Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.

Mechanisms of drug combinations: interaction and network perspectives.

The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant bacteria until 10-20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this effort. The alternative is Medicine without effective antibiotics.

/pdf/novel-classes-of-antibiotics-or-more-of-the-same-4np9my1qg7.pdf

Novel classes of antibiotics or more of the same

The data base for rational guidelines to safe, efficacious drug prescribing in adults with renal insufficiency are presented in tabular form. Current medical literature was extensively surveyed to provide as much specific information as possible. When information is lacking, however, recommendations are based on pharmacokinetic variables in normal subjects. Nephrotoxicity, important adverse effects, and special considerations in renal patients are noted. Adjustments are suggested for hemodialysis and peritoneal dialysis when appropriate.

https://www.ajkd.org/article/S0272-6386(83)80060-2/pdf

Drug Prescribing in Renal Failure: Dosing Guidelines for Adults

Many advances have been made in antifungal therapy over the last three decades. Itraconazole and fluconazole, two investigational triazole agents, are the most recent additions to the list of antifungal drugs. This review has focused primarily on their mechanisms of action, favorable pharmacologic properties, and spectra of activity against a broad range of systemic pathogens. Itraconazole and fluconazole show much promise as orally active agents, with less potential for toxicity than the currently available azoles. Fluconazole and, to a lesser degree, itraconazole are especially promising therapies for cryptococcal meningitis. In addition, fluconazole may prove to be highly effective in urinary tract infections caused by Candida species and other fungi. Ongoing and future clinical trials will more clearly define the specific roles of itraconazole and fluconazole in the treatment of systemic mycoses.

Azole antifungal agents: emphasis on new triazoles.

Ketoconazole is an imidazole derivative that is chemically related to miconazole (Fig. 1). It is an oral antimycotic agent with broad-spectrum activity and low toxicity.1 2 3 The drug is considered to represent an important innovation in the treatment of fungal disease and has been used extensively in clinical practice for the past five years. The development of gynecomastia in some patients treated for mycosis first led to the investigation of the drug's effect on the production of testosterone.4 , 5 Thereafter, ketoconazole was shown to be a potent inhibitor of gonadal and adrenal steroid synthesis in vitro and in vivo.5 6 7 8 9 10 The finding of . . .

The Use of Ketoconazole as an Inhibitor of Steroid Production

Synopsis: Ketoconazole1 is an imidazole antifungal drug structurally related to the earlier compounds in this series, such as miconazole and econazole. However, while retaining a similarly broad spectrum of antifungal activity, it differs from the earlier members of this group in that it can be administered orally to treat a wide variety of superficial or ‘deep’ fungal infections. In open studies in superficial mycoses orally administered ketoconazole was effective in patients with dermatophyte or yeast skin infections, pityriasis versicolor, onychomycoses and oral or vaginal candidosis. Additionally, results were encouraging in chronic mucocutaneous candidosis. In open studies in systemic mycoses it was effective in patients with systemic candidosis, paracoccidioidomycosis and histoplasmosis, and moderately effective in patients with coccidioidomycosis, chromomycosis or asymptomatic candiduria. Few controlled studies have been performed, and a small number of well-designed comparative studies are needed to more clearly establish the relative efficacy of ketoconazole, particularly with regard to amphotericin B in the systemic mycoses in which amphotericin B has proved useful.

Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections

Synopsis: Zomepirac1,2 is an analgesic which is closely related chemically to the non-steroidal anti-inflammatory agent, tolmetin. In short term studies mainly involving patients with acute pain of moderate severity, zomepirac was at least as effective as usual therapeutic doses of aspirin, codeine alone or with aspirin, phenacetin and caffeine, dextropropoxyphene with paracetamol, or orally administered pentazocine. Additionally, zomepirac may provide analgesia comparable to that with standard doses of intramuscular morphine in patients with acute pain of moderate intensity, but in severe pain states strong analgesics may be more appropriate. Zomepirac has also been studied in patients with chronic orthopaedic pain or osteoarthritic pain for up to several months, without the need for increased doses. It appears to be at least as effective as usual doses of aspirin when used in this way, with a lower incidence of some side effects such as gastrointestinal disturbances and hearing disorders. Preliminary studies suggest that zomepirac may also be effective in patients with chronic cancer pain who have not been previously maintained on strong analgesics, but further experience is needed to clarify its usefulness in this difficult treatment area. From animal studies and limited long term experience in man, it appears that zomepirac is not likely to produce tolerance, or physical or psychological dependence. Thus, it appears that zomepirac is a useful alternative in a variety of acute and chronic pain states in which analgesics such as aspirin, dextropropoxyphene with paracetamol or orally administered pentazocine would be considered appropriate. Whether its usefulness extends beyond this spectrum, into more severe pain states, needs further clarification. Pharmacodynamic Studies: In vitro studies using homogenised bovine seminal vesicles and human platelets have shown that, in common with aspirin and other non-steroidal anti-inflammatory agents, zomepirac is a potent inhibitor of prostaglandin synthesis. It has typical antinociceptive activity in a standard animal model, showing similar potency (on a weight-for-weight basis) to subcutaneously administered morphine and greater potency than orally administered aspirin, paracetamol and pentazocine and subcutaneously administered codeine and pentazocine in the acetylcholine-induced writhing test in mice, which also detects narcotic-type analgesic activity. However, zomepirac is devoid of activity in other standard animal tests which are specifically designed to detect narcotic-type analgesic activity. Zomepirac showed more potent anti-inflammatory activity than aspirin in a range of animal models to detect both acute (adjuvant-induced arthritis and carrageenan-induced oedema tests in rats) and chronic (adjuvant-induced arthritis test in rats) anti-inflammatory activity, but its anti-inflammatory effects have not been investigated in man. As with other prostaglandin synthetase inhibitors, zomepirac produces dose-dependent increases in gastrointestinal blood loss in healthy subjects and in patients. Ulcerogenic activity has been demonstrated in animals, but the incidences of gastrointestinal bleeding and peptic ulcer have been low in patients who have received long term zomepirac therapy to date. Zomepirac has an antiplatelet effect similar to that found with aspirin, but the duration of this effect after discontinuation is shorter with zomepirac (about 12 hours) than with aspirin (4 to 7 days). Studies in healthy subjects have indicated that zomepirac has no clinically significant effects on other haematological parameters, including haemoglobin concentration, haematocrit, platelet count, prothrombin time and red blood cell survival time. Elevations of blood urea nitrogen and creatinine have occasionally been found in patients receiving long term zomepirac therapy. Studies in animals and patients receiving long term zomepirac therapy for chronic pain have suggested that zomepirac has little or no dependence liability or abuse potential, but only wider use over longer periods will determine this with certainty. Pharmacokinetic Studies: On the basis of urinary recovery data, zomepirac is almost completely absorbed after oral administration of dosages of 25 to 200mg to healthy subjects. Mean peak plasma concentrations of 2.47, 4.42 and 7.94μg/ml were attained 44, 57 and 80 minutes after a single oral dose of 50, 100 or 200mg, respectively. Bioavailability is the same after ingestion of tablets, capsules or an aqueous solution. In common with aspirin and other non-steroidal anti-inflammatory agents, zomepirac is extensively bound (98.5 %) to plasma albumin. The elimination half-life of zomepirac is about 4 hours following a single dose, but may be increased following multiple doses. Zomepirac is excreted almost exclusively in the urine, the major metabolite being the glucuronide conjugate, which accounts for about 57 % of radioactivity after a 25mg dose. Hydroxyzomepirac and 4-chlorobenzoic acid are minor metabolites. About 22 % of the dose is excreted in the urine in unchanged form. Zomepirac metabolites (type not stated) are approximately 200 to 300 times less active than zomepirac as inhibitors of human platelet aggregation in vitro. Therapeutic Trials: Zomepirac has been evaluated in several single dose or short term studies in patients with acute pain of moderate (most patients) to severe intensity due to headache, oral surgery, a variety of other surgical procedures, episiotomy, or orthopaedic disorders. Most of these studies were of a similar design and have made reasonable attempts to overcome the inherent difficulties in evaluating an analgesic drug. In single-dose studies in patients with acute pain, zomepirac 50mg was less effective than zomepirac 100mg in providing analgesia. Zomepirac 100mg produced greater analgesia than aspirin 650mg, dextropropoxyphene 100mg + paracetamol 650mg, codeine 60mg, or 2 capsules of aspirin 227mg + phenacetin 162mg + caffeine 32mg (APC), and provided similar analgesia to APC (1 capsule) + codeine 60mg. In multiple-dose studies, zomepirac 50 or 100mg every 4 hours when required for pain was as effective as APC (1 capsule) + codeine 30 or 60mg, or orally administered pentazocine 50mg, and usually caused fewer side effects than these agents. Zomepirac 100 or 200mg has been compared with morphine, in intramuscular doses of up to 16mg, in single-dose crossover studies involving patients with moderate (most patients) to severe postoperative pain. 100 and 200mg doses provided similar analgesic effects, suggesting either a ‘ceiling effect’ of analgesic activity or lack of sensitivity of the pain model. These studies indicated that oral zomepirac was about one-sixth as potent as intramuscular morphine (on a weight-for-weight basis) with a slower onset but longer duration of action. However, the effectiveness of zomepirac was reduced in the small number of patients with severe pain included in such studies, and its usefulness in severe pain states needs further clarification. The long term use of zomepirac in patients with chronic pain has also been reported. Studies in patients with pain secondary to osteoarthritis have indicated that daily doses of about 300 to 400mg of zomepirac provide at least equivalent analgesia to standard doses of aspirin. Although studies to date in patients with chronic cancer pain have indicated that zomepirac may be effective, experience is limited; further studies in such patients, who have not previously been maintained on strong analgesics, are required to determine the contribution which zomepirac can make to this difficult treatment area. Side Effects: Zomepirac has been well tolerated in most patients studied to date, but further data are needed to determine clearly its profile of side effects in patients receiving long term therapy. In patients receiving zomepirac for more than 1 week, the most frequently reported side effect was nausea, occurring in approximately 12 % of the patients. Other gastrointestinal disturbances occurring in between 3 and 9 % of the patients were gastrointestinal distress, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence and vomiting. Central nervous system side effects (dizziness or insomnia) occurred in between 3 and 9 % of patients. The incidence of gastrointestinal bleeding and peptic ulcer appears to be below 1 %. In a long term comparative study, zomepirac produced a profile of side effects generally similar to that with aspirin, but the incidence of adverse reactions (apart from urogenital symptoms) was generally lower. In particular, the incidences of tinnitus 3.5 % compared with 15.3%) and hearing loss (1.0% compared with 6.9%) were considerably reduced in patients receiving zomepirac than in patients receiving aspirin. Dosage and Administration: The recommended dosage of zomepirac is 100mg every 4 to 6 hours as required for pain. In mild pain, 50mg every 4 to 6 hours may be adequate. Single doses of more than 100mg are not recommended. The daily dose of zomepirac should not exceed 600mg in patients with acute pain or 400mg in patients with chronic pain in whom treatment is expected to be continued for more than 3 months. As zomepirac has similar side effects to aspirin, it should be used with caution in patients with a history of upper gastrointestinal disease or coagulation disorders. Zomepirac is contraindicated in patients with active peptic ulcer or with a history of hypersensitivity to aspirin.

Zomepirac: A Review of its Pharmacological Properties and Analgesic Efficacy

Synopsis: Cefoperazone1 new ‘third generation’ semisynthetic injectable cephalosporin. It has a broad spectrum of antibacterial activity which includes Pseudomonas aeruginosa (unlike older cephalosporins), along with the Enterobacteriaceae and other Gram-negative bacteria, Gram-positive bacteria and anaerobic bacteria. Unlike other cephalosporins, cefoperazone is excreted to a considerable extent by extrarenal mechanisms. Given by intravenous or intramuscular injection, cefoperazone is effective against a wide variety of infections caused by Gram-negative or Gram-positive aerobes, including infections of the biliary tract, and in many anaerobic infections. It is generally well tolerated, diarrhoea and skin rashes being the most frequently reported side effects.

Cefoperazone: A Review of its In Vitro Antimicrobial Activity, Pharmacological Properties and Therapeutic Efficacy

Clavulanic acid is a beta-lactamase inhibitor produced from Streptomyces clavuligerus, which when combined with certain beta-lactam antibiotics extends their activity against bacteria which owe their resistance to the production of beta-lacatamases. In combination with amoxycillin it extends the antibacterial activity of amoxycillin to include beta-lactamase-producing strains, which are otherwise resistant, as well as amoxycillin-resistant species such as Bacteroides fragilis. The addition of clavulanic acid to amoxycillin occasionally extends (but does not decrease) the susceptibility of amoxycillin-sensitive bacteria. Clavulanic acid is adequately absorbed after oral administration and its basic pharmacokinetic characteristics are similar to those of amoxycillin. Preliminary therapeutic trials suggest that amoxycillin plus clavulanic acid is effective in urinary tract infections caused by amoxycillin-resistant organisms and in lower respiratory tract infections unresponsive to previous routine antibiotic therapy, in hospitalised patients. It is generally well tolerated; nausea, vomiting, diarrhoea and skin rash being the most frequently reported adverse effects.

Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use.

Popular Tasks used by Researchers

How can I help with your research?

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

We encountered an error while loading the panel. Please try refreshing the page.

Something went wrong

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

Anyone with the link can view this chat. You can switch it back to private anytime.

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

P. A. Morley

Author Tools

Chat about Author

Papers

Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections

Zomepirac: A Review of its Pharmacological Properties and Analgesic Efficacy

Cefoperazone: A Review of its In Vitro Antimicrobial Activity, Pharmacological Properties and Therapeutic Efficacy

Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use.