Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet

Quinolones are antibacterial agents that have the potential to induce Achilles tendon disorders - such as tendinitis or even ruptures - in patients treated with these drugs. We studied the effects of ciprofloxacin on several proteins of Achilles tendons from immature dogs, 10- to 11-weeks-old. The dogs were treated orally for 5 days with 30 or 200 mg ciprofloxacin/kg body weight or with the vehicle alone. Since quinolone-like alterations in joint cartilage were observed in magnesium-deficient animals, another group was fed a magnesium-deficient diet for 6 weeks. At necropsy, tendons (n=3 from each group) were frozen and stored until analysis when they were homogenized in a lysis buffer to release a soluble fraction of the tendon proteins. Densitometric analysis of the immunoblots with anticollagen type I, anti-elastin, anti-fibronectin, and antiintegrin antibodies showed a significant reduction of all proteins. For example, collagen type I concentrations (mean +/-SD, arbitrary densitometric units) were 3190+/-217 (controls), 1890+/-468 (30mg/kg), 1695+/-135 (200mg/kg) and 2053+/-491 in the magnesium-deficient dogs. The differences between concentrations in controls and all treated groups were statistically significant (P<0.01, t-test). Similarly, compared with control samples, relative concentrations of other proteins in tendons from ciprofloxacin-treated dogs (30 mg/kg) decreased by 73% (elastin), 88% (fibronectin), and 96% (beta1 integrin) (data from low-dose group only). A very similar pattern of protein alterations was detected in samples from magnesium-deficient dogs. In conclusion, rather low doses of a fluoroquinolone or a diet-induced magnesium deficiency caused similar biochemical alterations in the soluble fraction of proteins from canine tendons. These findings support our hypothesis that quinolone-induced toxic effects on connective tissue structures are due to the magnesium-antagonistic effects of these antibacterial agents. They also indicate that patients with a latent magnesium deficiency could be at an increased risk of quinolone-induced tendon disorders.     

The comparative arthropathy of fluoroquinolones in dogs.

1. Fluoroquinolone antibiotics are generally only prescribed to paediatric patients on compassionate grounds. This is because they are known to cause lesions in the cartilage of the major diarthroidal joints in immature experimental animals. As dogs are considered to be the most sensitive species, a series of studies was performed to compare the potential for grepafloxacin (a new fluoroquinolone) to cause arthropathy to that of ofloxacin and ciprofloxacin in juvenile (3 month old) beagles. 2. Grepafloxacin was administered once daily to male juvenile dogs at dosages of up to 100 mg/kg/day (intravenously), 60 mg/kg/day (orally) or 30 mg/kg/day (subcutaneously) for 1 week. Blister formation was observed on the surface of the joints in one of the three animals treated with grepafloxacin intravenously at 100 mg/kg/day. No abnormalities were observed at lower dosages or when grepafloxacin was administered orally or subcutaneously, regardless of dose. In animals treated with ofloxacin or ciprofloxacin at dosages of 10-30 mg/kg/day, blister formation or erosion was observed on the surface of joints regardless of dose or route of administration. 3. Histopathological examination of the joint surfaces of affected animals revealed the loss of cartilaginous matrix and chondrocytes, cavitation within the intermediate zone of cartilage accompanied by cartilage fibrillation or chondrocyte clustering, or loss of the surface layer which covers the cavitation (or loss of outer wall of the cavity). These findings were not present in the absence of grossly observed lesions. 4. Absorption following oral administration of grepafloxacin was low. Examination of plasma concentrations of drug following intravenous administration showed that joint toxicity was seen with ofloxacin and ciprofloxacin at maximum concentrations as low as 3.80 and 4.24 mg/l, respectively, while plasma levels of grepafloxacin of up to 11.95 mg/l failed to cause such lesions. When the concentration of grepafloxacin was 18.69 mg/l a single joint lesion was seen. Following subcutaneous administration of grepafloxacin, systemic exposure (area under the curve) of approximately 1.5 times that seen in man was not associated with joint lesions. However, lesions were noted for ofloxacin and ciprofloxacin treated animals at exposures equal to or below those seen in man. Therefore grepafloxacin appeared to have a relatively low potential for joint toxicity; this was not due to lack of penetration into the synovial fluid.     

Concentrations of the des-F(6)-quinolone garenoxacin in plasma and joint cartilage of immature rats

Garenoxacin is a des-F(6)-quinolone with a broad antibacterial spectrum, which has previously been shown to exhibit low chondrotoxicity in juvenile dogs compared with several other quinolones. A study was performed to determine whether the low chondrotoxicity observed in immature rats following garenoxacin treatment could be explained by poor penetration into cartilage tissue. Garenoxacin was orally administered to immature (4- to 5-week-old) Wistar rats as a single dose—or as doses given on 5 consecutive days—of 0 (vehicle), 200, 400, and 600 mg/kg (n=5 per dose level). Additional groups of rats were orally dosed with 600 mg/kg ofloxacin and ciprofloxacin. One knee joint of each animal (24 h after the last dose) was studied histologically after staining with Toluidine blue. The pharmacokinetics of garenoxacin in plasma (200, 400, and 600 mg/kg) and in knee joint cartilage (200 and 600 mg/kg) was assessed in separate groups of rats (n=55 per dose level). Concentrations of garenoxacin in plasma and cartilage were measured using an HPLC method. No signs of chondrotoxicity were observed in the immature rats treated with garenoxacin or ciprofloxacin for 5 days at the doses investigated in this study. However, ofloxacin was found to induce cartilage lesions that were typical of those seen for this quinolone. Systemic exposure to garenoxacin increased as a function of dose. Across dose and study day, mean garenoxacin plasma maximum concentration (C _max) and area under the concentration–time curve (AUC_tau) values were in the range 12–26 mg/l and 33–133 mg×h/l, respectively. Garenoxacin C _max and AUC were similar on days 1 and 5, within each dose, indicating the absence of accumulation or reduction in the systemic exposure. Values determined for T _max (0.25–1.0 h) and T _1/2 (3.8–6.4 h) of garenoxacin in plasma did not vary with dose or study day. Although peak garenoxacin concentrations in cartilage were between equal levels to and 2.5-fold of those found in plasma, the observed ratios were somewhat lower than those reported for other quinolones, e.g. ofloxacin or sparfloxacin. Since garenoxacin appeared to be well absorbed following oral administration and concentrations in cartilage tended to be higher than those in plasma, it is unlikely that the low chondrotoxicity in comparison with other quinolones is explained by differences in the pharmacokinetics of these compounds.     

Dopamine and isoproterenol in imipramine intoxication in the dog

Artificially ventilated anesthetized dogs were given imipramine 7.5 mg/kg/hr i.v. In the first group (n = 6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 +/- 6.6 mg/kg (mean +/- sd). When aortic flow had decreased to 75% of its initial value, in a second group (n = 5) of experiments dopamine 10 micrograms/kg/min and in a third group (n = 5) isoproterenol 1 microgram/kg/min were administered i.v.. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 +/- 13.3 in the dopamine and 42.5 +/- 8.0 mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 greater than p greater than 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 +/- 0.66, in the second 3.36 +/- 0.66 and in the third 3.32 +/- 1.10 mg/1. Desipramine concentrations were 0.078 +/- 0.06, 0.162 +/- 0.076 and 0.383 +/- 0.09 mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.     

Long-term effects of nicotine on bone and calciotropic hormones in adult female rats

This study determined the effects of nicotine on serum concentrations of several calciotropic hormones, and bone formation and resorption end-points in 7 month old, adult female rats. Animals were administered either saline (n= 9/group), low dose nicotine at 3.0 mg/kg/day (n=10/group) or high dose nicotine at 4.5 mg/kg/day (n=11/group) by subcutaneous osmotic minipumps. At the end of a three months treatment period, serum concentrations of calcium, phosphorus, parathyroid hormone, calcitonin, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were determined. Femora, tibiae, and lumbar vertebrae (3-5) were collected and bone parameters evaluated included mineral density and content (femora and vertebrae), strength (femora and vertebrae) and histomorphometry (tibiae). Animals given nicotine had significantly lower levels of 25-hydroxyvitamin D than controls [20.8+/-1.4 ng/ml for the low dose group and 20.7+/-1.0 ng/ ml for the high dose group versus 27.6+/-1.3 ng/ml for the control group (mean+/-S.E.M.), P<0.01]. The high dose nicotine group had smaller vertebral areas (5.4+/-0.2 mm2 versus 6.2+/-0.2 mm2, P<0.05) and a lower bone mineral content than the controls (0.024+/-0.001 g versus 0.030+/-0.001 g, P<0.05). Tibial endocortical mineral apposition rate was also significantly lower in the high dose nicotine group than in the control group (1.06+/-0.13 microm/day versus 1.42+/-0.08 microm/day. P<0.05). No significant treatment differences were detected in bone density, cancellous bone histomorphometry, or bone strength. Results from the present study suggest that nicotine administration may adversely affect bone formation and decrease body storage of vitamin D.     

Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period

A study in young beagle dogs was performed in which the animals were treated for 2 weeks with ciprofloxacin at oral doses of 0, 10, 30 or 90 mg/kg per day. Immediately after treatment half of the number of animals were killed and all weight-bearing joints were subject to a thorough gross and histopathological investigation, including special staining of the cartilage matrix, and immunohistochemistry as well as electron microscopy. The remaining animals were maintained for an additional 5-months treatment-free period before being killed. Again, all weight-bearing joints were subject to a thorough gross and histopathological investigation. After 14 days of treatment with ciprofloxacin, oral doses of 30 and 90 mg/kg induced the characteristic arthropathy (blisters, erosions) in juvenile beagle dogs. As expected the lesions persisted while the animals were growing. In contrast, and to our knowledge demonstrated for the first time, an oral dose of 10 mg/kg ciprofloxacin did not induce joint lesions after short-term treatment in juvenile beagle dogs and was also not associated with arthrotoxicity when the dogs became older.     

Comparative articular toxicity of garenoxacin,a novel quinolone antimicrobial agent,in juvenile beagle dogs

The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs. Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg. Each group consisted of 3 male dogs (Experiment I). Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days. We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin. In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group. One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints. In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs. The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively. In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group. The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group. The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups. The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups. As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.     

Steady-state serum pharmacokinetics and bioequivalence of 500 mg oral versus 200 mg intravenous ciprofloxacin

The pharmacokinetics of ciprofloxacin were examined after five days of treatment with 500 mg orally and 200 mg intravenously twice a day, in six healthy volunteers in an open, randomized crossover study. The ciprofloxacin concentrations were determined in serum by high performance liquid chromatography. The mean serum peak concentrations were obtained in 1 to 1.5 h by the oral route and the values reached were similar after the oral and intravenous dose (2.56 +/- 0.62 micrograms/ml and 2.6 +/- 0.67 micrograms/ml respectively). The terminal elimination half-life was about 4.5 h for oral form and 5 h for intravenous form. The absolute bioavailability of the oral ciprofloxacin was about 83%.     

The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing

AIMS: To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. METHODS: Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. RESULTS: The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8-2.3) and 1.2 (0.4-1.9) h later than in plasma on day 1 and day 3, respectively (mean difference +/- 95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52+/-0.07) and sputum (accumulation index 1.79+/-0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3-4 h). CONCLUSIONS: The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half-life.     

A comparison of two dosing regimens of succimer in children with chronic lead poisoning

There is limited information defining the optimal dosing regimen of succimer in the treatment of children with chronic lead poisoning. It is typically administered as a five day course of high dose therapy (1,050 mg/m2/day) followed by 14 days of low dose therapy (700 mg/m2/day). This study compared the effect on blood lead concentrations (BPb) of treatment with this standard regimen and an alternate regimen consisting of two courses of high dose therapy separated by one week. There were significant reductions in the mean BPb in both the standard (n = 7) and alternate (n = 4) treatment groups but there was not a significant difference between the groups. In the standard group, the BPb decreased from 33 +/- 4 to 27 +/- 6 mcg/dL. The BPb decreased from 33 +/- 6 to 23 +/- 4 mcg/dL in those treated with alternate therapy. This study suggests that two short courses of high dose therapy may be an acceptable alternative to standard succimer therapy. Because of the small size of this study, other studies are warranted.     

Estimation of pharmacokinetic parameters of sodium tungstate after multiple-dose during preclinical studies in beagle dogs

In this paper, an empirical Bayes methodology was used to determine the pharmacokinetic profile of sodium tungstate in beagle dogs after multiple oral dosing using the P-PHARM computer program. The population estimation algorithm used in P-PHARM is an EM-type procedure. Sodium tungstate was administered orally, three times a day, (i) for 11 days (21 and 42 mg/kg per day) to 18 dogs (nine males and nine females) and (ii) for 13 weeks (15, 30 and 60 mg/kg per day) to 28 dogs (14 males, 14 females). Six other dogs received the compound intravenously (25 and 50 mg/kg). Plasma concentration profiles versus time were compatible with a two-compartment model and first-order kinetics. After oral administration, F (0.61+/-0.086 vs. 0.48+/-0.093), and normalized (to a 7-mg/kg dose of sodium tungstate) AUC (54+/-8.4 vs. 41.2+/-8.5 mg/l x h), C(max) (10.6+/-0.49 vs. 8.5+/-0.57 microg/ml) and C(min) (3.04+/-0.23 vs. 2.04+/-0.22 microg/ml), were higher in male than in female dogs. However, the introduction of the gender in the final model did not contribute statistically to an improvement of the fit of the population pharmacokinetic model. In males, t(1/2) elimination averaged 3.1+/-0.56 vs. 2.6+/-0.18 h in females. The duration of treatment did not modify statistically the pharmacokinetic parameters. After repeated multiple oral administration of 15-60 mg/kg per day of sodium tungstate, tungsten plasma concentrations increased in proportion to dose. No dose-dependent changes in pharmacokinetic parameters occurred.     

Theophylline: pharmacokinetics, metabolism and urinary excretion in dogs

The disposition of theophylline (aminophylline) administered either parenterally or orally to anesthetized dogs was studied. Pharmacokinetics of theophylline (8.2 mg/kg, n = 10) following intravenous administration could be analyzed by a two-compartment open model. The half-time (T1/2 beta) of theophylline was 5.63 +/- 0.83 hr, and the volume of distribution (Vd) was 0.73 +/- 0.04 l/kg. The elimination rate constant was 0.37 +/- 0.05 hr-1. Two metabolites of theophylline were isolated from urine and identified as 3-methyl xanthine (3-MX) and 1,3-dimethyl uric acid (1,3-DMU) by HPLC. The dogs excreted about 85% (n = 4) of the dose in urine in 24 hr. The majority (2/3) was excreted as changed theophylline, i.e., 3-MX 40.2 +/- 3.5% and 1,3-DMU 26.2 +/- 4.3%, while unchanged theophylline amounted to 18.2 +/- 2.4%. Absorption of theophylline (8.2 mg/kg, n = 5) administered intramuscularly was good as indicated by its high bioavailability (101.9 +/- 6.5%), but the value of bioavailability was low in oral administration (72.8 +/- 11.8%, n = 5). The percentage of protein binding (about 44%, n = 3-7) did not change by increasing the serum concentration (8.2-24.6 micrograms/ml).     

Bioavailability of ciprofloxacin and fleroxacin: results of a preliminary investigation in healthy adult Nigerian male volunteers

The absolute bioavailability (BA) of ciprofloxacin and fleroxacin were evaluated in 19 adult Nigerian male volunteers. Subjects meeting the selection criteria were randomized to receive treatment either with fleroxacin (200 mg-i.v. and 200 mg oral dose) or ciprofloxacin (200 mg-i.v. and 250 mg oral dose). The i.v./oral or oral/i.v. switch was made after a one week washout period. Blood and urine samples were collected at pre-determined time intervals over a 72 h period for analysis of drug levels. Following intravenous administration the maximum serum concentration (Cmax) was 2.7+/-1.06mg/l for ciprofioxacin and 0.99+/-0.41 mg/l for fleroxacin; the area under the blood level curve (AUC) was 8.82+/-3.19 mg x h/l with ciprofloxacin and 8.52+/-3.83 mg x h/l with fleroxacin. Following oral administration the Cmax was 1.52+/-0.94 mg/l with ciprofloxacin and 0.57+/-0.08 mg/l with fleroxacin; the AUC was 9.87+/-4.10 and 7.55+/-1.42 mg x h/l, respectively. The absolute BA following oral administration was found to be 0.79+/-0.47 for ciprofloxacin and 1.01+/-0.78 for fleroxacin. When these BA results were corrected for renal clearance [Cl(r)] and elimination half-life (t1/2) the values were reduced to 0.37+/-0.17 and 0.31+/-0.18, respectively, for ciprofloxacin and 0.53+/-0.23 and 0.99+/-0.38, respectively, for fleroxacin. Only 38% with ciprofloxacin and 59% with fieroxacin, of the administered dose, was excreted unchanged following oral administration. More work, however, needs to be done on ciprofloxacin to support and/or confirm the above findings. Fleroxacin, on the one hand, exhibited a different trend from that observed in the literature with respect to Cmax and AUC where the values observed in this study were 3--4 fold lower than expected following identical doses, whilst on the other hand the observed BA profile in this study was consistent with literature trends.     

Penetration of ciprofloxacin into the spinal fluid in patients with viral and bacterial meningitis

Cerebrospinal fluid (CSF) concentrations of ciprofloxacin (Ciprobay) were measured by high performance liquid chromatography (HPLC) in 20 patients with varying degrees of meningeal inflammation. Underlying clinical syndromes were viral meningitis (n = 10), convalescent phase of acute bacterial meningitis (n = 9), and acute phase of bacterial meningitis (n = 1). CSF concentrations following an intravenous dose of 200 mg ranged between 0.028 and 0.11 mg/l (5.8-26.8% of corresponding serum levels) in patients with viral meningitis, and between 0.049 and 0.389 mg/l (5.9-77.0% of corresponding serum levels) in patients with bacterial meningitis. Taken together with the findings of other authors, the results indicate a potential usefulness of ciprofloxacin as an alternative agent for treatment of meningitis due to susceptible gram-negative microorganisms.     

Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus

AIM: This Swiss multicentre study examined the efficacy and safety of oral pioglitazone in patients with type 2 diabetes. METHODS: Patients were randomised to pioglitazone at once-daily doses of 30 mg for 20 weeks (n = 76), 30 mg for 12 weeks followed by 45 mg for 8 weeks (n = 74), or 45 mg for 20 weeks (n = 84); 94.9% of patients completed 12 weeks and 88.9% completed all 20 weeks. Almost all (96.6%) patients received pioglitazone in combination with other anti-diabetic treatments. RESULTS: Mean HbA(1c) at baseline was 8.8 +/- 1.2%, and changes to endpoint were -1.1 +/- 1.1%, -1.1 +/- 1.4% and -0.9 +/- 1.6%, respectively for the three dose groups ( p < 0.001 for each group). Triglyceride concentrations decreased in each group and the overall mean change during the study was -0.58 mmol/l (p < 0.001 versus baseline). HDL-cholesterol increased, with an overall mean change of 0.10 mmol/l (p < 0.001 versus baseline). Blood pressure decreased from baseline, particularly for hypertensive patients with mean changes: systolic -10 mmHg, p < 0.001, diastolic -8 mmHg, p < 0.001 versus baseline. Serum alanine aminotransferase and gamma-glutamyl transferase concentrations were significantly (p < 0.001 for each) reduced during the study. CONCLUSIONS: The study demonstrates the efficacy of pioglitazone 30 mg/day and 45 mg/day in the treatment of type 2 diabetes, with an improved lipid profile and decreased blood pressure in addition to improved glycaemic control.     

A comparative study of plasma concentrations of liposomal amphotericin B (L-AMP-LRC-1) in adults, children and neonates

Amphotericin B (AmpB) incorporated into small unilamellar liposomes prepared from soya phosphatidylcholine and cholesterol (L-AMP-LRC-1) has been shown to be safe and effective in patients with systemic fungal infections. In this report, we compared the plasma levels of AmpB in adults, children and neonates following administration of L-AMP-LRC-1. A 1.0 mg/kg dose of L-AMP-LRC-1 in adult patients resulted in peak concentrations of 1.02+/-0.14 mg/l (mean+/-S.D.) on day 1, which increased to 1.66+/-0.19 mg/l on day 28 after continued therapy. The area under the plasma concentration-time curve also increased from 13.05+/-1.52 on day 1 to 19.85+/-5.41 mg h/l on day 28. In children, the peak plasma concentration following 1.0 mg/kg per day dose of L-AMP-LRC-1 increased from 0.63+/-0.20 on day 1 to 1.10+/-0.53 mg/l on day 28. While in neonates, the levels increased from 0.54+/-0.17 on day 1 to 0.73+/-0.29 mg/l on day 28. These levels of AmpB in children and neonates were found to be significantly lower than in adults. This may be due to higher volume of distribution, since 1.0 mg/kg per day dose of L-AMP-LRC-1 was found to be effective in neonates.     

High dose parenteral ciprofloxacin in pleuro-pulmonary disease: a comparative pharmacolinetics of 400 and 200 mg intravenous

In this study we determined the pharmacokinetics of higher IV doses of ciprofloxacin (Cipro) in patients with pleuro-pulmonary diseases undergoing treatment for various bacterial infections. Cipro IV was infused over 30-45 min in 11 patients (seven on 400 mg bid, four on 200 mg bid). Blood samples were taken at intervals of up to 4 h and assayed for Cipro using the HPLC method. The 'mean' peak concentration (C(max)) was 6.9 +/- 2.2 (S.D.) and 11.8 +/- 5.2 (S.D.) for the 200 and 400 mg groups, respectively. The mean concentrations at 1.5 h were 1.2 and 2.6 mg/l and the area under the curve in 0-4 h was 4.6 +/- 0.9 (S.D.) and 7.5 +/- 2.4 (S.D.), respectively for the 200 and 400 mg groups. Steady state serum concentrations of 400 mg were approximately double those for the 200 mg group. IV 200 mg did not reach the required levels to cover the minimum inhibitory concentrations (MICs), whereas, 400 mg IV dose clearly will provide an improved coverage for the commonly encountered organisms with MICs in the 1-4 mg/l range.     

The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects.

1. The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2. Subjects were given a single oral dose of theophylline (3.4 mg kg-1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3. Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg-1 h-1 (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg-1 h-1 (-2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 ml kg-1 h-1 (-17.2, -8.1)). 4. Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of 1-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of 1-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)). 5. The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6. The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects of flecainide relative to serum and tissue concentrations in rabbits after chronic drug administration

The effects of chronic treatment with flecainide on the cellular electrophysiology and the relationship of the electrophysiologic effects to serum and myocardial flecainide concentrations were determined in rabbit ventricular myocardium. Two groups of rabbits were administered flecainide at doses of 7.5 mg/kg body weight (dose I) and 20 mg/kg body weight (dose II) intraperitoneally (i.p.) twice daily for 12-14 days; a third group received saline. Serum and myocardial flecainide concentrations with dose II (0.44 +/- 0.15 micrograms/ml and 3.0 +/- 1.4 micrograms/g, respectively) were significantly (p less than 0.01) higher than with dose I (0.19 +/- 0.11 micrograms/ml and 0.81 +/- 0.15 micrograms/g, respectively). At 1.0-Hz stimulation, only the high dose produced significant changes in transmembrane action potentials of right ventricular myocardial fibers, which showed a 17.6% (n = 6, p less than 0.05) decrease in maximal upstroke velocity (Vmax) of phase 0 and 19.5% (n = 6, p less than 0.05) prolongation of effective refractory period (ERP). Repetitive stimuli led to an exponential decline in Vmax with both dosage regimens. The magnitude of Vmax decrease was frequently dependent and was greater with the higher dose. The rate of decrease of Vmax per action potential (AP) during train of stimuli in rabbits treated with dose II was 0.037 +/- 0.012 (n = 5) at 2.0-Hz stimulation, and the recovery time constant from use-dependent block at 4.0-Hz stimulation increased significantly from 12.6 +/- 3.6% decrease in Vmax with the low dose to 35.6 +/- 7.1% decrease with the high dose. The data show that sodium channel inhibition by chronic flecainide administration is a function of dose, serum, and myocardial flecainide concentrations.     

Antiarrhythmic effects of optical isomers of cibenzoline on canine ventricular arrhythmias.

Antiarrhythmic effects of (+)-cibenzoline and (-)-cibenzoline were examined using two canine ventricular arrhythmia models. Digitalis arrhythmia, which is suppressed by Na channel blockers, was induced by intermittent intravenous (i.v.) injection of ouabain in pentobarbital-anesthetized dogs. Adrenaline arrhythmia, which is suppressed by Ca channel blockers, was induced by adrenaline infusion in halothane-anesthetized dogs. Ten and 5 mg/kg i.v. (+)-cibenzoline suppressed digitalis- and adrenaline-induced arrhythmias, respectively. The minimum effective plasma concentrations of (+)-cibenzoline for digitalis- and adrenaline-induced arrhythmias were 1.4 +/- 0.4 and 2.0 +/- 0.6 micrograms/ml, respectively (mean +/- SD, n = 6). A lower dose of 1 mg/kg i.v. of (-)-cibenzoline suppressed the digitalis-induced arrhythmia, whereas 5 mg/kg i.v. was needed to suppress adrenaline-induced arrhythmias. The minimum effective plasma concentrations of (-)-cibenzoline for digitalis- and adrenaline-induced arrhythmia were 0.06 +/- 0.04 and 0.7 +/- 0.1 micrograms/ml, respectively (mean +/- SD, n = 6). The stronger antiarrhythmic effect of (-)-cibenzoline indicates that (-)-isomer may have an effect nearly 5-20 times stronger in suppressing Na channels, but effects of both drugs on Ca channels may be almost equipotent.