Third-generation Drug Research Articles

Molecular Biology of Plasminogen Activators: What Are the Clinical Implications of Drug Design?

The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminoger, activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials. © 1996 by Excerpta Medica, Inc. Am J Cardiol 1996;78(suppl 12A):2–7

Cycling of antibiotics: an approach to circumvent resistance in specialized units of the hospital

Cycling of antibiotics: an approach to circumvent resistance in specialized units of the hospital

Third-generation cephalosporins

Third-generation cephalosporins are broad-spectrum antimicrobial agents useful in a variety of clinical situations. No one cephalosporin is appropriate for all infectious disease problems. Cefotaxime and ceftizoxime have the best gram-positive coverage of the third-generation agents. Ceftazidime and cefoperazone are the only third-generation drugs that provide antipseudomonal coverage. Ceftriaxone's long half-life allows for once-daily dosing, making ceftriaxone an excellent drug for outpatient antibiotic therapy of community-acquired infections. Ceftriaxone is also useful for the treatment of Lyme disease and sexually transmitted diseases. The third-generation cephalosporins except for cefoperazone penetrate cerebrospinal fluid and are indicated for the treatment of bacterial meningitis. Their proven record of clinical efficacy, favorable pharmacokinetics, and low frequency of adverse effects make third-generation cephalosporins the preferred antibiotic in many clinical situations.

A cooperative study on ProMACE-CytaBOM in aggressive non-Hodgkin's lymphomas.

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytaBOM) for patients with intermediate or high grade non-Hodgkin lymphomas (G, H and K according to the Working Formulation), was tested by the Gruppo Cooperativo Lombardo to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimen in a cooperative group setting. Among 64 previously untreated patients, aged between 20 and 71 years, 7 had stage IB-IIB, 12 had stage IIIA-B, 45 (67%) had stage IVA-B. There were 44 complete remissions (CRs) (69%) and 14 partial remissions (22%); the difference between patients in stage I-II-III (84% complete remissions) and those in stage IV (62% complete remissions) was statistically significant. The median length of follow up was 20 months (range 1-60 months), with 56% of patients alive at 60 months and 53% of CRs patients free of disease at 60 months. Patients in stage I-II-III have the best survival and disease free survival compared to stage IV, 87% versus 42% and 72% versus 32% respectively (both with high statistical significance). Grade 3-4 (WHO) haematological toxicity was observed in 39% of patients, with 3 septic deaths. Two more patients died with chemotherapy related toxicity (1 stroke and 1 acute renal insufficiency). Administration of ProMACE-CytaBOM is a feasible and safe regimen although it presents moderate toxicity. ProMACE-CytaBOM may represent improved treatment for aggressive lymphomas, in terms of duration of response and survival, but a longer follow up is needed.

Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study.

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytoBOM) for patients with intermediate- and high-grade non-Hodgkin's lymphomas was tested by the Southwest Oncology Group (SWOG) to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimens in a cooperative group setting. On day 1, cyclophosphamide, doxorubicin, and etoposide were administered, followed by cytarabine, bleomycin, vincristine and methotrexate with leucovorin given on day 8. There were 51 complete remissions (CRs) among 78 previously untreated patients (65%) having clinical stage II-IV disease. The median length of follow-up is 37.9 months with 57% of patients alive at 3 years and 50% of CR patients free of disease at 3 years. Patients with diffuse large-cell lymphoma have the best survival (63% at 3 years) and relapse-free survival (RFS; 68% at 3 years with no relapses seen after 14 months). Administration of ProMACE-CytoBOM is feasible and safe in a cooperative group setting with 84% of 537 courses of treatment given exactly according to schedule and fatal toxicities seen in five patients (6%). ProMACE-CytaBOM may represent improved treatment for diffuse large-cell lymphoma, but the modest differences compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) indicate the need for a prospective randomized comparative trial.

Endemic emergence of cephalosporin-resistant Enterobacter: relation to prior therapy.

The “second” and “third” generation cephalosporins offer striking antimicrobial activity against a wide spectrum of Enterobacteriaceae. Nevertheless, mutants resistant to these drugs have emerged in both laboratory and clinical settings. For example, before the commercial availability of the third-generation agents, we treated three cardiac surgery patients for Enterobacter mediastinitis with aminoglycosides and high doses of cefamandole. In two, initial treatment failed due to emergence of strains that were not only resistant to cefamandole, but also to then experimental third-generation drugs. Despite such reports and in vitro studies of the mechanisms of resistance, the frequency with which broad-spectrum cephalosporin resistance develops in clinical practice is not clear. To help delineate this problem, we have reviewed our hospital's experience with Enterobacter strains resistant to newer cephalosporins (using cefamandole and cefotaxime as prototypes) and the relation of resistant strains to cephalosporin use, with special attention to our cardiac surgery patients.

Ceftazidime Review

The chemistry, in vitro activity, adverse effects, and clinical indications for the new third-generation cephalosporin, ceftazidime, are reviewed. Ceftazidime appears to have a unique place among the third-generation agents in the treatment of some infectious processes caused by Pseudomonas aeruginosa. It does not demonstrate superiority to other third-generation drugs against Enterobacteriaceae, aerobic gram-positive cocci, or anaerobes. It is eliminated renally and is similar to ceftizoxime, cefoperazone, and moxalactam in half-life. Ceftazidime shares the safety profile of most of the cephalosporins, and has not been shown to have an effect on prothrombin or produce the disulfuram reaction seen with moxalactam and cefoperazone. Specific indications for its use are discussed.

Cephalosporin antibiotic agents.

The cephalosporins are a group of antibiotic agents that have been available now for 20 years. Three classes, or generations, of cephalosporins are recognized. The newer third-generation drugs have wider spectra of antibacterial activity; because of this attribute and their ability to achieve high bactericidal titres in CSF these newer compounds constitute an advance in antibiotic therapy by providing safe and effective treatment for Gram-negative bacillary meningitis. The earlier cephalosporins provide cheap, useful and convenient prophylaxis for vascular and orthopaedic operations near the inguinal area. Comparative trials with other broad-spectrum agents need to be performed before the true place of the third-generation agents in anti-infective therapy and prophylaxis is finally determined.

Changing Patterns of Resistance to New Beta-Lactarn Antibiotics: In Vitro Efficacy of Cefoperazone against Bacterial Pathogens

No evidence for significant increase in resistance to cefoperazone was detected in susceptibility test surveillance programs or in the literature through 1983, but rare endemic resistance to cefoperazone and some other newer beta-lactams was found. Medical centers contemplating the use of .a third-generation drug for cost-containment should be aware of the susceptibility of isolates in their hospitals, and the drug's ability to withstand beta-lactamase hydrolysis by local pathogens. The possible dangers of inducible cephalosporins in certain Enterobacteriaceae and strains of Pseudomonas aeruginosa are discussed in the light of the physical and chemical characteristics of the newer antimicrobial agents. Criteria for judging the values of investigational beta-lactams are presented. These focus on the interaction of antimicrobial agents with host defense mechanisms and circulating blood elements.

High hopes for 'third generation' cephalosporins

A wide therapeutic range, low toxicity, and strong clinical efficacy against previously hard-to-treat, antibiotic-resistant infections are the main advantages of what is now being called the third generation of cephalosporin antibiotics. Scores of papers covering the drugs' microbiologic, pharmacologic, and clinical performance were presented at the 12th International Congress of Chemotherapy in Florence, Italy. What is intriguing about these relatively new cephalosporins and their relatives is that they are able to destroy many of the Gram-negative microorganisms that are not affected by or have become resistant to the first-generation cephalosporins. In addition, through chemical modification of the basic cephalosporin molecular structure, the third-generation drugs are able to sidestep most of the β lactamase enzymes, which have allowed microorganisms to neutralize the effects of many of the first- and second-generation agents. Currently, the only member of the new cephalosporin family on the American market is cefotaxime, developed by Hoechst-Roussel Pharmaceuticals, Inc,