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PubMed1990

Biphasic effects of prostaglandin E2 on bone formation in cultured fetal rat calvariae: interaction with cortisol.

Previous studies have shown that prostaglandin E2 (PGE2) has both inhibitory and stimulatory effects on the incorporation of proline into collagenase-digestible protein (CDP) in cultured fetal rat calvaria. The present studies were undertaken to analyze further these biphasic effects of PGE2. PGE2 increased [3H]thymidine incorporation at 24 h, and this effect was enhanced in the presence of cortisol (10(-8) and 10(-7) M). An inhibitory effect on CDP labeling was observed at 96 h with PGE2 (10(-6) M) in the absence or presence of indomethacin (10(-6) M), but not in the presence of cortisol (10(-8) or 10(-7) M). When the central osteoblast-rich bone and periosteum were analyzed separately, the inhibitory effect of PGE2, with or without indomethacin, was confined to the central bone. Addition of aphidicolin (30 microM), an inhibitor of cell replication, did not prevent the inhibitory effect of PGE2 on CDP labeling. Analysis of labeled collagen by polyacrylamide gel electrophoresis showed a decrease in labeling of type I collagen in central bone. Moreover, mRNA for alpha 1(I)procollagen was decreased, as measured by dot blot hybridization and Northern blot analysis. Cortisol (10(-8)-10(-6) M) decreased the labeling of CDP as well as noncollagen protein (NCP) at 96 h. In the presence of cortisol, PGE2 (10(-8)-10(-5) M) consistently stimulated labeling of CDP and NCP, with a greater increase in CDP, resulting in an increase in the percentage of collagen synthesized. In the presence of low concentrations of cortisol (10(-8) or 3 x 10(-8) M), PGE2 (10(-7) M) increased CDP labeling by 260-480%, and the absolute value was 145-160% of that in control cultures without any hormone addition. The stimulatory effect was seen in both central bone and periosteum, although absolute values for CDP and percentage of collagen synthesized were higher in central bone. PGE2 (10(-7) M) had similar effects on CDP at 24 and 96 h in the presence of cortisol, and the stimulation at 10(-7) M was the same in the presence and absence of aphidicolin, suggesting that it was not dependent on cell replication. Cortisol decreased labeling of type I collagen, determined by polyacrylamide gel electrophoresis, and alpha 1(I)procollagen mRNA levels, determined by both Northern and dot blot analysis. PGE2 reversed these effects, increasing both radiolabeled collagen type I chains and alpha 1(I)procollagen mRNA levels. These results indicate that PGE2 can regulate bone collagen synthesis at a pretranslational site.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Effect of sodium diclofenac on serum and tissue concentration of amoxicillin and on staphylococcal infection.

The effect of sodium diclofenac on serum and tissue amoxicillin concentration as well as their effect against staphylococcal infection was observed. Four polyurethane sponges were placed in the back of thirty rats. After 14 d, two granulomatous tissues received 0.5 ml of 10(8) cfu/ml (Staphylococcus aureus). Two days later, the rats were divided into five groups: group 1 received amoxicillin 50 mg/kg/p.o., group 2 received amoxicillin 25 mg/kg/p.o., group 3 received sodium diclofenac 2.5 mg/kg/i.m. and amoxicillin 50 mg/kg/p.o., group 4 received sodium diclofenac 2.5 mg/kg/i.m., and group 5 (control group) received NaCl 1 ml/p.o. After six hours of drug administration, blood serum (10 microl) and noninfected granulomatous tissues were placed on Mueller-Hinton agar inoculated with 10(8) cfu/ml (S. aureus). Infected tissues were dispersed in a sonic system and were spread (10 microl) on salt mannitol agar. Microorganisms were counted and the inhibition zones were measured after 18 h of incubation at 37 degrees C. Amoxicillin tissue concentration was 6.27 microg/g for group 1, 2.18 microg/g for group 2, and 0.72 microg/g for group 3. The serum concentrations were 11.56 microg/ml for group 1, 5.36 microg/ml for group 2, and 1.34 microg/ml for group 3. No differences were observed among group 1, 2, and 3 regarding staphylococci counts (Kruskall-Wallis test p>0.05). Group 4 reduced (p<0.05) staphylococci counts comparing to group 5. It was concluded that sodium diclofenac reduced serum and tissue amoxicillin concentration and, even in large doses, amoxicillin was not effective in eradicating the staphylococcal infection after 6 h of administration.

Amoxicillin↗
PubMed2000

Antimycotic agents in oral candidosis: an overview: 2. Treatment of oral candidosis.

As both humans and fungi are eukaryotic organisms, antifungal agents affect their cellular metabolism. Thus, a relatively few antifungals with minimal toxicity and side-effects are available compared with a plethora of antibacterials. These agents currently prescribed in dentistry belong to two major groups, the polyenes (nystatin and amphotericin B) and the azoles (imidazoles and triazoles). A newly recognized phenomenon known as the post-antifungal effect implies that antifungals, even at sub-therapeutic concentrations, may suppress the virulent attributes of yeasts, especially intra-orally where topical drug levels fluctuate dramatically during dosing intervals.

Amphotericin B↗
PubMed1998

Levofloxacin and sparfloxacin: new quinolone antibiotics.

OBJECTIVE: To discuss the pharmacology, pharmacokinetics, spectrum of activity, clinical trials, and adverse effects of levofloxacin and sparfloxacin, two new fluoroquinolone antibiotics. DATA SOURCES: Literature was identified by a MEDLINE search from January 1985 to September 1997. Abstracts and presentations were identified by review of program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy from 1988 to 1996. STUDY SELECTION: Randomized, controlled clinical studies were selected for evaluation; however, uncontrolled studies were included when data were limited for indications approved by the Food and Drug Administration (FDA). In vitro data were selected from comparison trials whenever available. Only in vitro trials that provided data on the minimum inhibitory concentrations required to inhibit 90% of isolates were used. Data from North American studies were selected whenever available. DATA EXTRACTION: Data were evaluated with respect to in vitro activity, study design, clinical and microbiologic outcomes, and adverse drug reactions. DATA SYNTHESIS: Levofloxacin and sparfloxacin are active against pathogens frequently involved in community-acquired upper and lower respiratory tract infections, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae. Both compounds have enhanced activity compared with ciprofloxacin against most gram-positive bacteria, including enterococci, streptococci, and staphylococci, and retain good activity against most Enterobacteriaceae and Pseudomonas aeruginosa. Sparfloxacin has greater anaerobic activity than levofloxacin, which is more active than ciprofloxacin or ofloxacin. Although many clinical studies are available only in abstract form, the clinical data demonstrate that these new quinolones are effective for most community-acquired upper and lower respiratory tract infections, urinary tract infections, gonococcal and nongonococcal urethritis, and skin and skin structure infections. FDA-approved indications are limited for both compounds to date. CONCLUSIONS: Levofloxacin and sparfloxacin have improved gram-positive activity compared with that of older fluoroquinolones, and are administered once daily. Sparfloxacin-associated photosensitivity may limit its therapeutic usefulness. Clinical trials confirm that these agents are as effective as traditional therapies for the management of community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis, urinary tract infections, acute gonococcal and nongonococcal urethritis, and skin and skin structure infections.

Absorption↗
PubMed1999

Intravenous azithromycin.

OBJECTIVE: To review the pharmacology, microbiology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous azithromycin. DATA SOURCES: A MEDLINE search from 1978 to May 1998 of the English-language literature and an extensive review of journals and meeting abstracts was conducted. Due to the lack of published literature concerning the efficacy, safety, and pharmacokinetics of the intravenous formulation of azithromycin, the manufacturer was also contacted and requested to supply information concerning intravenous azithromycin. DATA EXTRACTION: In vitro and preclinical studies were included, as well as data from Phase II and III clinical trials. Efficacy, pharmacokinetic, safety, and tolerability data were also supplemented with information from the manufacturer, due to the lack of published reports. DATA SYNTHESIS: Azithromycin, an azalide subclass of the macrolide antibiotics, is now available as an intravenous formulation. The intravenous form is approved for the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae. Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus (methicillin-sensitive), and Streptococcus pneumoniae, and for the treatment of pelvic inflammatory disease caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in situations in which intravenous therapy is required. Its spectrum of activity, unique pharmacokinetics, and high and sustained tissue penetration allow for once-daily dosing with monotherapy in many cases. Clinical and bacteriologic response rates as well as the adverse event profile have been similar to or better than comparative agents. CONCLUSIONS: Azithromycin offers advantages over other agents due to its unique pharmacokinetics, high and sustained tissue penetration, and spectrum of activity. This allows for monotherapy and once-daily intravenous dosing for mild-to-moderate community-acquired pneumonia or pelvic inflammatory disease in many instances. Future research should focus on total duration of antibiotic therapy and the need, or lack thereof, for extensive oral antibiotic follow-up.

Anti-Bacterial Agents↗
PubMed2000

Voriconazole: a new triazole antifungal.

OBJECTIVE: To review the currently available information on the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of voriconazole. Comparative data for voriconazole and other azole antifungal agents are described where available. DATA SOURCES: A MEDLINE search restricted to English-language articles (1966 to September 1999) was conducted, and an extensive review of journals and meeting abstracts was performed. MeSH headings included itraconazole, fluconazole, voriconazole, UK-109,496, and amphotericin B. DATA EXTRACTION: The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled studies and case reports were evaluated to demonstrate the efficacy of voriconazole in treatment of various fungal infections. DATA SYNTHESIS: Voriconazole is a derivative of fluconazole that demonstrates enhanced in vitro activity against existent and emerging fungal pathogens. Limited data have revealed a favorable pharmacokinetic and safety profile for the agent. Moreover, select clinical trials and case studies of voriconazole suggest good in vivo efficacy against several fungal pathogens including Candida, Aspergillus, and Scedosporium. CONCLUSIONS: Voriconazole has shown promise in the treatment of superficial and systemic mycoses. While several unresolved issues remain, voriconazole may be a viable therapeutic alternative for fluconazole-resistant mucocutaneous candidiasis and in cases of mild to moderate systemic mycoses requiring chronic treatment or that are refractory to currently available agents.

Antifungal Agents↗
PubMed2002

Caspofungin.

Available systemically effective antifungal agents for the treatment of invasive fungal infections are few. With the increasing recognition of a need for newer antifungal drugs, caspofungin has been introduced as the first member of a new class of compounds called echinocandins. This paper reviews the chemistry and mechanism of action of caspofungin, its activity in vitro and in animal models, and clinical pharmacokinetics,clinical efficacy and safety in patients.

Animals↗
PubMed2001

Telithromycin: a new ketolide antimicrobial for treatment of respiratory tract infections.

Telithromycin is a new ketolide antimicrobial, specifically developed for the treatment of community-acquired respiratory tract infections. It has a wide spectrum of antibacterial activity against common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. It also has activity against atypical pathogens, such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. Telithromycin maintains activity against beta-lactam and macrolide-resistant respiratory tract pathogens and does not appear to induce cross-resistance to other members of the macrolide-lincosamide-streptogramin (MLS) group of antimicrobials. It demonstrates bactericidal activity against S. pneumoniae and H. influenzae and has a prolonged concentration-dependent post-antibiotic effect (PAE) in vitro. The drug has favourable pharmacokinetics following oral administration. It is well absorbed, achieves good plasma levels and is highly concentrated in pulmonary tissues and white blood cells. In clinical trials, telithromycin given orally at a dose of 800 mg once daily for 5 - 10 days was as effective as comparator antimicrobials for the treatment of adults with community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis and group A-beta-haemolytic streptococcal pharyngitis or tonsillitis. The adverse events and safety profile were similar to comparator antimicrobials. The most common adverse events were diarrhoea, nausea, headache and dizziness. Telithromycin should provide an effective, convenient and well-tolerated once-daily oral therapy for treatment of respiratory infections.

Anti-Bacterial Agents↗
PubMed2000

A review of clinical trials with fluoroquinolones with an emphasis on new agents.

This review aims to provide a comparison between the antimicrobial spectra, pharmacokinetics and clinical efficacy of the newer fluoroquinolones with older agents in this class, as well as other antibiotics used to treat lower respiratory and urinary tract infections (LRTIs and UTIs) respectively. Increasing antimicrobial resistance among common uro- and respiratory pathogens has focused attention on the development of fluoroquinolones, which have a broad spectrum of activity and improved tissue penetration. The new and developmental quinolones can be administered on a once-daily basis and exhibit high oral bioavailability, which reduces the need for parenteral therapy in hospitalised patients and may therefore potentially reduce the need for hospitalisation. These attributes, coupled with their expanded spectrum suggest that the newer fluoroquinolones are so far the most ideal agents for the empirical treatment of many common infections.

Anti-Infective Agents↗
PubMed2002

Ketolides in the treatment of respiratory infections.

The ketolides are a new class of macrolides specifically designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. There are currently two ketolides in the late stages of clinical development in the US (telithromycin [HMR-364, Kelek; Aventis] and ABT-773 [Abbot Laboratories]), as well as newer compounds in earlier stages of testing. Ketolides have a mechanism of action very similar to that of erythromycin A. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive and some Gram-negative aerobes and have are active against macrolide-resistant Streptococcus species, including most mef A and erm B strains of Streptococcus pneumoniae. Ketolides have pharmacokinetics which allow once-daily dosing and extensive tissue distribution with very high uptake into respiratory tissues and fluids relative to serum. Evidence suggests the ketolides are primarily metabolised by the cytochrome P450 (CYP) enzyme system in the liver and that elimination is a combination of biliary, hepatic and urinary excretion. Clinical trial data are only available for telithromycin and have focused on respiratory tract infections (RTIs) including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Ketolides have similar safety profiles to the newer macrolides. In summary, early clinical trials support the clinical efficacy of the ketolides in common RTIs, including activity against macrolide-resistant pathogens.

Anti-Bacterial Agents↗
PubMed1999

Human immunodeficiency virus protease inhibitors.

Human immunodeficiency virus (HIV) protease inhibitors have revolutionized the treatment of individuals infected with this pathogen. The protease is an enzyme that is essential for viral replication because it cleaves both structural and functional proteins from precursor viral polyprotein strands. Inhibition of this process suppresses viral replication, which produces immature noninfectious virions. When combined with reverse transcriptase inhibitors, these agents are very potent in suppressing viral replication. Pharmacologic properties, toxic profile, drug interactions, and resistance patterns differ among protease inhibitors, and all must be considered when selecting the drugs for therapeutic use in humans. The best combination, sequence of use, durability of response, and magnitude of immune reconstitution and function are issues that have yet to be fully elucidated.

Clinical Trials as Topic↗
PubMed1994

Pefloxacin clinical pharmacokinetics.

Pefloxacin has a broad spectrum of activity against a great number of Gram-negative and Gram-positive bacteria. It is also capable of penetration into cells, yielding high tissue:serum ratios, with implications for the treatment of infections caused by intracellular pathogens. Pefloxacin is well absorbed from the gastrointestinal tract. Its elimination half-life ranges from 6.2 to 12.4 hours. After repeated administration, a major change in pharmacokinetic parameters is observed. Pharmacokinetic parameters are minimally altered or not altered in patients with impaired renal function. Altered plasma pharmacokinetics in patients with liver insufficiency and in elderly patients are observed, so dosage adjustments are necessary. In addition, pefloxacin interacts with a number of other compounds at hepatic (e.g. theophylline and cimetidine) and gastrointestinal (e.g. antacids) sites. With the exception of saliva, cerebrospinal fluid, aqueous humor, vitreous fluid and amniotic fluid, body fluid concentrations reach plasma concentrations. Studies on tissue penetration show that concentrations exceeding plasma concentrations are obtained in most tissues. The highest tissue:plasma concentration ratios are achieved in lung and kidney, whereas concentrations in fat are considerably lower than those in plasma.

Absorption↗
PubMed1971

Rifampicin: a review.

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Abnormalities, Drug-Induced↗