Transintestinal elimination of ciprofloxacin.

This study identified the routes of elimination of ciprofloxacin in two groups of five subjects each: one of healthy volunteers; the other of patients with severe renal failure having mean creatinine clearance of 12 ml/min (range, 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously (IV) over 30 min. In an effort to recover the total drug administered, all urine and feces were collected for 7 days following dosing. Blood samples were drawn at set intervals. Serum, urine, and feces were assayed for ciprofloxacin and metabolites by high-pressure liquid chromatography. The ciprofloxacin elimination half-life was 3.9 +/- 0.4 hr in the healthy volunteers and 11.2 +/- 2.5 hr in the patients with severe renal failure. The total 7-day recovery of ciprofloxacin and its metabolites in urine and feces ranged from 74.0% to 114.7% of the dose (mean, 96.3 +/- 14.1%) in normal subjects and from 48.5% to 109.1% (mean, 88.1 +/- 20.9%) in patients. The dose of ciprofloxacin recovered in urine was 65.3 +/- 10.7% in healthy subjects and 19.0 +/- 15.9% in impaired patients (reduction factor, 3.4). In contrast, the dose recovered in feces was 11.4 +/- 2.6% in the group of normal subjects and 37.2 +/- 12.5% in the group of patients with impaired renal function in a 3.3-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ciprofloxacin.

The fluorination of piperazinyl substituted quinolones has led to an interesting development of a series of new broad spectrum antibacterial agents that may be administered orally as well as parenterally and are well tolerated. Norfloxacin was an early compound, later followed by ciprofloxacin, enoxacin, ofloxacin and pefloxacin. In this overview the emphasis will be on the most extensively studied compound including comparisons, where data are available, with norfloxacin and ofloxacin. Enoxacin and pefloxacin will be omitted due to their pattern of side effects, which at present curtail their therapeutic use. More recent substances such as fleroxacin and defloxacin have not been sufficiently investigated to be considered in this context.

Nine months' subcutaneous therapy with synthetic growth hormone releasing factor in children with short stature.

The growth promoting potential of GRF(1-29)NH2 was studied in nine boys with short stature over three periods of 3 months. Their short stature was due to partial hGH deficiency/hGH neurosecretory dysfunction and was diagnosed by arginine and insulin stimulation tests and hGH nocturnal profiles. Four patients (Group I) were given GRF, 3-4 micrograms/kg s.c. b.d. during the first period of 3 months, and after an interval of 1 month, the same dose once daily during the second treatment period of 3 months. Five patients (Group II) were given GRF, 3-4 micrograms/kg s.c., once daily during the first and b.d. during the second 3 months of therapy. After a second interval of 1 month without any GRF treatment, the third 3-month period for both groups consisted of one daily injection of GRF, 8-10 micrograms/kg s.c. at 19.00 hours. Total body height and lower leg length were measured by stadiometry and knemometry, respectively. GRF intravenous bolus tests were performed in each patient following fasting, before and at the end of the first and second 3-month periods. Serum IGF-1 and urinary hydroxyproline excretion were determined monthly. Stadiometric growth rate, determined over the whole study period of 11 months including the treatment-free intervals, increased from 4.92 cm/year to 5.97 cm/year (p greater than 0.05). Mean knemometric growth rates increased from 0.28 mm/week before therapy, to 0.35 mm/week during the one injection/day period at low dose, to 0.39 mm/week (p less than 0.05) during the b.d. period, and to 0.40 mm/week during the last 3 months of high-dose GRF given once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerance of intravenously administered ciprofloxacin.

Twelve healthy volunteers received single doses of 200, 300, and 400 mg ciprofloxacin intravenously (30-min infusion). Crystals appeared in the urine of only 1 subject after the 400 mg dose. The crystals appeared in the 0-2 h urine specimen only and were observed immediately upon voiding while the urine was maintained at 37 degrees C. The pH of the urine was 7.3. The event was without untoward consequences to the person as evidenced by urinalysis and blood chemistry. Local skin reactions occurred on the arm of the infusion (cutaneous erythema, itching and burning sensation). The reactions were less after the lowest dose. The reactions started within minutes after the beginning of the infusion and disappeared either during the infusions or immediately after the end of administration. These local reactions were of moderate degree and did not necessitate termination of the infusion.

Transintestinal elimination of ciprofloxacin.

This study elucidates the routes of elimination of ciprofloxacin and its metabolites in two groups of 5 subjects each, one of healthy volunteers, the other of patients with severe renal failure having a creatinine clearance of 12 ml/min (range 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously over 30 min. In an effort to recover the total dose administered, all urine and faeces were collected for the 7 days following dosing. Blood was collected at set intervals after dosing. Serum, urine, and faeces were assayed by high-pressure liquid chromatography for ciprofloxacin and metabolites. The ciprofloxacin serum half-life in healthy volunteers was 3.9 +/- 0.4 h and in patients with marked renal failure 11.2 +/- 2.5 h. The total amount of ciprofloxacin recovered in urine fell by a multiple of 3.4 from 65.3 +/- 10.7% in healthy subjects to 19.0 +/- 15.9% in patients with renal failure, and the metabolites from 12.2 +/- 2.3% in the former group to 5.8 +/- 5.1% in the latter. In contrast, the amount of ciprofloxacin eliminated in faeces increased, by a similar factor, from 11.4 +/- 2.6% in healthy subjects to 37.2 +/- 12.5% in patients with renal failure. The amount of metabolites in faeces increased analogously from 7.3 +/- 1.6 to 26.2 +/- 6.5%. Since ciprofloxacin was administered intravenously and biliary elimination of the drug and its metabolites is negligible, we propose that elimination by faeces is due primarily to transintestinal elimination. This study demonstrates that transintestinal elimination of ciprofloxacin serves as an extrarenal safety factor compensating for reduced elimination by the renal route.

Elimination of ciprofloxacin and three major metabolites and consequences of reduced renal function.

The pharmacokinetics and elimination of ciprofloxacin and its three major metabolites desethylene ciprofloxacin (M1), sulfonylciprofloxacin (M2), and oxociprofloxacin (M3) were determined in 18 volunteers with normal and varying degrees of reduced renal functions. One dose of 500 mg ciprofloxacin was given orally. Samples were assayed by high-pressure liquid chromatography. Serum concentrations of both ciprofloxacin and its metabolites were only slightly influenced by the renal function. The serum concentrations of the metabolites were less than 10% of the ciprofloxacin levels, even in reduced renal function, and were overlapping within groups of patients arranged according to renal function. Dialysis reduced the serum concentration of the parent compound and its metabolites. The serum half-life of ciprofloxacin in normal renal function was 5.8 +/- 1.2 h; this rose to 10.8 +/- 2.3 h in the group with clearances of 10-30 ml/min. Compared to the latter group, the t1/2 was lower (7.0 +/- 2.9 h) in the patients with terminal renal failure. The period of monitoring has a distinct consequence for the t1/2 of ciprofloxacin. The shorter t1/2 values emanate if monitoring had stopped after 10 or 12 h. A slower gamma-phase of elimination was observed and this was particularly distinct in subjects with renal functions within the normal range. The total renal elimination of the parent compound and its metabolites was approximately 60% over the 48-hour collection period in normal renal function and was reduced by about 20% in the group with clearances within the range of 10-30 ml/min. In renal impairment, there was a shift towards a higher proportion of the dose being eliminated as M2. M1 contributed only up to 2% of the dose in urine. Irrespective of the renal capacity, the amount of M3 recovered in urine was 3-4%.

Single-dose oral ciprofloxacin plus parenteral metronidazole for perioperative antibiotic prophylaxis in colorectal surgery.

From 1983 until 1990 our standard antibiotic prophylaxis in colorectal surgery has been 80 mg gentamicin plus 500 mg metronidazole, both administered intravenously at the beginning of anesthesia, and then 80 mg gentamicin every 8 h for 3 days. In this time period, 718 patients undergoing elective colorectal surgery by abdominal approach were treated with this prophylactic procedure. The mean wound infection rate was 13.4% with no significant differences between years. In the present study, including 100 adult patients, intravenous gentamicin has been replaced by a single oral dose of 750 mg ciprofloxacin randomly administered 1, 2 or 3 h (+/- 30 min) before anesthesia. All other procedures remained unchanged including intravenous metronidazole. In order to correlate an eventual infection with the actual tissue concentrations during surgery, samples of colon, peritoneum, muscle, subcutaneous fat and skin were obtained from all patients and assayed by HPLC. In only 3 cases (3% of them casuistic) was a wound infection observed, 2 of minor importance and 1 case with wound dehiscence. This infection rate is significantly lower than 13.4% obtained with our previous standard regimen, and lower than the 9% wound infection rate considered to be the 'gold standard' for elective colon resections. The effective ciprofloxacin concentrations in tissues were usually notably higher than the MICs of the pathogens commonly observed in surgical infections of colorectal surgery. By far the highest ciprofloxacin concentrations were observed in colon tissue which may explain the absence of anastomotic dehiscence or peritoneal sepsis in our series.(ABSTRACT TRUNCATED AT 250 WORDS)

Penetration of ciprofloxacin and metabolites into human lung, bronchial and pleural tissue after 250 and 500 mg oral ciprofloxacin.

Ciprofloxacin (CIP) and metabolite concentrations in lung tissue, parietal pleura and bronchial tissue were assessed in 43 adult patients who underwent lung surgery. A single oral dose of CIP was given for prophylaxis of bacterial infections. Two to 6 h prior to tissues sampling, 23 patients received 250 mg and 20 subjects 500 mg of the substance. Blood plasma samples were obtained at the same time as the lung tissue samples. CIP and its metabolites were assayed chemically by high-pressure liquid chromatography (HPLC). After 250 mg CIP, the individual lung tissue CIP concentrations during the 2- to 6-hour post-dose period ranged from 0.5 to 4.8 mg/kg. In 20 of the 23 lung samples, the CIP concentrations were above 1 mg/kg. After 500 mg CIP, the corresponding lung CIP concentrations ranged from 1.6 to 6.0 mg/kg. The CIP lung concentrations were, irrespective of the dose size, between 2 and 7 times higher than the simultaneous blood plasma concentrations. This indicates an excellent penetration of CIP and its metabolites into lung tissue. Bronchial tissue was obtained in 9 cases. Penetration into bronchial mucosa tissue was good as well, as indicated by tissue/plasma ratio values between 1.5 and 4.4. Individual CIP concentrations in the patients given 250 mg CIP, ranged from 1.0 to 1.6 mg/kg. In the patients who received 500 mg, the range was from 1.7 to 3.4 mg/kg. Tissue/plasma ratio values between 0.8 and 2.1 indicated that penetration to pleural tissues was good as well. Metabolite concentrations in all of the tissues assayed (lung, bronchial mucosa, pleural tissue) were low when compared to the concentrations of CIP. The concentrations in lung, pleural and bronchial tissue will probably permit low doses in the treatment of most respiratory tract infections. The broad spectrum of antibacterial activity, the good tissue penetration, chemical stability and the good safety record of the substance means that the drug is potentially a useful agent for perioperative antibiotic prophylaxis.

Tolerance of ciprofloxacin at injection site, systemic safety and effect on electroencephalogram.

The safety of ciprofloxacin, given via 30- and 60-min intravenous infusions at a dose of 300 mg every 12 h for 4 days, was studied in 12 healthy subjects (6 females, 6 males). Local effects of the drug were assessed by frequent examination at the infusion site while systemic safety was determined by haematological and biochemical tests and by careful microscopic examination of the urine for drug crystals and by electroencephalographic studies performed in all subjects before and after dosing. At the site of infusion erythema, itching and a burning sensation developed 10-15 min after onset of infusion in some subjects. These symptoms were slight and did not necessitate termination of the infusions. The rash disappeared in some instances during the infusion and in others within minutes after the end of infusion. The changes usually disappeared, even during the infusion. The incidence of the adverse reactions was not related to the duration of the infusion (30 or 60 min), but was less (frequency and extent) when the anticubital vein was used for infusion rather than when smaller more peripheral veins were employed. Thrombophlebitis occurred after 1 of 96 administrations, and was followed by a return to normal. The electroencephalograms remained normal in all instances. One subject experienced mild nausea of a few hours duration. Only 1 volunteer showed crystalluria; the two such specimens from this subject had the most alkaline pH of all urine samples collected in this study. The probability of crystalluria upon intravenous administration appears not to be higher than after oral administration of ciprofloxacin.

Enrichment in spontaneous and complement dependent rosette forming cell populations using Ficoll-Hypaque gradient centrifugation.

Peripheral blood human T (TL) and B (BL) lymphocytes were separated by continuous Ficoll-Hypaque (FH) gradients. BL were found at the 1050 density interfase (70.5% EAC rosettes) with no TL (0% EAC rosettes); while at the 1068 density interfase there was an enrichment of TL (68% E rosettes) with very few BL (8.5% EAC rosettes).

Treatment of superficial candidiasis with bifonazole 1% gel.

Sixty-one patients with superficial candidiasis, confirmed on entry by clinical examination and mycological culture, were treated with a single daily application of a 1% bifonazole gel over a period of 4 weeks. Patients were seen every week during treatment and then followed-up for 2 weeks. An overall assessment of response to treatment, based on the clinical and mycological culture findings at the 14-day follow-up visit, showed that the results were very good in 49 and moderate in 9 patients, with only 3 patients being considered as failing to respond. Local tolerance was very good, but burning was reported by 1 patient, burning and itching by 1, and ardor and irritation by one. All these side-effects occurred at the start of treatment and they subsided without interruption of bifonazole treatment.

Treatment of tinea corporis or tinea cruris with bifonazole 1% gel: an open, multicentre study.

An open, multicentre study was carried out in 103 patients with confirmed dermatophyte infections (tinea cruris or tinea corporis). The fungi isolated were Tr. rubrum (45), Tr. mentagrophytes (11), Ep. floccosum (26) and M. canis (21). All patients were treated with a single daily application of bifonazole (1% gel) and the duration of treatment was 3 weeks. Weekly clinical controls were performed during the therapeutic period and at least two clinical and mycological examinations were given after the end of treatment. Treatment was evaluated according to the clinical and mycological findings at the 14th post-therapeutic day. The results obtained were classified as very good in 80 patients, good in 11, moderate in 11 and failure in 1 patient. Local tolerance was very good and no side-effects were observed in any patients.

Crystalluria and ciprofloxacin, influence of urinary pH and hydration.

Ciprofloxacin is one of the newer 4-quinolones. It combines a high antibacterial activity and a broad spectrum with favourable pharmacokinetic properties. The present study was designed to detect the influence of urinary pH and fluid consumption on crystalluria. Six healthy volunteers aged 25-41 years, 3 of each sex, participated in the study. Single doses of 1,000 and 500 mg of ciprofloxacin were given orally. The urinary pH was varied by giving each subject three different diets: a regular diet, a diet supplemented by ammonium chloride to acidify urine, and a diet supplemented by sodium bicarbonate to obtain alkaline urine. The urine volume and pH were measured and microscopically examined at 37 degrees C immediately after voiding. After the very high dose of 1,000 mg ciprofloxacin the regular diet regimen led to crystalluria in only one subject. Even with this high dose, but with the acidifying regimen, no crystals were observed in any one of the volunteers. When bicarbonate was supplemented 5 to 6 volunteers presented crystals in 22 of the 36 urine samples. 21 of the crystalluric urine samples showed a pH greater than or equal to 7.3. After the usual 500-mg dose and regular diet no crystals were observed at all; only in 3 subjects who received bicarbonate supplement crystals have been seen. In the urine of two subjects crystals emerged 'ex vivo' after some hours of storage at both 37 degrees C and room temperature; these results show the importance of sediment observation at 37 degrees C immediately after voiding to differentiate between real and 'ex vivo' crystalluria. Results of different examinations permit the conclusion that the crystals contain mostly unchanged ciprofloxacin as major component and magnesium as characteristic element. Participation of the metabolite 2 in the crystal formation cannot be excluded. No significant change was observed in blood counts and blood chemistry of any subject. Urinalysis showed no modifications except the eventual presence of the typical drug-related crystals. Hematuria never occurred.

Long-term effectiveness of BAY e 5009-nitrendipine in the treatment of mild and moderate arterial hypertension.

Thirty-seven white patients of both sexes were studied to determine the efficacy and tolerance of nitrendipine for long ambulatory treatment in patients suffering from mild to moderate essential arterial hypertension whose response to the drug had been effective in a previous study. They all suffered from mild essential arterial hypertension, with diastolic arterial blood pressure (DBP) of 95-104 mm Hg, and moderate arterial hypertension with DBP of 105-114 mm Hg, in WHO Stage I or II, according to the clinical, radiological, electrocardiographic, and ophthalmoscopic examinations. In a previous study, all of them had been subjected to tensional controls, performed hourly during an 8-h period to assess their hypertension. Later, they were treated with increasing doses of nitrendipine, administered once or twice daily, until DBP figures under 90 mm Hg were obtained in at least five of the eight controls of each daily profile. All of them agreed to take part in the present research and underwent heart rate and arterial blood pressure controls in supine and standing position every 14 days during 24 periods. Simultaneous clinical and weight controls were performed. Moreover, an electrocardiogram was made every 28 days, and blood and urine tests were performed every 3 months. Of the 37 patients, 31 completed the 24 periods of 2 weeks each. Therefore, of 888 possible controls only 837 controls were made and submitted for assessment. Eighteen patients (48.6%) went on with the initial dose throughout the study or were able to reduce it. Eleven (29.7%) had to increase it, and in eight cases (21.6%) it was either increased or reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of tinea pedis interdigitalis with bifonazole, 1% gel.

329 adult patients with tinea pedis interdigitalis, which clinical diagnosis was confirmed by positive direct microscopic examinations and cultures of organisms from the lesions, were enrolled in this open and multicentric study. Informed consent was requested and obtained in each case. The bifonazole, 1% gel, tested was applied topically once daily for 3 weeks. Weekly clinical controls were performed during the treatment period and, at least, two clinical mycological posttreatment assessments were carried out. The evaluation criteria were based on the clinical and mycological findings at the end of the second posttreatment week. According to these criteria, the results obtained were: very good (clinical cure, negative mycology) 276 (84.0%); good (clinical improvement, negative mycology) 32 (9.5%); moderate (clinical improvement, positive mycology) 20 (6.0%), and failure (no clinical and mycological changes) 1 (0.5%). Tolerance was excellent, side effects were not observed in any case.

Prophylaxis of tinea pedis interdigitalis with bifonazole, 1% powder.

With the objectives of determining the effectiveness of bifonazole 1% powder in the prophylactic treatment of tinea pedis interdigitalis and its local tolerance, 200 patients who achieved clinical and mycological cure in another previous trial with bifonazole 1% gel, and who were also reliable in the compliance of the treatment, were included in this study. Informed consent was requested and obtained in each case. This was a multicenter, double-blind, controlled and comparative study of one group (100 patients) treated with bifonazole verum against another group (100 patients) treated with bifonazole placebo. The allocation to each group was performed by randomization. Bifonazole was applied once daily in the morning on both feet, after showering, and inside shoes; patients applied it again when changing shoes or socks during the day. Treatment lasted up to 6 months. During the treatment, patients were clinically and mycologically assessed once a month and, if it was necessary, when signs and/or symptoms of infection reappeared. The evaluation criteria were based on the reinfection, clinically and mycologically demonstrable, during the treatment. 29 patients abandoned the treatment. Reinfection was observed in 57 out of the 171 patients who finished the treatment, 47 reinfections occurred in the placebo group and the remaining 10 in the verum group. Tolerance was excellent, no side effects were observed in any patient.