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D M Cocchetto

Publications and source records attributed to D M Cocchetto.

At least 19 recordsLinked to original sources
PubMed1995

The Investigators' Brochure: a comparison of the draft international conference on harmonisation guideline with current Food and Drug Administration requirements.

For several years, the United States Food and Drug Administration (FDA) has participated in a collaborative effort to harmonize the technical procedures for development and regulatory approval of human pharmaceuticals in multiple countries. This harmonization effort is the work of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). At this point, ICH focuses on achieving harmonization of technical requirements in three major regions of the world, i.e., the United States, European Union, and Japan. One area for which harmonization is being sought is the format and content of the Investigators' Brochure. On October 27, 1993, the ICH Steering Committee agreed that the ICH draft guideline on the Investigators' Brochure should be made available for public comment. On August 9, 1994, the FDA published the draft guideline for the format and content of the Investigators' Brochure. This draft guideline was prepared by the Efficacy Expert Working Group of the ICH. FDA solicited written comments on this draft guideline until October 11, 1994. Ultimately, FDA intends to adopt the ICH Steering Committee's final guidelines on Investigators' Brochures as part of a larger document on good clinical practices. Therefore, the content of this draft guideline warrants careful attention. In this paper, ICH's proposed information for inclusion in the Investigators' Brochure is reviewed and compared with current regulatory requirements of FDA. The expanded contents of the Investigators' Brochure proposed by ICH, which represent potential new requirements beyond current FDA regulations, are highlighted. The major controversial elements of this draft guideline are summarized.

Drug Approval↗
PubMed1993

Dose-response study of inhaled salmeterol in asthmatic patients with 24-hour spirometry and Holter monitoring.

Salmeterol is a new long-acting beta 2-selective adrenoceptor agonist. In this double-blind, 6-way crossover study, four single doses of salmeterol by metered dose inhaler (12.5, 25, 50, 100 micrograms) were compared with albuterol aerosol 200 micrograms and placebo in 24 patients with moderate asthma with 24-hour pulmonary function testing and Holter monitoring. Salmeterol was an effective bronchodilator at each dose evaluated and demonstrated a greater increase in FEV1 above baseline, a slightly slower onset and a longer duration of bronchodilation than albuterol. Median durations of bronchodilation were 9.0, 15.6, 13.4, and 18.4 hours with increasing doses of salmeterol in comparison to 4.2 hours for albuterol. Holter monitoring showed (1) a mean maximum heart rate 2 to 5 bpm higher after salmeterol 50 and 100 micrograms compared with placebo and (2) supraventricular premature beats (> 30 per hour or > 100 per 24 hours) more often in the salmeterol 100-micrograms group (13% to 17% of patients) than in the placebo (4%), albuterol (4% to 8%), or other salmeterol groups (4% to 9%). These differences were not statistically significant. Tremor and palpitations were the most frequently reported drug-related adverse events and their frequencies increased with increasing doses of salmeterol. This study demonstrated that single doses of salmeterol given by metered dose inhaler over an 8-fold range possess substantial, long-lasting bronchodilator activity.

Administration, Inhalation↗
PubMed1991

Paradoxical bronchospasm after use of inhalation aerosols: a review of the literature.

Various formulations of beta-agonists and other bronchodilators have been associated with unexpected bronchoconstriction in certain individuals. Even though the number of affected individuals represents a relatively small percentage and the etiologies may differ among patients, it is important for the public to be aware of the potential for paradoxical bronchospasm and for the physician to investigate each case accordingly.

Administration, Inhalation↗
PubMed1991

Improved stability in oral delivery of albuterol provides less variability in bronchodilation in adults with asthma.

The objective of this randomized, single-blind, parallel group study was to determine whether a more constant rate of albuterol delivery from tablets provides less variability in bronchodilation. Thirty-eight adult patients were enrolled with FEV1 between 40% to 80% of predicted normal and greater than or equal to 15% reversibility. Eighteen patients received Volmax, 8 mg bid, and 20 patients received Proventil Repetabs, 8 mg (as two 4-mg tablets) bid. The magnitude and duration of bronchodilation were determined after the first dose and at steady state on treatment day 7 by measuring serial values of pulmonary function for 12 hours on each day. Interpatient variability in bronchodilation was calculated for each study day did not differ significantly between treatments, the interpatient variability in bronchodilation with Volmax was, on average, one-half of that experienced with Proventil Repetabs. Adverse events, mainly headache and tremor, were comparable between Volmax and Proventil Repetabs. This study demonstrates that Volmax achieves less variable bronchodilation through a more constant rate of drug delivery from the onset of therapy.

Administration, Oral↗
PubMed1990

Treatment of Pseudomonas meningitis with ceftazidime with or without concurrent therapy.

In ongoing studies in Europe and the United States, 10 pediatric patients with bacterial meningitis caused by Pseudomonas species were treated with ceftazidime. Pseudomonas aeruginosa was isolated from the CSF of 7 patients and other Pseudomonas species from the remaining 3. Eight of the 10 patients had received previous antimicrobial treatment which included aminoglycosides in 6, along with ticarcillin and ureidopenicillins in 3. Ceftazidime was administered 10 to 42 days in dosages ranging from 109 to 300 mg/kg/day. Seven of the 10 patients received ceftazidime only for 10 to 42 days. The other 3 patients received amikacin in 2 and gentamicin and tobramycin in the other. Seven patients were cured clinically and 3 died; 9 were cured bacteriologically and one who was presumed cured on the basis of clinical response subsequently died. Sterilization of the cerebrospinal fluid occurred at 48 hours to 12 days. Ceftazidime appears useful in treating bacterial meningitis caused by Pseudomonas species.

Adolescent↗
PubMed1990

Ceftazidime/clindamycin versus tobramycin/clindamycin in the treatment of intra-abdominal infections.

In order to assess the efficacy and toxicity of ceftazidime as a substitute for aminoglycosides in the treatment of intra-abdominal sepsis, a prospective randomized trial was conducted. Ninety-four patients (49% trauma) were randomized to receive ceftazidime/clindamycin (CAZ/C) (n = 47) or tobramycin/clindamycin (T/C) (n = 47). CAZ (2.0 gm) and C (0.9 gm) were administered intravenously every 8 hours while T dosage was adjusted to maintain peak (5-8 mg/L) and trough (less than 2 mg/L) concentrations. Age, sex, baseline serum creatinine, and etiology of infection were comparable in the two groups. Clinical cure was similar in culture-positive and culture-negative patients who received CAZ/C (94% vs 88%). The clinical cure rate however was significantly lower in the T/C culture positive (73%) than in the culture negative patients (100%) (P = 0.016). Pathogenic organisms were eradicated in 100% (30/30) and 76% (13/17) of CAZ/C and T/C patients, respectively (P = 0.0006). Nephrotoxicity Nephrotoxicity or ototoxicity was observed in none of the CAZ/C patients and in one and two T/C patients, respectively. CAZ/C more effectively eradicated the bacteria isolated from these patients and no significant difference in clinical response was observed in culture-positive patients. These findings plus the lack of toxicity suggest that CAZ/C is an effective alternative for treatment of IAI.

Abdomen↗
PubMed1989

Comparative evaluation of cefuroxime axetil and cefaclor for treatment of acute bacterial maxillary sinusitis.

Cefuroxime axetil, a new beta-lactamase-stable cephalosporin, was compared with cefaclor for the treatment of acute bacterial maxillary sinusitis in 106 adult patients. Direct sinus aspirations for quantitative bacterial culture were done for all patients before treatment; aspiration was repeated for most patients after treatment. Pretreatment sinus aspirates were positive for 63 of 134 sampled sinuses. Of specimens yielding at least 10(4) CFU/mL, Haemophilus influenzae (38%) and Streptococcus pneumoniae (37%) were the most common pathogens. Ten (42%) of 24 strains of H influenzae, 2 (40%) of 5 Haemophilus parainfluenzae, and all 3 isolates (60%) of Branhamella catarrhalis produced beta-lactamase. Cefuroxime axetil, 250 mg twice a day, was compared with cefaclor, 500 mg three times a day. Among culture-positive sinuses, bacteriologic cure was achieved in 36 (95%) of 38 sinuses and 15 (71%) of 21 sinuses treated with cefuroxime axetil and cefaclor, respectively. The overall frequencies of adverse events were similar between drugs, although cefuroxime axetil was associated with more frequent diarrhea. Cefuroxime axetil was an effective therapy for the treatment of acute bacterial maxillary sinusitis in adults.

Acute Disease↗
PubMed1989

Clinical comparison of single-oral-dose cefuroxime axetil and amoxicillin with probenecid for uncomplicated gonococcal infections in women.

Four hundred sixty-six female patients were enrolled in a randomized study that compared the clinical efficacies of single oral doses of cefuroxime axetil and amoxicillin with probenecid in the treatment of uncomplicated gonorrhea. Two hundred ninety-five patients had culture-positive gonococcal infections and completed the investigation. Cure rates for the patients treated with cefuroxime axetil and those treated with amoxicillin with probenecid were high (greater than 95%) for genitorectal infections. Pharyngeal infections, however, were not uniformly eradicated by either cefuroxime axetil (60%) or amoxicillin with probenecid (64%). Approximately 13% of each patient group suffered adverse events, which were gastrointestinal in the majority and were transient. Compared with amoxicillin plus probenecid, cefuroxime axetil in a single oral dose was an equally safe and effective drug for the treatment of uncomplicated gonorrhea in women caused by penicillin-susceptible strains.

Adolescent↗
PubMed1988

Disposition of ceftazidime in surgical patients with intra-abdominal infection.

The disposition of ceftazidime was assessed in 11 surgical patients with suspected intra-abdominal infection. All patients had normal hepatic function, and creatinine clearances ranged from 43 to 186 ml/min. Patients received 2 g of ceftazidime intravenously every 8 h. Trough and peak concentrations in serum were measured on day 2, and trough and postdose concentrations in serum were determined on 10 samples collected during a dosage interval between days 3 and 6 of therapy. Ceftazidime peak and trough concentrations in serum at steady state determined by high-performance liquid chromatography were 257.4 +/- 122.0 (mean +/- standard deviation) and 13.1 +/- 20.6 mg/liter. The serum-concentration-versus-time profile was multiexponential. The elimination half-life, steady-state volume of distribution, and total body clearance were 2.52 +/- 1.39 h, 0.31 +/- 0.12 liter/kg, and 0.11 +/- 0.05 liter/h per kg, respectively. Total predicted body clearance significantly correlated with the measured values (r = 0.868; P = 0.001). The disposition of ceftazidime is dependent on creatinine clearance and is not significantly altered by surgery or acute infectious processes.

Abdomen↗
PubMed1987

Ceftazidime as single-agent therapy for gram-negative aerobic bacillary osteomyelitis.

The cases of 28 patients who received ceftazidime as single-agent therapy in prospective clinical trials for biopsy culture-proven osteomyelitis were reviewed. These cases all involved infection caused by gram-negative aerobic bacilli, the most frequent agent (83% of patients) being Pseudomonas aeruginosa. Posttreatment follow-up for patients with acute osteomyelitis was continued for at least 6 months, while follow-up for at least 12 months was done for patients with chronic osteomyelitis. A regimen of 2 g of ceftazidime intravenously every 12 h was used for most patients. The overall cure rates were 77% (acute disease) and 60% (chronic disease). Development of resistance to ceftazidime was not problematic, and the drug was well tolerated. Ceftazidime is effective for serious gram-negative bacillary osteomyelitis, including that due to P. aeruginosa. The twice-daily regimen did not cause major organ toxicity, eliminating the need for concentration monitoring and making it feasible to use the drug for home parenteral therapy.

Adolescent↗
PubMed1987

Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drugs.

The ability of a wide variety of anionic, cationic, and neutral drugs to bind in a reversible manner to plasma proteins has long been recognised. Non-steroidal anti-inflammatory drugs (NSAIDs) are distinguished as a class by the high degree to which they bind to plasma protein. Plasma protein binding properties are primary determinants of the pharmacokinetic properties of the NSAIDs. Theoretical relationships are reviewed in order to define quantitatively the impact of plasma protein binding on clearance, half-life, apparent volume of distribution, and the duration and intensity of pharmacological effect. The quantitative relationships governing competitive displacement binding interactions are also presented. Experimental methods for in vitro and in vivo determination of the degree of plasma protein binding are discussed. The more common in vitro methods are equilibrium dialysis and ultrafiltration. Methods for characterising the degree of plasma protein binding in vivo consist of either measuring the concentration of drug at equilibrium in an implanted semipermeable vessel or measuring the relative drug concentrations in two body spaces with different protein content. Emphasis is given to the comparative advantages and disadvantages of experimental application of the various in vitro and in vivo methods. Plasma protein binding is discussed as a determinant of the trans-synovial transport of NSAIDs. Trans-synovial transport of NSAIDs appears to be a diffusional process. Limited data in humans receiving ibuprofen, indomethacin, aspirin, carprofen, alclofenac, or diclofenac suggest that clearance of each of these NSAIDs from the synovium is slower than clearance from plasma. The clinical data relevant to the relationship between plasma NSAID concentration and various measures of anti-inflammatory effect are reviewed. A positive correlation between plasma NSAID concentration and anti-inflammatory effect has been observed in only one study on naproxen and one study on piroxicam. In several other studies, the lack of concentration-response correlations is generally attributed to the relatively subjective, quantitatively inexact methods used to assess anti-inflammatory effect and analgesia in arthritic patients, as well as the substantial interpatient variabilities in the fraction of unbound NSAID and the unbound plasma NSAID concentration. In view of the generally poor correlation between concentration and therapeutic response, routine therapeutic monitoring of total plasma NSAID concentration is not recommended as a means of titrating individual dosages to the desired effect in each patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Cefuroxime axetil and penicillin V compared in the treatment of group A beta-hemolytic streptococcal pharyngitis.

Patients with the signs and symptoms of acute tonsillopharyngitis were treated with cefuroxime axetil, an orally administered, beta-lactamase stable cephalosporin, or penicillin V for ten days. Group A beta-hemolytic streptococcal (GABHS) infection was confirmed bacteriologically in 115 patients. Patients aged 13 to 18 years received 250 mg of cefuroxime or 500 mg of penicillin V twice daily. Bacteriologic cure was found in 33 (94%) of 35 patients treated with the cefuroxime and in 12 (67%) of 18 treated with penicillin (P less than 0.05). Patients aged 4 to 12 years who received 125 mg of cefuroxime axetil twice daily also experienced a greater rate of bacteriologic cure than patients who received 250 mg of penicillin V three times daily, but the difference was not statistically significant. Cefuroxime axetil is at least as effective as penicillin V in the management of streptococcal pharyngitis and may be more effective in preventing the carrier state.

Adolescent↗
PubMed1986

Bimodal frequency distribution of rat hepatic vitamin K-dependent carboxylation rate.

The time course of vitamin K-dependent carboxylation was studied in an in vitro rat hepatic microsomal system. This method is based on incorporation of radiolabelled CO2 into endogenous substrate proteins. Forty rats were studied in order to characterize the intrinsic formation rate (V/KM) of carboxylated vitamin K-dependent proteins and the maximum amount of endogenous substrate available for vitamin K-dependent carboxylation (P infinity; normalized for the total amount of microsomal protein harvested). The frequency distributions of V/KM and P infinity values were both well described as the sum of two Gaussian components, each representing about 40% and 60% of the populations.

Animals↗
PubMed1986

Studies in rats on in vitro inhibition and in vivo activity of vitamin-K-dependent carboxylation.

Vitamin-K-dependent procoagulant activity was studied in vitro by characterizing vitamin-K-dependent carboxylation and in vivo by assessing prothrombin complex activity (PCA). The kinetics of endogenous substrate carboxylation were apparently first order. Inhibition of vitamin-K-dependent carboxylation versus antagonist concentration was determined for 2,3,5,6-tetrachloropyridin-4-ol (TCP), phenindione, 2,6-dichloroindophenol sodium (2,6-DIP), 2-chloro-1,4-naphthoquinone (chloro-K3), 2-chloro-3-phytyl-1,4-naphthoquinone (chloro-K1) and warfarin. These compounds represent different chemical classes of anticoagulants that exert their effects via vitamin K antagonism. The percent inhibition versus concentration plots exhibited a sigmoidal shape and were described by the logistic function. The following concentrations were associated with 50% inhibition of vitamin-K-dependent carboxylation: TCP = 1.23 +/- 0.238 microM (mean +/- SD), phenindione = 19.0 +/- 11.2 microM, 2,6-DIP = 116 +/- 39.2 microM, chloro-K3 = 146 +/- 62.1 microM, chloro-K1 = 285 +/- 89.3 microM and warfarin = 6.63 +/- 2.82 mM. The slope parameters of the percent inhibition versus concentration plots for chloro-K1 and phenindione were different from those for the other antagonists, suggesting a mechanism of action consistent with other data in the literature, i.e. competitive antagonism of the vitamin-K-dependent carboxylase. The relationships between in vitro parameters of vitamin-K-dependent carboxylation of precursor proteins and in vivo indices of rate of production of vitamin-K-dependent coagulation factors were studied in control animals and animals pretreated with compounds perturbing hepatic function. The in vivo rate of synthesis of prothrombin complex activity and the circulating levels of PCA were correlated with the in vitro first-order rate constant of vitamin-K-dependent carboxylation, but not with the amount of precursor proteins present. The results of these studies suggest that the rate of vitamin-K-dependent carboxylation is intimately involved in the regulation of levels and activity of vitamin-K-dependent coagulation factors.

2,6-Dichloroindophenol↗
PubMed1986

Ceftazidime versus tobramycin plus ticarcillin in the treatment of soft-tissue infections.

Case report forms from a multicenter, randomized trial comparing ceftazidime (50 patients) with tobramycin plus ticarcillin (control group, 44 patients) in the treatment of skin and soft-tissue infections were reviewed. Two subsets of patients were identified. The target patient population (group I) comprised older patients with predisposing chronic disease (eg, diabetes mellitus) and an average of 1.8 bacterial pathogens per patient. Necrotizing soft-tissue and postoperative wound infections predominated. Group II comprised younger patients with acute onset of monomicrobial cellulitis or staphylococcal or streptococcal abscess. Clinical cure or improvement was achieved in 93% of ceftazidime-treated and 94% of control group I patients. Bacteriological eradication of the initial pathogens without superinfection was obtained in 85% and 82%, respectively, of the two treatment groups. In group II, each of the nine ceftazidime-treated patients was cured or improved and bacteria were eradicated; in the control group, nine of ten patients were clinically and bacteriologically cured. Among all patients, Staphylococcus aureus was eradicated in 18 of 19 treated with ceftazidime and in 14 of 15 treated with the control agents. The results of the study demonstrate the efficacy of ceftazidime as initial monotherapy for soft-tissue infections in patients with compromised vascularity.

Abscess↗
PubMed1985

Behavioral perturbations in the vitamin K-deficient rat.

Anecdotal observations of the behavior of rats with a vitamin K-deficiency suggested that this deficiency was associated with hypoactivity, general malaise, and a lack of exploratory behavior. These observations were pursued by assessing locomotor activity in a circular photocell-monitored track, open-field activity, and radial-arm maze performance in rats rendered vitamin K-deficient by dietary depletion or by warfarin treatment. There was a significant reduction (approximately 25% at the median) in the locomotor activity of dietary vitamin K-deficient rats compared with rats fed a control diet. In the open-field, warfarin administration was associated with a significant shift from more exploratory behaviors to less exploratory behaviors. Consistent with these findings, radial-arm maze assessment showed a comparative reduction in locomotor activity in the dietary vitamin K-deficient rats with no alteration in performance, i.e., short-term memory. These animal behavioral studies suggest that sub-clinical and clinical vitamin K-deficiency may contribute to physical and psychiatric symptomatology.

Animals↗