[Antihistaminics in pediatric age]. / Gli antistaminici in età pediatrica.

Histamine determines a variety of physiologic and pathologic responses in different tissues and cells and it is an important chemical mediator on inflammation in allergic disease. Therefore the H1-receptor antagonist are among the most widely used medications in the world. We review here the molecular basis of their action and their clinical pharmacology, efficacy in allergic disorders and adverse reaction with a particular attention in children. We will also underline the different role of first generation H1-receptor, relatively sedating, and the second generation H1-receptor antagonist, relatively non-sedating.

Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation.

Six hundred and thirty four adolescents and children aged three days to 17 years treated with ciprofloxacin on a compassionate basis were analysed for drug safety. 62% of the ciprofloxacin courses were given to patients with respiratory tract infection, primarily those with acute pulmonary exacerbation of cystic fibrosis. The mean daily oral dose was 25.2 mg/kg body weight. The duration of treatment ranged from one to 880 days (mean 22.8 days). Because of the arthropathogenic potential of quinolones in juvenile animals special emphasis was placed on the evaluation of musculoskeletal adverse events. Arthralgia considered by the treating physicians to be related to ciprofloxacin was reported in eight children, all of whom were females. Arthralgia resolved in all children. Some of these children were given subsequent courses of ciprofloxacin with no complaints of arthralgia. Overall, the safety profile of ciprofloxacin in children is not substantially different from that of adults.

Safety of intravenous ciprofloxacin. A review.

Data from 1,878 courses of intravenous ciprofloxacin therapy, administered to 1,869 patients in 59 clinical trials, were analyzed for drug safety. The 985 men and 884 women had a mean age of 50 years, and more than one third were over 60 years of age. An overwhelming majority had at least one accompanying systemic illness, and the condition of more than half the patients was only fair or poor at the onset of therapy. Ciprofloxacin was administered in a unit dose of either 200 mg (68 percent of the patients) or 300 mg (28 percent) by intravenous infusion, generally over 30 minutes every 12 hours, at a mean daily dosage of 456 mg. The duration of intravenous therapy ranged from one to 57 days, with a mean of seven days; over 1,000 patients were treated for more than five days. Adverse events considered probably or possibly related to intravenous ciprofloxacin were reported in 15.8 percent of the courses; therapy was discontinued prematurely in 3 percent. Local reactions at the site of infusion were the most common, occurring in 4.4 percent of the courses. Changes in blood chemistry values (4.1 percent) included increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Reports of adverse effects referable to the gastrointestinal tract (3.0 percent) were primarily nausea and diarrhea. Central nervous system reactions (1.8 percent) included convulsive seizures, headache, and dizziness. In comparative trials, events considered probably or possibly drug related were reported for 17.3 and 13.6 percent of the ciprofloxacin- and ceftazidime-treated patients, respectively. The incidence of adverse events other than local reactions at the infusion site was not significantly different between the ciprofloxacin- and ceftazidime-treated patients (12.7 percent versus 11.0 percent, p greater than 0.2).

Safety of oral ciprofloxacin. An update based on clinical trial results.

The safety of ciprofloxacin was established on a data base (compiled through the end of 1988) of 9,473 well-documented treatment courses world-wide. The daily dosages ranged between 200 and 2,000 mg orally. Thirty-eight percent of the patients received doses between 1 and 10 mg/kg body weight, 46 percent between 11 and 20 mg/kg, and the remaining 16 percent more than 20 mg/kg body weight daily. Ciprofloxacin was administered to 4,214 women (45 percent) and 5,252 men (55 percent). The duration of treatment ranged from less than two days to more than 90 days. A 600-mg daily dose of ciprofloxacin was used mostly in Japan (2,341 patients). The daily dose of 1,000 mg was administered chiefly in the United States and Europe (2,288 patients). The age of the patients ranged from less than one year to 99 years (mean, 50.6 years). More than 38 percent were older than 60 years. According to COSTART terminology, the following drug-related side effects were observed in the different organ systems: digestive, 4.9 percent; metabolic-nutritional, 4.4 percent; central nervous system, 1.5 percent, skin, 1.1 percent; hemic and lymphatic, 0.9 percent; urogenital, 0.8 percent; body as a whole, 0.5 percent; cardiovascular, 0.2 percent; special senses, 0.2 percent; musculoskeletal, 0.1 percent; and respiratory, 0.1 percent. Several patients had more than one reaction. The total incidence of side effects for the treated patients was 9.3 percent. The vast majority of adverse reactions were mild or moderate (94 percent). Serious side effects were reported for 55 patients (6 percent). Based on the 9,473 courses, the incidence of severe reactions was 0.6 percent. Ciprofloxacin treatment was discontinued due to side effects in 146 patients (1.5 percent), mostly due to gastrointestinal reactions (80 patients). The worldwide data from clinical trials with oral ciprofloxacin clearly demonstrate that the drug is relatively safe, and the side effects are usually mild or moderate in intensity and are reversible.

A survey of clinical experience with ciprofloxacin, a new quinolone antimicrobial.

Ciprofloxacin is a new quinolone antimicrobial agent with activity against a broad spectrum of gram-negative and gram-positive organisms, including Pseudomonas aeruginosa and methicillin-resistant strains of staphylococci. The efficacy and safety results of 80 clinical studies of the oral form of ciprofloxacin are reported. Drug safety was assessed in 2236 courses in 2203 adult patients treated primarily in the United States. Data from 1676 courses were suitable for analysis of drug efficacy. The unit dose for most patients ranged from 250 mg to 750 mg (median, 500 mg), usually given every 12 hours. The duration of treatment ranged from 3 to 231 days (median, 10 days). Predominant among 1722 infections were those of the urinary tract (43%), skin structures (29%), and respiratory tract (19%); the remainder were bone and joint infections (5%), bacteremias (2%), and intra-abdominal (1%), gastrointestinal (1%), and pelvic infections (less than 1%). Signs and symptoms of infection resolved in 79% of all cases; a further 15% improved, and 5% failed to improve. Pathogens were eradicated in 89% of urinary tract infections and persisted in 5%; 80% of patients still had sterile urine at the 3-to 6-week follow-up. In 81% of nonurinary tract infections, pathogens were eradicated; they persisted in 11%, and superinfection occurred in less than 5%. After treatment, 89% of the 2253 causative organisms were eradicated and 2% were reduced to clinically insignificant counts; 8% persisted. Of 411 isolates of P. aeruginosa, 77% were eradicated, as were 97% of 421 Escherichia coli and 80% of 248 Staphylococcus aureus isolates. Also eradicated were 95% of 166 Klebsiella, 96% of 139 Proteus mirabilis, 100% of 20 other Proteus, 94% of 123 Enterobacter, 100% of 68 Haemophilus influenzae, 96% of 49 Citrobacter, 89% of 45 Serratia, 95% of 41 Streptococcus pneumoniae, 91% of 43 Salmonella, 100% of 38 Morganella morganii, and 100% of 35 Providencia isolates. Adverse reactions were judged probably or possibly drug-related in 14.8% of courses; drug treatment had to be stopped prematurely in 3.5%. The most frequent reactions were gastrointestinal complaints (chiefly nausea, diarrhea, and vomiting), metabolic disorders (elevated SGOT, SGPT, serum creatinine, or blood urea nitrogen), and nervous system effects (dizziness, light-headedness, restlessness, tremor, and headache). Crystalluria, judged to be related to ciprofloxacin, occurred in two patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Worldwide clinical data on efficacy and safety of ciprofloxacin.

During the clinical trials 8,861 patients have been treated with ciprofloxacin worldwide. 3,822 of the therapeutic courses were valid for analysis of efficacy according to FDA standards. The following dosages were usually administered: UTI: 100 to 500 mg twice daily orally or 100 mg twice daily intravenously; RTI: 250 to 1000 mg twice daily orally or 200 mg twice daily intravenously; septicemia: 200 mg intravenously twice daily; gonorrhea: 250 to 500 mg single tablet orally; all other infections: 500 to 1000 mg twice daily orally or 200 mg twice daily intravenously. Ciprofloxacin was administered to 762 courses of lower RTI, 88 courses of upper RTI, 108 courses of bacteremia, 766 courses of skin structure infection, 142 courses of bone and joint infections, 149 courses of intra-abdominal infections, 33 courses of gastrointestinal infections, 1,633 courses of UTI, 49 courses of pelvic infections, 279 courses of STD, mainly gonorrhea, and three courses of meningitis. The clinical response was resolution in 76%, improvement in 18% and failure in only 6%. Bacteriologic response by all sites evaluable: pathogens were eradicated from 74%, markedly reduced in 2%, persisted in 10%. Relapse occurred in 4% and reinfection was observed in another 6%. The overall response was favourable for 90% of the patients. Drug safety was established on a data base of 8,861 courses worldwide. The following side-effects according to COSTART terminology were observed: digestive 5%, metabolic nutritional 4.6%, central nervous 1.6%, skin 1.4%, hemic and lymphatic 1%, cardiovascular 0.4%, body as a whole 0.4%, urogenital 0.3%, special senses 0.3%, musculo-skeletal 0.1%, respiratory 0.08%. Several courses had more than one reaction. Thus the total incidence of side-effects for the treated patient population was 10.2%. Ciprofloxacin is a highly effective drug and a breakthrough in several areas of medical interest. It is relatively safe and side-effects are usually mild or moderate in intensity and transient.

Ciprofloxacin: an update on clinical experience.

This report presents the results of 146 clinical trials of the oral form of ciprofloxacin, a new quinolone antimicrobial agent active against a broad spectrum of gram-negative and gram-positive organisms, including Pseudomonas aeruginosa and methicillin-resistant strains of staphylococci. The safety of ciprofloxacin was assessed in 2,829 patients, most of whom were treated in the United States, and the analysis of efficacy was based on data from 3,981 patients evaluated through June 1986. In general, the patients received ciprofloxacin at a dosage of 250 to 750 mg every 12 hours; the median dose was 500 mg twice daily. Dose-ranging studies in male patients with urinary tract infections indicated that a regimen of 500 or 750 mg twice daily was not substantially more effective than a regimen of 250 mg twice daily. Forty-four double-blind, controlled trials were conducted to compare the efficacy and safety of oral ciprofloxacin with those of standard therapeutic agents in the treatment of infections of the urinary tract, skin and skin structure, respiratory tract, and bone. Ciprofloxacin at 250 mg twice daily was as effective as trimethoprim/sulfamethoxazole at 160/800 mg twice daily in the treatment of urinary tract infections. Orally administered ciprofloxacin in a regimen of 750 mg twice daily was shown to be as effective as cefotaxime administered intravenously at 2 g three times daily in the treatment of infections of the skin and skin structure. When compared with ampicillin for the treatment of respiratory tract infections, ciprofloxacin was as effective in resolving or improving markedly the signs and symptoms of infection and eradicated a higher percentage of causative organisms. Adverse reactions considered probably or possibly related to the drug were reported for 16.2 percent of the patients treated; most were of only mild or moderate intensity and resolved after therapy was completed. Emergence of resistant organisms associated with ciprofloxacin therapy has been reported infrequently.

Clinical experience with ciprofloxacin in the USA.

This interim analysis of the efficacy and safety of ciprofloxacin is based on case reports of 1241 adult patients treated primarily in the USA; 1026 were suitable for analysis of drug efficacy. The daily dose ranged from 500 to 1500 mg, the unit dose being given every 12 h. Duration of treatment ranged from 5 to 211 days (mean 12.6 days). In 1046 cases of infection the site was the urinary tract (514), skin structures (218), respiratory tract (215), blood (43), bone (27), abdomen (13), gastrointestinal tract (13) and pelvis (3). Organisms responsible for infection were Escherichia coli (282), Pseudomonas aeruginosa (238), Staphylococcus spp. (149), Streptococcus spp. (107), Klebsiella spp. (105), Proteus spp. (97), Haemophilus spp. (71), Enterobacter spp. (58), Salmonella spp. (44), Citrobacter spp. (27), and Serratia spp. (22). Signs and symptoms of infection resolved in 84% of all cases; 12.6% improved and 3.4% failed to improve. Pathogens were eradicated in 91% of urinary tract infections and in 87% of all other cases of infection combined; superinfections occurred in 5.3% of all patients. At the four-week follow-up 83% of patients with urinary tract infection still had sterile urine. Adverse reactions during therapy were considered probably or possibly drug-related in 166 patients. Nausea (37), diarrhea (25), vomiting (15), nervousness (28), and rash (9) were the most frequent; in only 2% of cases was it necessary to discontinue the drug. Results of ophthalmologic studies were generally unremarkable. Occasional elevations of SGOT and SGPT, and rare elevations of NPN related to ciprofloxacin therapy were seen.

International clinical experience with azlocillin.

Clinical studies with azlocillin were conducted in North America and Europe to assess its efficacy and to monitor its safety. The results of studies from these two areas are compared retrospectively. In North America 631 multiple-dose courses were monitored, while 887 were given in Europe. The most frequently administered daily dose was 18 g in North America and 15 g in Europe. In 71% of the courses a Pseudomonas species was the causative infecting organism in the former area and 51% in the latter. Over 60% of the patients were seriously ill, and about a third were over 60 years of age. A satisfactory bacteriological response, as defined by the eradication or a marked reduction of the organism causing infection was obtained in 74% of patients in North America and in 75% in Europe. 89% of the patients in America responded clinically compared to 92% in Europe. Ps. aeruginosa was eradicated in over 70% of instances. Azlocillin, like other penicillins, possesses a low potential for toxicity. Hypersensitivity reactions and gastrointestinal effects were the most common adverse experiences. No serious problems were encountered with impairment of renal or hepatic function, or blood coagulation. Azlocillin was effective for treating serious infections caused primarily by Ps. aeruginosa.

Process of developing a new antimicrobial drug.

The network for development of a new antimicrobial drug, from discovery of the compound to submission of the New Drug Application, is reviewed. The key problems encountered during this process, as elucidated through a survey of 62 American pharmaceutical companies, include difficulties in discovering new and significant antimicrobial drugs, the unpredictability of in-vitro and animal studies, lack of specific criteria for the bacteriologic response to therapy, difficulties in setting up well-controlled clinical studies, and difficulty with the timely enrollment of suitable patients with precise microbiologic diagnosis before treatment.

Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoside antibiotic.

Netilmicin (Sch 20569) is a new broad-spectrum semisynthetic aminoglycoside derived from sisomicin. Netilmicin was compared to gentamicin, tobramycin, and amikacin in a variety of in vitro test systems as well as in mouse protection tests. Netilmicin was found to be similar in activity to gentamicin against aminoglycoside-susceptible strains in both in vitro and in vivo tests. Netilmicin was also active against many aminoglycoside-resistant strains of gram-negative bacteria, particularly those known to possess adenylating enzymes (ANT 2') or those with a similar resistance pattern. Netilmicin was found to be markedly less toxic than gentamicin in chronic studies in cats, although gentamicin appeared less toxic in acute toxicity tests in mice. The concentrations of netilmicin and gentamicin in serum were compared in dogs after intramuscular dosing, and the pharmacokinetics including peak concentrations in serum were found to be similar.