obtained in saliva. The urinary excretion during 10 h was 37--43% of the doses given. The pharmacokinetic results indicated that phenoxymethyl penicillin in the present formulation is rapidly and well absorbed up to as high doses as 3 g. The tablet formulations used were better absorbed than previous ones. The percent of absorption was relatively lower with the highest doses, but this probably has only minor therapeutic consequences.

Simple screening method for gram-positive bacterial beta-lactam antibiotic tolerance on routine laboratory Bauer-Kirby antibiogram plates.

Abstract: A simple screening method served to detect β -lactam antibiotic-tolerant variants of clinical isolates and laboratory control strains of Staphylococcus aureus , <

Pharmacokinetics of a New, Microencapsulated Erythromycin Base after Repeated Oral Doses

Abstract: Pharmacokinetics of a new preparation of microencapsulated erythromycin base was studied in 16 healthy subjects. They received 250 mg base 6-hourly or 500 mg 12-hourly for 7 days. The mean maximal serum peaks ( ± SD) after morning doses on days 1, 2, 3, and 7 were 1.4 ± 0.9, 3.2 ± 1.1, 3.6 ± 0.6, 3.5 ± 1.2 mg/l after the 250-mg dose and 3.2 ± 1.5, 3.7 ± 2.1, 3.6 ± 1.8, and 3.0 ± 2.0 mg/1 after the 500-mg dose. The mean 24-hour urine recoveries were 1.8 and 1.2°/o, the serum half-lives were (days 1–7) 1.4–2.1 h and 1.9–2.8 h for the 250-mg and 500-mg doses. The mean areas under the serum concentration curves ( ± SD) were 5.8 ± 2.2, 11.9 ± 2.2, and 15.3 ± 5.1 mg h 1-1 after 250 mg and 14.2 ± 4.9, 16.4 ± 7.6, and 14.3 ± 9.0 mg · h-1 after 500 mg on days 1, 2, and 7. The inter- and intrasubject variability was larger after the 500-mg dose. The pharmacokinetic results indicate that both dosage alternatives are suitable and result in similar steady-state peak levels, but the initial dose should be 500 mg.

Polymyxin B-induced cocarde growth phenomenon of Serratia marcescens due to cationic detergent-like activity of polymyxin B.

Abstract: 14 of 74 test strains of Serratia marcescens yielded reproducible cocarde-like growths (coc+) around 30-micrograms disks of polymyxin B (PB) on Muller-Hinton, brain heart infusion and tryptic soy agar. The coc+ phenomenon was not due to nutrient effects of growth medium nor did it correlate with either group A (phage tail) bacteriocinogeny or colicinogeny as determined with 32 selected test strains; mitomycin C failed to give rise to coc+ growths. The anionic bile salts of MacConkey agar as well as aqueous sodium deoxycholate neutralized the coc+ activity of PB. Benzalkonium chloride, chlorhexidine digluconate, and cetyltrimethylammonium bromide by themselves did not produce cocardes. Rather, these cationic detergents enhanced PB activity somewhat against selected coc+ and coc- strains of S. marcescens. It was concluded that the PB-induced growth phenomenon of S. marcescens was due to the cationic detergent-like activity of this polypeptide antibiotic.

Vaginal secretion levels after 6 days, 3 days and 1 day of treatment with 100, 200 and 500 mg vaginal tablets of clotrimazole and their therapeutic efficacy.

Abstract: Patients with a mycologically confirmed vaginal mycosis were treated either with one 100-mg vaginal ovule of clotrimazole each for 6 days, or with one 200-mg vaginal ovule of clotrimazole each for 3 days, or with one 500-mg vaginal ovule of clotrimazole for 1 day, the ovule having been supplied in a novel, acid formulation. 24, 48 and 72 h after the last dose, samples of secretion were taken from the fornix vaginae. The intravaginal secretion levels were determined semiquantitatively on the basis of the measured inhibition zones obtained with Candida albicans growth on agar plates, and the levels obtained with the different treatment regimens were compared. The vaginal secretion levels after a single 500-mg dose of the new formulation were higher, even after 3 days, than those measured in the 6-day treatment, while administration of 200 mg clotrimazole on 3 days resulted in no increase of the secretion levels over those seen in 6-day treatment with 100 mg.

Bactericidal Activity of Cefazolin, Cefoxitin, and Cefmetazole against Escherichia coli and Klebsiella pneumoniae

Abstract: The bactericidal activity of cefazolin, cefoxitin, and cefmetazole against clinical isolates of Escherichia coli and Klebsiella pneumoniae was investigated. The mean geometric minimum inhibition concentrations against 200 strains each of the test organisms were lowest for cefmetazole, followed by cefazolin and cefoxitin. The killing activity at 5 and 50 microgram/ml of cefazolin and cefmetazole was almost the same and was superior to that of cefoxitin. In the kinetic model under conditions simulating the serum levels of the two drugs in humans after intravenous injection (1 g), cefazolin was the strongest of the three drugs in bactericidal activity. The results indicate that the highest and most prolonged serum concentrations of cefazolin reflected the strong bactericidal activity and the longest inhibition period of bacterial regrowth.

On the Action Kinetics of Clotrimazole

Abstract: The introduction of clotrimazole into the therapy of vaginal Candida and Torulopsis infections has significantly shortened the previously customary duration of tr

Clinical presentation of candidal balanitis--its differential diagnosis and treatment.

Abstract: The clinical presentation of candidal balanitis is discussed. Differential diagnosis from other forms of balanitis and dermatoses affecting the genitals is made. Treatment of candidal balanitis is then mentioned. General measures, contact investigation and specific measures such as the polyene antibiotics and the newer imidazole group of antifungal drugs are exemplified.

A new model of experimental Bacteroides fragilis infection in mice and rats.

Abstract: We describe a method, based on Selye's granuloma pouch, for establishing reproducible Bacteroides fragilis infections in both mice and rats starting from rather low inocula. The infected pouches resemble abscesses and phlegmons. This model is promising for studies of antibiotic therapy in that both bacterial kinetics and antibiotic levels can be followed in the exudates.

Pharmacokinetics of Tetracycline in Nutritional Oedema

Abstract: Tetracycline pharmacokinetics were studied in a group of normal subjects and in patients with nutritional oedema. Though both groups of subjects received similar dose per kilogram body weight, plasma concentrations and area under the curve (AUC) were significantly higher in nutritional oedema patients. The total body clearance of the drug was reduced due to significant reductions in renal and non-renal clearance of drug. The volume of distribution (VB) was low, with significant increase in rate of transfer of drug from peripheral to central compartment (K21), indicating poor tissue sequestration of the drug in nutritional-oedema patients. In some respects, these alterations in kinetics of tetracycline in nutritional-oedema patients are different from our earlier observations made in undernourished subjects who had mild and moderate forms of malnutrition. These results suggest that changes in disposition of drugs are also influenced by the severity of malnutrition, and demand suitable alterations in dosage regimen.

Candida albicans vaginitis: the problem is diagnosis, the enigma is treatment.

Abstract: At the UCLA Vulvovaginitis Clinic, 63 patients were diagnosed as having symptomatic Candida albicans vaginal infections. In a random select manner 3-day treatment with 200-mg clotri

Effects of 5,8-dideazaisofolic acid (IAHQ) on human tumor cells in culture and on normal and tumor-bearing hamsters.

Abstract: The quinazoline analog of folic acid, 5,8-dideazaisofolic acid (IAHQ), was tested for its effects on the growth of human tumor cells in vitro and in vivo. Of 23 human tumor cell lines tested in vitro, 7 were inhibited by IAHQ (ED50, 5 × 10-6 to 5 × 10-7 M). For in vivo studies, human osteosarcoma (OS) cells from the IAHQ-sensitive line TE-85 were implanted intraperitoneally in newborn hamsters: in the group treated with IAHQ, only 30% of the animals developed OS, compared with 100% of those not treated with IAHQ. The effects of IAHQ injections on mitogenic responses and natural killer activity of lymphocytes from normal 3-month-old hamsters were also examined.

Induced Resistance in Leukaemia L1210 to Adriamycin and Its Cross-Resistance to Vincristine and Bouvardin

Abstract: The induction of complete resistance to adriamycin in L1210 leukemia was accomplished after 10 transplant generations. The adriamycin-resistant subline showed cross-resistance to vincristine and bouvardin. It was sensitive to methotrexate; this was observed by a 50% increase in life span compared to the life span of untreated control animals.