Cost-effective use of once-daily ceftriaxone: overview of a symposium.
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Ambulatory Care↗
Biomedical subjects
P Periti
Publications and source records attributed to P Periti.
Combination chemotherapy with cyclophosphamide, fluorouracil, and either epirubicin or mitoxantrone: a comparative randomized multicenter study in metastatic breast carcinoma.
From February 1987 to January 1989, 60 patients with advanced breast cancer and no prior chemotherapy for advanced disease were randomized and studied, with 31 treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) and 29 patients with fluorouracil, mitoxantrone, and cyclophosphamide (FNC). Doses were 500 mg/m2 fluorouracil, 500 mg/m2 cyclophosphamide, and 50 mg/m2 epirubicin2 or 10 mg/m mitoxantrone, i.v. Day 1 every 3 weeks. There were no statistically significant differences in pretreatment patient characteristics between the groups. Fifty-six patients were evaluable for response (29 in the FEC arm and 27 in the FNC arm). The response rates were 48.2% for the FEC group (complete response (CR) 10.3% and partial response (PR) 37.9%) and 40.7% for the FNC group (CR 3.7% and PR 37%) (not significantly different, NS). The median response duration was 247 and 267 days, respectively (NS), the median time to progression and time to treatment failure was 244 and 155.5 days for the FEC group and 86 and 98 days for the FNC group, respectively (NS). The incidence of nausea/vomiting was 87.1% in the FEC group and 79.3% in the FNC group, with comparable severity. Alopecia occurred in 80.6% of FEC patients and 44.8% of FNC patients (p less than 0.05). The incidences and degrees of severity of leukopenia, anemia, and cardiotoxicity were comparable in the two treatment groups. Efficacy and toxicity of the two regimens were quite similar. FNC can improve the quality of life of patients by providing significantly less alopecia.
Antineoplastic Combined Chemotherapy Protocols↗
Concentration-effect relationship for antimicrobial drugs.
The many relevant pharmacokinetic aspects influencing the relationship between antimicrobial drug concentration in the blood and at infection site with their pharmacodynamic effects are discussed, with particular regard to rules upon which clinical treatment modalities are based.
Anti-Bacterial Agents↗
Anandron (RU 23908) in metastatic prostate cancer: preliminary results of a multicentric Italian study.
Between March 1986 and March 1987, 48 patients with stage D prostate carcinoma were entered into a multicentric pilot study using the pure nonsteroidal antiandrogen nilutamide (Anandron--RU 23908) at the dose of 100 mg t.i.d. as the only therapy until disease progression or the occurrence of toxicity. Minimum follow-up was 15 months. Median age of patients was 72 (56 to 83) and median initial Performance Status (PS) was 1 (0 to 3). Of the 48 patients, 29 were untreated, while 19 patients were progressing following treatment by orchiectomy, LHRH analogs, or other endocrine therapies. According to the National Prostatic Cancer Project (NPCP) criteria, 43 patients were evaluable for response. Overall best response in untreated patients was partial response (PR), 41.6%; stationary disease (SD), 54.1%; 73.6% of pretreated patients achieved SD. Median progression-free survival and overall survival in untreated patients were 325 and 696 days, respectively, and 174 and 447 days, respectively, in pretreated patients. The more common side effects were G.I. toxicity (65%), hemeralopia (27%), and alcohol intolerance (6.2%). Results of this study suggest that Anandron may be a safe and effective treatment for patients with advanced prostatic cancer.
Aged↗
Biochemical modulation of fluoropyrimidines by antifolates and folates in an in vitro model of human leukemia.
Although 5-fluorouracil (FUra) is one of the most effective cytotoxic agents in the treatment of various solid tumors (carcinomas of the gastro-intestinal tract, breast, head and neck), remissions occur in only 20 to 30% of cases and usually are of short duration. Recently, preclinical studies have shown that the antitumor activity of FUra can be potentiated by modulating the metabolism of this drug by using other substances, in particular antifolates of folates. Pretreatment with antifolates may, by blocking de novo purine biosynthesis and consequently increasing phosphoribosyl pyrophosphate (PRPP) pools, enhance the conversion of FUra to active fluoronucleotide pools via orotate phosphoribosyltransferase. Methotrexate (MTX) pretreatment may also enhance binding of the fluoropyrimidine inhibitor, 5-fluodeoxyuridylate (FdUMP), to the target enzyme, thymidylate synthase (TS), indirectly by increasing dihydrofolate polyglutamates or directly, as MTX polyglutamates, by enhancing the formation of ternary complexes with FdUMP and TS. Exogenous folates, in particular 5-formyltetrahydrofolate (folinate, leucovorin, LV), can, by raising the intracellular levels of 5, 10-methylenetetrahydrofolate, lead to increased formation and stabilization of the ternary complex formed by TS, the folate coenzyme, and FdUMP. In vitro studies have also shown potentiation of FUra cytotoxicity by antifolates and folates against human lymphoblastic leukemia cell lines. Thus, while FUra may have little or no single agent activity in leukemias and lymphomas, it may be converted to an active drug in these neoplasms by appropriate modulation. Clinical studies of sequential MTX-FUra or combined LV-FUra based upon experimental tumor results reviewed herein, are warranted.
Antineoplastic Combined Chemotherapy Protocols↗
Efficacy and tolerance of cefpodoxime proxetil compared with co-amoxiclav in the treatment of exacerbations of chronic bronchitis.
This European, multicentre trial evaluated the efficacy and tolerance of cefpodoxime proxetil in comparison with co-amoxiclav (amoxycillin plus clavulanic acid) in the treatment of acute exacerbations of chronic bronchitis. The study design was double-blind and double-placebo controlled. Doses of either 200 mg bd of cefpodoxime proxetil or 500 mg/125 mg tds amoxycillin plus clavulanic acid were given orally for 9.6 +/- 1.8 days. Two hundred and fifty-one patients were enrolled in 27 centres in West Germany, France, and Italy. The overall clinical efficacy was 97.2% in the cefpodoxime proxetil group compared with 94.7% in the co-amoxiclav group. Fifty-eight adverse events, mainly gastrointestinal, occurred in 42 patients with no significant difference between the groups. A significant difference in the number of resistant pathogens on pre-treatment culture to the advantage of cefpodoxime was noted. In our experience, both drugs were of similar value in the treatment of respiratory tract infections. Thus, cefpodoxime proxetil should be an effective antibiotic for the treatment of acute exacerbations of chronic bronchitis.
Adult↗
Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients.
A total of 21 patients with advanced prostatic cancer and one patient with benign prostatic hypertrophy received 3.75, 7.5 or 15 mg leuprorelin acetate depot subcutaneously. Serum leuprorelin concentrations increased immediately after injection, reaching a peak concentration (range 13.1-54.5 ng/ml), which was directly proportional to dose, within 3 h. Mean drug levels subsequently declined to a plateau directly proportional to dose at 5 weeks. There was also a significant (P less than 0.01) dose-dependent increase in the area under the concentration-time curve for 0-35 days. Serum concentrations of luteinizing hormone and follicle stimulating hormone rose initially with all doses, followed by a rise in serum testosterone and dihydrotestosterone concentrations, which then fell sharply, within 3 weeks. A reduced level of follicle stimulating hormone subsequently occurred in all 20 evaluable patients and was maintained in 17 patients over 5 weeks. There was also marked initial suppression of luteinizing hormone levels in 15 patients and in 13 this continued. Castration levels of testosterone and dihydrotestosterone were maintained in all patients for up to 5 weeks. In two patients there was a complete response, in 14 a partial response and in three stable disease, with no significant differences in relation to dose. Clinical improvement and serum hormonal changes suggest that leuprorelin acetate depot is effective at a dose as low as 3.75 mg when given once every 4 weeks.
Aged↗
Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicentre trial.
The therapeutic efficacy and safety of various doses of leuprorelin acetate depot were determined in an open, multicentre study of patients with locally advanced or metastatic prostatic cancer (stages C, D1 or D2). Patients were randomly assigned to receive 3.75 mg (30 cases), 7.5 mg (eight cases), 15 mg (eight cases) and 30 mg (one patient) leuprorelin acetate depot administered subcutaneously once every 4 weeks. Of the 43 patients evaluable, two (5%) had complete remission, 23 (53%) partial remission and 13 (30%) patients stable disease. No significant differences were observed in response rates in relation to dose, disease stage or previous hormonal therapy. Disappearance or improvement in bone pain and urinary symptoms occurred in 63% and 79% of cases, respectively. Serum androgen concentrations decreased rapidly and persistently to castration levels, without significant differences for different doses. Treatment was well tolerated with a low incidence of mild side-effects - gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%). It is concluded that 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks is able to produce hormonal effects in all patients, an overall objective response comparable to that obtained using higher doses.
Aged↗
Comparative in vitro activity of the new oxazolidinones DuP 721 and DuP 105 against staphylococci and streptococci.
The in vitro activity of DuP 721 and DuP 105, two orally active members of the oxazolidinones, was compared with that of glycopeptides and ciprofloxacin against 185 gram-positive isolates. Ninety percent of Staphylococcus aureus isolates, including penicillin- and methicillin-resistant strains, were inhibited by DuP 721 at 1 micrograms/ml and by DuP 105 at 16 micrograms/ml; DuP 721 inhibited 90% of coagulase-negative staphylococci tested at 1 micrograms/ml. The MIC90 for Streptococcus faecalis was 4 micrograms/ml with DuP 721 and 16 micrograms/ml with DuP 105; DuP 721 inhibited 90% of beta-hemolytic streptococci of group A at 0.5 micrograms/ml. Similar results on selected strains were obtained by continuously recording the optical density of cultures.
Anti-Bacterial Agents↗
Single-dose cefotetan vs. multiple-dose cefoxitin--antimicrobial prophylaxis in colorectal surgery. Results of a prospective, multicenter, randomized study.
This multicenter, prospective, randomized trial of short-term antimicrobial prophylaxis in colorectal surgery was designed to compare the efficacy of a single dose of cefotetan vs. multiple doses of cefoxitin. Of the 403 evaluable patients, 206 received cefoxitin (1 gm intravenously at the beginning of surgery and after 3, 6, and 12 hours, group A) and 197 cefotetan (2 gm intravenously at the beginning of surgery, group B). The two groups of patients were similar in respect to age, sex, obesity, preoperative weight loss, diabetes, type of disease, type, and mean duration of surgery. The abdominal wound infection rate was 11.2 percent in group A and 9.1 percent in group B (difference not significant). The number of patients with infections at nonsurgical sites (respiratory and urinary tract, phlebitis, and septicemia) was significantly greater in group A than in group B (17 vs. 9.1 percent, P less than .05). The mean postoperative hospital stay was similar in both the cefoxitin and cefotetan groups (15.1 vs. 15.9 days). Both regimens were inadequate in preventing infections in the presence of severe contamination of the operative field.
Adult↗
Drug resistance in cancer: an overview of the clinical aspects.
The primary cause of failure of the pharmacological treatment of cancer is the occurrence of intrinsic or acquired resistance to drugs in tumor cells. Drug resistance occurs through a variety of mechanisms and usually results from mutation or amplification of genes. Biochemical and genetic mechanisms by which tumor cells may become resistant clinically to chemotherapeutic agents are reviewed. Strategies for preventing or circumventing drug resistance are also discussed.
Antineoplastic Agents↗
Tissue distribution of antimicrobial drugs.
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Anti-Bacterial Agents↗
Ceftriaxone as short-term antimicrobial chemoprophylaxis in orthopedic surgery: a 1-year multicenter follow-up. Preliminary results of a controlled multicentre study.
In this multicentre study, 883 evaluable patients undergoing orthopedic surgery were randomly assigned to receive antiinfective prophylaxis with either ceftriaxone (Rocephin) or cefamandole. 25 patients in the ceftriaxone group and 29 patients in the cefamandole group (5.6 vs 6.5%) presented with infectious complications within the first 60 days after surgery. Delayed deep wound infections developed in only 1 of 435 patients in the ceftriaxone group compared with 4 of 413 patients in the cefamandole group. Both drugs were well tolerated. The infection rate was twice as high after surgery in conventional operating theatres than after treatment in hypersterile operating theatres (3.3 vs 6.5%); this difference is not statistically significant.
Adolescent↗
Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I).
The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t1/2) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t1/2 ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t1/2 (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t1/2 values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient.(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗
Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II).
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Aging↗
Clinical pharmacokinetics of enoxacin in subjects with renal or hepatic impairment.
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Administration, Oral↗
Beta-lactamase evaluation of the amoxycillin-clavulanate association.
The capability of potassium clavulanate to protect amoxycillin from destruction by three partially purified beta-lactamases (from E. cloacae, B. cereus 569/H9 and E. coli R-TEM) was evaluated. The enzymatic inhibition was determined spectrophotometrically by assessing the ability of either amoxycillin or potassium clavulanate or their combination (at a 7:1 ratio by weight) to prevent the hydrolysis of a chromogenic substrate (nitrocefin) after different pre-incubation times, thus determining the IC50 and Ki values. Potassium clavulanate significantly reduced the IC50 values of amoxycillin for B. cereus and TEM enzymes by a factor ranging from 500 to 1200, by inhibiting these beta-lactamases at concentrations ranging from 4 to 0.008 microM. However, clavulanic acid was quite ineffective against type I enzymes (from E. cloacae), while amoxycillin was found to be sufficiently stable (IC50 of 0.8-1.4 microM).
Amoxicillin↗
Pharmacokinetics, endocrine and antitumour effects of leuprolide depot (TAP-144-SR) in advanced prostatic cancer: a dose-response evaluation.
Twenty-two patients with advanced prostatic cancer and one with benign prostatic hypertrophy were given the GnRH analogue leuprolide in the form of a slow-release depot formulation by subcutaneous injection at doses of 3.75, 7.5, 15 or 30 mg. Following the first dose, drug levels were measured by a double-antibody RIA over an observation period of 5 weeks. Thereafter patients continued long-term subcutaneous treatment at the same dose every 4 weeks. Serum levels of leuprolide showed a rapid increase immediately after injection, reaching a peak proportional to dose within 3 h (range of mean values 13.1-54.5 ng/ml). Subsequently, mean drug levels declined to a plateau proportional to dose (0.49-1.99 ng/ml at 5 weeks). A significant dose-dependent increase in the area under the serum concentration-time curve from zero to 35 days (AUC0-35 days) from 541.7 to 1653.9 ng/ml.h was also noted (p less than 0.01). With all doses there was an initial rise in serum LH and FSH, followed by a rise in testosterone and dihydrotestosterone, then a sharp decrease within 3 weeks. FSH inhibition was achieved in all the 20 evaluable patients and was maintained in 17 of them (85%) over 5 weeks. Fifteen subjects (75%) had marked suppression of LH levels. In 13 of them (65%) this condition continued for the entire observation time. Castration levels of serum testosterone and dihydrotestosterone, however, were maintained in all patients for up to 5 weeks. Two of the 21 evaluable patients (10%) had a complete response; 15 a partial response (71%) and 3 stable disease (14%). No significant differences were observed in relation to dose. Clinical improvement and serum hormonal changes support this as a new and superior method of administration of leuprolide at a dose as low as 3.75 mg.
Aged↗