Biomedical subjects

M A Shapiro

Publications and source records attributed to M A Shapiro.

At least 37 records · Page 2Linked to original sources

PubMed1997

Comparative therapeutic efficacy of clinafloxacin in leucopenic mice.

A cyclophosphamide-induced leucopenic mouse model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of ciprofloxacin and imipenem/cilastatin, two clinically relevant standard drugs. Acute systemic infections induced by Escherichia coli, Pseudomonas aeruginosa, a penicillin-resistant Staphylococcus aureus and a methicillin-resistant S. aureus (MRSA) were used to evaluate drug efficacy. Median protective values (PD50) with 95% confidence limits were determined in both leucopenic and normal mice. Results show that clinafloxacin is potentially a useful agent in the treatment of neutropenic patients.

Animals↗

PubMed1996

Structure-activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes at N-1 and C-7.

The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.

Anti-Bacterial Agents↗

PubMed1996

A novel rapid throughput phototolerance screen in mice.

A relatively simple, rapid throughput phototolerance screen in small animals would be very useful in early drug development. It could prioritize or select potential lead compounds from among a number of analogs with similar biological activities. This study describes an in vivo mouse phototolerance screen established for that purpose. It also reports phototolerance data with standard reference drugs obtained using this screen.

Animals↗

PubMed1996

Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position.

A series of quinolones with substitutions at the 8 position has been prepared as part of a study to examine the relationship between structural modifications at this position and activity against mycobacteria. The compounds were prepared by procedures described in the literature and were evaluated for their activities against Mycobacterium fortuitum and Mycobacterium smegmatis. The activities of the compounds against these two organisms were used as a measure of Mycobacterium tuberculosis activity. The results demonstrate that the contribution of the 8 position to antimycobacterial activity was dependent on the substituent at N-1 and was in the order (i) COMe approximately CBr > CCI > CH approximately CF approximately COEt > N > CCF3 when N-1 was cyclopropyl; (ii) N approximately CH > CF > COMe when N-1 was 2,4-difluorophenyl; (iii) N > or = CH when N-1 was tert-butyl; and (iv) N > CH when N-1 was ethyl. In general, derivatives with piperazine substitutions at C-7 were slightly less active against mycobacteria than the analogs with pyrrolidine substitutions, regardless of the pattern of substitution at the 8 position. Several of the best compounds were evaluated for their potential side effects as well as their activities against Mycobacterium aurum, Mycobacterium avium-M. intracellulare, and M. tuberculosis. These agents exhibited biological profiles similar to or better than those of the positive controls ciprofloxacin and sparfloxacin.

4-Quinolones↗

PubMed1995

The synthesis, structure-activity, and structure-side effect relationships of a series of 8-alkoxy- and 5-amino-8-alkoxyquinolone antibacterial agents.

A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methyoxy and 8-ethoxy)-quionoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity. In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxicity assay. The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to the most active 8-substituted compounds (8-F and 8-Cl). There was also a concomitant reduction in several of the potential side effects (i.e., phototoxicity and clonogenicity) compared to the most active quinolones with classic substitution at C-8. The 8-ethoxy derivatives had an even better safety profile but were significantly less active (2-3 dilutions) in the antibacterial assay.

Animals↗

PubMed1995

Effect of lipophilicity at N-1 on activity of fluoroquinolones against mycobacteria.

The dramatic increase in drug resistant Mycobacterium tuberculosis has caused a resurgence in research targeted toward these organisms. As part of a systematic study to optimize the quinolone antibacterials against mycobacteria, we have prepared a series of N-1-phenyl-substituted derivatives to explore the effect of increasing lipophilicity on potency at this position. The compounds, synthesized by the modification of a literature procedure, were evaluated for activity against Gram-negative and Gram-positive bacteria, Mycobacterium fortuitum and Mycobacterium smegmatis, and the results correlated with log P, pKa, and other attributes. The activity of the compounds against the rapidly growing, less hazardous organism M. fortuitum was used as a measure of M. tuberculosis activity. The results demonstrate that increasing lipophilic character by itself does not correlate with increased potency against mycobacteria. Rather, intrinsic activity against Gram-negative and/or Gram-positive bacteria is the governing factor for corresponding activity against mycobacteria.

Anti-Infective Agents↗

PubMed1995

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency.

PD 138312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoronaphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively. They have been demonstrated to have excellent in vitro activity against gram-positive organisms. These compounds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model. They were very effective by both the oral and subcutaneous routes of administration. Most remarkable were their comparative median protective values against methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In general, these compounds were 28- to 100-fold more active than ciprofloxacin against these clinically significant organisms when the drugs were given orally and 10- to 38-fold more active when the drugs were given parenterally. Average ratios of drug concentrations in mice after drug administration by the oral route to that after administration by the subcutaneous route indicate 34 to 44% greater bioavailabilities of PD 138312 and PD 140248 compared with that of ciprofloxacin. In a multidose pneumococcal mouse pneumonia model these new quinolones were extremely effective, with median curative doses of 2 to 2.8 mg/kg of body weight per dose. Ciprofloxacin was ineffective (median curative dose, >100 mg/kg per dose) in this model. Comparative pharmacokinetic studies in mice revealed a relative superiority of PD 140248. Peak levels of PD 140248 in blood after the administration of a single oral 50-mg/kg dose were twice those of PD 138312 and ciprofloxacin, with PD 140248 having a substantially longer half-life. These results indicate that PD 138312 and PD 140248 have excellent therapeutic potential against clinically important gram-positive pathogens when the drugs are administered both orally and parenterally.

Animals↗

PubMed1994

In vitro evaluation of cefdinir (FK482), a new oral cephalosporin with enhanced antistaphylococcal activity and beta-lactamase stability.

Cefdinir (FK482), a new oral cephalosporin with enhanced beta-lactamase stability, was tested by microbroth dilution against respiratory, urogenital, and skin and skin-structure bacterial pathogens. Included were beta-lactamase (beta LAC)-producing and -nonproducing isolates. Activity was compared with that of other orally administered beta-lactams. Cefdinir minimum inhibitory concentrations for 90% of isolates MIC90s (microgram/ml) were < or = 0.5 versus beta LAC+/oxacillin-susceptible Staphylococcus, aureus, S. epidermidis, and S. saprophyticus; < or = 0.06 versus Streptococcus groups A and B, and Neisseria gonorrhoeae beta LAC+; 0.125 versus S. pneumoniae penicillin-susceptible and Proteus mirabilis beta LAC+; 0.25 versus beta LAC+ versus strains of Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca; 0.5 versus Haemophilus influenzae beta LAC-; 1 versus H. influenzae beta LAC+; 4 versus Legionella pneumophila beta LAC+; and 8 versus Enterococcus faecalis beta LAC-strains. Cefdinir was equally effective against both standard and high inocula of S. aureus strains producing A, B, C, or D beta LAC types. MICs were also generated versus quality-control reference strains.

Bacteria↗

PubMed1994

Posterior urethral valve: transperineal US for imaging and diagnosis in male infants.

PURPOSE: To compare routine pelvic and transperineal scanning in the ultrasonographic (US) diagnosis of posterior urethral valve (PUV). MATERIALS AND METHODS: Longitudinal and transverse transperineal views were obtained in addition to routine renal and transvesicle views in the prospective US evaluation of 10 male infants (aged 2 days to 6 weeks) clinically suspected of having PUV. High-frequency (5.0- and 7.5-MHz) transducers were used. RESULTS: Five of the boys proved to have PUV. Each had urethral dilation clearly imaged at transperineal US. Only two of these boys had urethral dilatation imaged with the transvesicle approach. In three of the boys, a linear area of echogenicity, consistent with a valve, was imaged, but only with the transperineal approach. The other five boys had no urethral dilatation noted at transperineal or transvesicle US and proved to not have PUV. CONCLUSION: Transperineal imaging can aid in the diagnosis of PUV at US. Transperineal US may enable imaging of the valve itself.

Congenital Abnormalities↗

PubMed1993

Quinolone antibacterials containing the new 7-[3-(1-aminoethyl)-1- pyrrolidinyl] side chain: the effects of the 1-aminoethyl moiety and its stereochemical configurations on potency and in vivo efficacy.

A series of stereochemically pure 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1, 4-dihydro-4-oxoquinoline and 1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, were synthesized to study the effects of the 7-[3-(1-aminoethyl)-1- pyrrolidinyl] moiety on potency and in vivo efficacy relative to the known 7-[3-(aminomethyl)-1- pyrrolidinyl] derivatives. The antibacterial efficacies of the target compounds and their relevant reference agents were determined in vitro using an assortment of Gram-negative and Gram-positive organisms and in vivo using Escherichia coli and Streptococcus pyogenes mouse infection models. The effects of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] moiety were also examined at the level of the target enzyme by employing a DNA-gyrase supercoiling inhibition assay. Selected compounds were further evaluated for potential phototoxic and clastogenic liabilities using a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity assay. It was found that the differences in in vitro antibacterial activity between the stereoisomers were significantly greater than previously reported for other optically pure 3-substituted pyrrolidinyl side chains. Relative to their 7-[3-(aminomethyl)-1-pyrrolidinyl] analogs, the (3R,1S)-3-(1-aminoethyl)pyrrolidines generally conferred a 2-4-fold increase in Gram-positive in vitro activity and an average of 10-fold improvement in oral efficacy. The level of phototoxicity and cytotoxicity of the product quinolones was ultimately determined by the combined influence of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] side chains and the other quinolone substituents. From this study, several compounds were identified with outstanding antibacterial activity and low degrees of phototoxicity and mammalian cell cytotoxicity. One such agent, 34F-R,S (PD 140248), showed the best overall blend of safety and efficacy.

4-Quinolones↗

PubMed1993

Normal ovaries in neonates and infants: a sonographic study of 77 patients 1 day to 24 months old.

OBJECTIVE: Normal values for ovarian measurements in adults have been revised over the past decade. A recent report stated that ovarian cysts were common in healthy girls 2-13 years old, refuting the findings of a 1984 study. No large sonographic study of normal ovaries in girls 1 day to 24 months old has been performed. We evaluated ovaries in girls in this age group to determine the normal volume and prevalence of ovarian cysts. SUBJECTS AND METHODS: The ovaries of 77 consecutive patients 1 day to 24 months old were evaluated during routine pelvic sonography. Patients were divided into three age groups: 1 day to 3 months old (when gonadotropin levels are highest because of loss of placental hormonal influence), 4-12 months old (an intermediate group), and 13-24 months old (when gonadotropin levels are low). RESULTS: Ninety-eight ovaries were imaged in three dimensions. The mean volume was 1.06 cm3 (range, 0.7-3.6 cm3) among girls up to 3 months old; 1.05 cm3 (range, 0.2-2.7 cm3) among girls 4-12 months old; and 0.67 cm3 (range, 0.1-1.7 cm3) among girls 13-24 months old. We found no significant difference in mean volumes among the three groups. The prevalence of ovarian cysts was similar in all three groups; ovarian cysts were seen in 84% of all imaged ovaries. Macrocysts (cysts larger than 9 mm) were seen in 18% of all cystic ovaries. CONCLUSION: Ovaries of girls 1 day to 24 months old can have volumes greater than 1 cm3. Ovarian cysts are common. Macrocysts can be seen despite claims that they are rare in girls less than 11 years old.

Analysis of Variance↗

PubMed1992

New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.

4-Quinolones↗

PubMed1992

Torsion of the testicular appendage. Sonographic diagnosis.

Torsion of the testicular appendages may simulate the clinical and physical examination findings of testicular torsion. Real-time imaging and duplex Doppler scanning aided the diagnosis of this entity in three children. The testes appear normal on sonograms and have normal vascular flow. A circular mass of increased echogenicity with a variably sized central hypoechoic region is seen adjacent to the testicle. We could not relate variations in echogenicity to time delay between clinical pain and sonographic examination.

Adolescent↗

PubMed1989

Comparative chemotherapeutic activity of new fluorinated 4-quinolones and standard agents against a variety of bacteria in a mouse infection model.

The new fluorinated 4-quinolones appear to represent orally effective alternatives to parenteral and oral agents currently in use. A number of new fluorinated 4-quinolones were compared in acute systemic mouse-infection models with various Gram-positive cocci (streptococci and staphylococci), Enterobacteriaceae and Pseudomonas aeruginosa. Also included were standard oral and parenteral antimicrobial agents. CI-934 was the most potent quinolone in infections induced by Streptococcus pyogenes and Str. pneumoniae. CI-934, ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin were as effective as or superior to standard oral agents currently utilized in infections induced by the Enterobacteriaceae and staphylococci. They were active against antibiotic-susceptible strains and strains resistant to beta-lactams and gentamicin. Most were also quite potent against systemic P. aeruginosa mouse infections. These studies indicate good chemotherapeutic potential for the new generation fluorinated 4-quinolones in infections induced by the staphylococci, streptococci, Enterobacteriaceae and P. aeruginosa, including strains resistant to standard antimicrobial agents.

4-Quinolones↗

PubMed1989

Smooth vs. rough: an 8-year survey of mammary prostheses.

One-hundred and seventy patients (124 augmentations and 46 reconstructions) were followed for 8 post-operative years. Ninety patients received the "standard" smooth silicone mammary prosthesis, and 80 patients received a polyurethane-covered prosthesis. The longest follow-up was 4 years and the shortest was 1 year, with the average just over 2 years. Six types of complications were registered, with three attributed to implant design (wrinkles, draping, capsules) and three to the operator or surgery (infection, hematoma, extrusion). Firm capsule formation was considered a complication only if another intervention (reoperation, closed capsulotomy, etc.) was recommended by the surgeon or requested by the patient. Ninety-six percent of the patients with polyurethane prostheses had a satisfactory (grade II) or better than satisfactory (grade IA or IB) result, whereas 72 percent of the patients with a standard silicone-gel prosthesis achieved a satisfactory (grade II) or better than satisfactory (grade IA or IB) result. Technical details for use of polyurethane prostheses are given, as well as complications inherent to the polyurethane-covered implant.

Adult↗

PubMed1988

Enoxacin: in-vitro and animal evaluation as a parenteral and oral agent against hospital bacterial isolates.

Enoxacin was evaluated in in-vitro tests and in studies of effectiveness and blood concentrations in the mouse. Enoxacin was active against both susceptible and multiresistant hospital isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae and staphylococci. Less susceptible were streptococci and anaerobes. Of nine quinolones tested, only norfloxacin was equivalent in vitro. The MBCs of enoxacin were one- to twofold greater than the MICs, and enoxacin was rapidly bactericidal. No single-step resistant mutants could be detected at 10 mg/l against large inocula and six to 11 steps were required for selection of resistant clones. In systemic mouse infections, enoxacin was effective in a single oral or subcutaneous dose against one strain each of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Providencia rettgeri and Ps. aeruginosa, and two Staphylococcus aureus strains. Single oral and subcutaneous enoxacin doses (50 mg/kg) gave peak mouse blood levels of 4.9 and 9.5 mg/l and an elimination half-life of 1.8 h.

Animals↗

PubMed1988

Five primary disparate melanomas: a case report (the spectrum of melanoma).

A 75-year-old Caucasian female presented with a 20-year history of five primary disparate malignant melanomas and one small desmoplastic amelanotic satellite. In three generations, there was no family history of dysplastic nevi or malignant melanoma. Likewise, the patient had no history of dysplastic nevi or any other condition previously reported in the literature as being allied with melanoma. Dr. George Pack first reported that malignant melanoma may be multifocal. The wide spectrum of this disease and increased incidence of multiple primaries demand thorough, long term, follow-up.

Aged↗

PubMed1988

Sexually transmitted urogenital diseases.

Patients with sexually transmitted diseases (STDs) frequently present for care to the Emergency Department. Some of the more common STDs are increasing in number despite public health efforts to control their spread. Relatively simple diagnostic modalities for several of the more common STDs are presented. In addition, the most current treatment regimens for each STD discussed are described in detail.

Emergencies↗