Concentrations In Most Tissues Research Articles

Absorption, distribution and excretion of 14C-levofloxacin after single oral administration in albino and pigmented rats: binding characteristics of levofloxacin-related radioactivity to melanin in vivo.

After single oral administration of (14)C-levofloxacin at a dose of 20 mg kg(-1) under non-fasting conditions, the absorption, distribution and excretion of radioactivity were studied in albino and pigmented rats. Good penetration of radioactivity into tissues was indicated by higher concentrations in most tissues compared with serum and there were no quantitative differences in the distribution of radioactivity between albino and pigmented rats except for melanin-containing tissues such as the uveal tract of eyes and hair follicles. There was selective and strong binding of drug-related radioactivity to these tissues in pigmented rats. The uveal tract concentrations reached the maximum value (C(max)) of 26.33 +/- 0.75 microg eq. g(-1) at 24 h after dosing and declined slowly with a terminal half-life of 468.1 h (19.5 days). The uveal tract concentration at 12 weeks was 0.73+/- 0.12 microg eq. g(-1), which is c. 1/36 of C(max). The AUC(0- infinity ) for the uveal tract was 12.58 mg h(-1) g(-1). The uveal tracts separated from one eye of each rat were extracted with 0.067 M phosphate buffer (pH 7.4) and 1M HCl/EtOH (30:70), successively. In pigmented rats, approximately 85-48% of radioactivity bound to the uveal tract was released from the tissue by the washing procedures. Most of the eluted radioactivity was released with 1M HCl/EtOH (30:70), indicating that the binding to melanin is reversible, and hydrophobic and electrostatic interactions play an important role in the binding of levofloxacin and/or its metabolites with melanin-containing ocular tissues. Only unchanged drug was detected in the extracts of the uveal tracts. The concentrations and half-life of radioactivity in the uveal tract after dosing of (14)C-levofloxacin were found to be much lower and shorter than those after dosing of (14)C-chloroquine. It is unlikely that levofloxacin causes toxicity because of its much lower affinity to melanin-containing ocular tissues and shorter duration of therapy compared to chloroquine.

Absorption, distribution and excretion of 14C-chloroquine after single oral administration in albino and pigmented rats: binding characteristics of chloroquine-related radioactivity to melanin in-vivo.

Chloroquine is an antimalarial agent that has been reported to have distinct affinity to melanin. After single oral administration of 14C-chloroquine at a dose of 20mg kg-1 under non-fasting conditions, the absorption, distribution and excretion of 14C-chloroquine-related radioactivity were studied in albino and pigmented rats. The objectives of the study were to investigate differences in the disposition of chloroquine between albino and pigmented rats and to define its in-vivo binding characteristics to melanin-containing ocular tissues. Extensive uptake of radioactivity into tissues was indicated by higher concentrations in most tissues compared with serum and there was no quantitative differences in the distribution of radioactivity found between albino and pigmented rats except for melanin-containing tissues, such as the uveal tract of the eye and perhaps hair follicles. There was selective and strong binding of drug-related compounds to these tissues in pigmented rats. The uveal tract concentrations reached the maximum value of 158.42 +/- 7.86 micrograms equiv g-1 (mean+/-s.e.) at 1 week and decreased very slowly with a terminal half life of 4476 h (187 day). The uveal tract concentrations at 24 weeks were still high (67.75 +/- 6.19 micrograms equiv g-1). The AUC for uveal tract was 842.3 mg.h g-1. A relatively high concentration was still determined in the uveal tract even at 48 weeks after single oral dosing by whole-body autoradiography. The uveal tracts separated from one eye of each rat were extracted with 0.067 M phosphate buffer (pH 7.4) and 1 M HCl-EtOH (30:70) successively. In pigmented rats, almost all radioactivity was released from the tissue with 1 M HCl-EtOH (30:70), indicating that the strong binding by melanin was reversible, and that hydrophobic or electrostatic interaction would play a critical role in the binding of chloroquine and its metabolites with the melanin-containing ocular tissues. Approximately 70% of the radioactivity given was recovered in urine and faeces up to 144 h after dosing both in pigmented and albino rats. The excretion pattern in pigmented rats was similar to that seen in albino rats.

Bioaccumulation of heavy metals in Octopus vulgaris from coastal waters of Alexandria (Eastern Mediterranean)

Heavy metal concentrations (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn) were determined in various tissues (hepatopancreas, branchial hearts, salivary gland, gills, genital tract, mantle, arms and skin) of Octopus vulgaris collected from three different contaminated sites in front of Alexandria (Egypt) during 2000. All collected tissues displayed high enrichment factors when compared to ambient levels. Heavy metal concentrations in most tissues displayed significant differences among sites, sizes and sex. This study suggests that hepatopancreas, and to a lesser extent branchial hearts, are better indicators of chronic Cu, Fe, Zn and Cd contamination than edible tissues. The enrichment factor (EF) for heavy metals in the hepatopancreas and in edible tissues allowed discriminating our samples into three main groups; (1) EF > 55 (Cu), (2) EF ranging from 15 to 7.5 (Fe, Cd and Zn) and (3) EF < 2.5 (Mn, Co, Pb, Ni and Cr). In the Mex area, the most polluted site, the highest bioaccumulation of Cu, Fe, Zn and Mn was observed. In the Kayet Bey were observed high levels of Pb and in Agami high concentrations of Cd were recorded. Females bioaccumulated Pb and Fe and less Zn, Cr, and Co than males, whereas Ni and Mn concentrations were sex independent. Concentrations of both Mn and Co in gonads, Cr in branchial hearts and Zn in both gills and mantle increased linearly with animal weight. Conversely, concentrations of Cd and Ni in gonads, Mn in mantle and Pb in hepatopancreas were inversely related with body size. Finally, heavy metal bioaccumulations in the liver were independent from animal size.

Pharmacokinetic Studies of [14C]Urea. (1); Absorption, Distribution, Metabolism and Excretion after Single Administration of [14C]Urea in Fasted Rats.

Absorption, distribution, metabolism and excretion after a single intravenous and oral administration of [14C]urea at a main dose of 2 mg/kg were investigated in non-fasted rats. Comparison of the pharmacokinetics in rats between under non-fasted and fasted conditions was also investigated. 1. The radioactivity levels in plasma were decreased biphasically with t1/2α of 2-3 hr and t1/2β of 6-11 hr, irrespective of administration routes and doses. After oral administration at doses of 2, 62.5, 250 and 1000 mg /kg, the Cmax and AUC0-∞ were virtually proportional to the administered doses, suggesting linear-pharmacokinetics within the examined dose range. 2. The radioactivity levels in plasma and tissues reached Cmax at 0.5-1 hr after oral administration. The concentration in the kidney, which was 2.4 times as high as that in plasma, was the highest in the examined tissues. The concentrations in other tissues were similar to, or lower than the plasma concentration. After the Cmax, the concentrations in most tissues decreased in almost parallel with the plasma concentration. 3. In plasma at 1 hr after oral administration, only the unchanged drug was observed in the plasma radioactivity. On the other hand, at 8 hr, about 70% and 30% of the plasma radioactivity were unchanged drug and unknown components, respectively. In urine for 24 hr after dosing, only the unchanged drug was also observed, irrespective of administration routes. 4. Within 96 hr, 73.1%, 1.6% and 20.1% of dosed radioactivity were excreted in urine, feces and expired air after intravenous administration, and 54.0%, 1.0% and 42.9% after oral administration, respectively. The bioavailability estimated from the ratio of urinary excretion of urea after oral administration to that after intravenous administration was 74%. 5. Feeding condition in rats enhanced metabolism/decomposition of urea and influenced its plasma concentration-time profiles and excretion profile.

Sjögren–Larsson syndrome: accumulation of free fatty alcohols in cultured fibroblasts and plasma

Sjögren–Larsson syndrome (SLS) is an inherited disorder associated with deficient oxidation of long-chain aliphatic alcohols. Previous studies have reported modest elevations in total (free + esterified) fatty alcohols in SLS, but free fatty alcohols have not been selectively measured, in part because of their low concentrations in most tissues and the presence of trace fatty alcohol contaminants in some solvents used for their analysis. We adapted methods to measure free fatty alcohols in cultured cells and plasma that minimize exogenous alcohol contamination. Fatty alcohols were analyzed as acetate derivatives, using capillary column gas chromatography. By this method, cultured skin fibroblasts from SLS patients were found to have 7- and 8-fold elevations in the mean content of hexadecanol (16:0-OH) and octadecanol (18:0-OH), respectively. The mean plasma 16:0-OH and 18:0-OH concentrations in SLS patients (n = 11) were 9- and 22-fold higher than in normal controls, respectively. In SLS fibroblasts, most of the fatty alcohol (59%) that accumulated was free rather than esterified alcohol, whereas free alcohol accounted for 23% of the total alcohol in normal cells.These results indicate that elevations in free fatty alcohols provide a sensitive marker for the enzymatic defect in SLS. The ability to measure free fatty alcohols in cultured cells and plasma should prove useful for investigations of normal fatty alcohol metabolism and the deranged metabolism in SLS.

Arsenic, cadmium, lead, copper and zinc in cattle from Galicia, NW Spain

Knowledge of trace and toxic metal concentrations in livestock is important for assessing the effects of pollutants on domestic animals and contaminant intakes by humans. Metal levels in cattle have been measured in various countries but not in Spain. In this study, the (wet wt.) concentrations of three toxic elements (arsenic, cadmium, lead) and two trace elements (copper, zinc) were quantified in the liver (Li), kidney (Ki), muscle (M) and blood (Bl) of calves (males and females between 6 and 10 months old) and cows (2–16 years old) from Galicia, NW Spain. For the toxic elements, geometric mean concentrations of arsenic in calves (sexes combined) and cows were 10.8 and 10.2 μg/kg (Li), 11.3 and 15.2 μg/kg (Ki), 3.75 and 4.25 μg/kg (M), 3.23 and 2.92 μg/l (Bl). The corresponding cadmium concentrations were 7.78 and 83.3 μg/kg (Li), 54.3 and 388 μg/kg (Ki), 0.839 and 0.944 μg/kg (M), 0.373 and 0.449 μg/l (Bl). Geometric mean concentrations of lead in calves and cows were similarly low and were 33.0 and 47.5 μg/kg (Li), 38.9 and 58.3 μg/kg (Ki), 6.37 and 12.5 μg/kg (M), 5.47 and 12.2 μg/l (Bl). Sex had almost no effect on the amount of toxic metal accumulated except that kidney cadmium concentrations were significantly higher in females than males. Age did influence accumulation; cadmium and lead (but not arsenic) concentrations in most tissues were significantly greater in cows than female calves. For the trace elements, geometric mean copper levels in calf and cow tissues were 49.9 and 36.6 mg/kg (Li), 4.27 and 3.63 mg/kg (Ki), 0.649 and 1.68 mg/kg (M) and 0.878 and 0.890 mg/l (Bl). The corresponding zinc concentrations were 46.3 and 52.5 mg/kg (Li), 14.2 and 20.7 mg/kg (Ki), 47.3 and 52.5 mg/kg (M) and 2.80 and 2.22 mg/l (Bl). Female calves had significantly higher levels than males of muscle zinc and blood copper and zinc. Female calves accumulated more copper but less zinc in the liver and kidneys compared with cows; this may have been associated with the chronic, low-level cadmium accumulation observed in cows. Overall, the levels of arsenic, cadmium, lead and zinc in cattle in Galicia do not constitute a risk for animal health. However, up to 20% of cattle in some regions in Galicia had levels of copper in the liver that exceeded 150 mg/kg wet wt. These animals may be at risk from copper poisoning.

Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration-dependent bactericidal activity, prolonged half-life and sustained activity in plasma support the clinical evaluation of higher doses of metronidazole given less frequently. Metronidazole-containing regimens for Helicobacter pylori in combination with proton pump inhibitors demonstrate higher success rates than antimicrobial regimens alone. The pharmacokinetics of metronidazole in gastric fluid appear contradictory to these results, since omeprazole reduces peak drug concentration and area under the concentration-time curve for metronidazole and its hydroxy metabolite; however, concentrations remain above the MIC. Other members of this class include tinidazole, ornidazole and secnidazole. They are also well absorbed and distributed after oral administration. Their only distinguishing features are prolonged half-lives compared with metronidazole. The choice of nitroimidazole may be influenced by the longer administration intervals possible with other members of this class; however, metronidazole remains the predominant antimicrobial for anaerobic and protozoal infections.

Immunonutrition: the role of taurine

Taurine is a sulfonated beta amino acid derived from methionine and cysteine metabolism. It is present in high concentrations in most tissues and in particular in proinflammatory cells such as polymorphonuclear phagocytes. Initial investigation into the multifaceted properties of this non-toxic physiologic amino acid revealed a link between retinal dysfunction and dietary deficiency. Since then a role for this amino acid has been found in membrane stabilization, bile salt formation, antioxidation, calcium homeostasis, growth modulation, and osmoregulation. Our own group has demonstrated a key role for taurine in modulation of apoptosis in a variety of cell types. This review summarizes our current knowledge of taurine in nutrition, host proinflammatory cell homeostasis, therapeutic applications, and its potential immunoregulatory properties. It is our belief that taurine, similar to arginine and glutamine, is now more than worthy of critical clinical analysis.

Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability.

Ciprofloxacin is a broad spectrum fluoroquinolone antibacterial agent. Since its introduction in the 1980s, most Gram-negative bacteria have remained highly susceptible to this agent in vitro; Gram-positive bacteria are generally susceptible or moderately susceptible. Ciprofloxacin attains therapeutic concentrations in most tissues and body fluids. The results of clinical trials with ciprofloxacin have confirmed its clinical efficacy and low potential for adverse effects. Ciprofloxacin is effective in the treatment of a wide variety of infections, particularly those caused by Gram-negative pathogens. These include complicated urinary tract infections, sexually transmitted diseases (gonorrhoea and chancroid), skin and bone infections, gastrointestinal infections caused by multiresistant organisms, lower respiratory tract infections (including those in patients with cystic fibrosis), febrile neutropenia (combined with an agent which possesses good activity against Gram-positive bacteria), intra-abdominal infections (combined with an antianaerobic agent) and malignant external otitis. Ciprofloxacin should not be considered a first-line empirical therapy for respiratory tract infections if penicillin-susceptible Streptococcus pneumoniae is the primary pathogen; however, it is an appropriate treatment option in patients with mixed infections (where S. pneumoniae may or may not be present) or in patients with predisposing factors for Gram-negative infections. Clinically important drug interactions involving ciprofloxacin are well documented and avoidable with conscientious prescribing. Recommended dosage adjustments in patients with impaired renal function vary between countries; major adjustments are not required until the estimated creatinine clearance is < 30 ml/min/1.73m2 (or when the serum creatinine level is > or = 2 mg/dl). Ciprofloxacin is one of the few broad spectrum antibacterials available in both intravenous and oral formulations. In this respect, it offers the potential for cost savings with sequential intravenous and oral therapy in appropriately selected patients and may allow early discharge from hospital in some instances. In conclusion, ciprofloxacin has retained its excellent activity against most Gram-negative bacteria, and fulfilled its potential as an important antibacterial drug in the treatment of a wide range of infections. Rational prescribing will help to ensure the continued clinical usefulness of this valuable antimicrobial drug.

Manganese protects against heart mitochondrial lipid peroxidation in rats fed high levels of polyunsaturated fatty acids.

We demonstrated previously that dietary manganese (Mn) deficiency depressed Mn concentrations in most tissues and consistently depressed Mn superoxide dismutase (MnSOD) levels in heart. To examine the functional consequences of these effects, we fed weanling male Sprague-Dawley rats (n = 12/diet) diets containing 20% (wt/wt) corn oil or 19% menhaden oil + 1% corn oil by weight and 0.75 or 82 mg Mn/kg diet for 2 mo (the fish oil mixture was supplemented with (+)-(mixed)-alpha-tocopherol to the level in corn oil). Heart and liver Mn concentrations in the Mn-deficient rats were 56% of those in Mn-adequate rats (P < 0.0001), confirming Mn deficiency. The Mn-deficient rats had more conjugated dienes in heart mitochondria than Mn-adequate rats (P < 0.001); rats fed fish oil had more conjugated dienes than those fed corn oil (P < 0.001). The MnSOD activity was inversely correlated with conjugated dienes (r = -0.71, P < 0.005), and Mn-deficient rats had 37% less MnSOD activity in the heart than did Mn-adequate rats (P < 0.0001). The dietary treatments did not affect heart microsomal conjugated diene formation, possibly because of compensation by copper-zinc (CuZn) SOD activity; CuZnSOD activities were 35% greater in the hearts of Mn-deficient animals (P < 0.01). Liver was less sensitive to Mn deficiency than was the heart as judged by MnSOD activity and conjugated diene formation. This work is the first to demonstrate that dietary Mn protects against in vivo oxidation of heart mitochondrial membranes.

Effect of Shading and Nitrogen Source on Growth, Tissue Ammonium and Nitrate Status, and Inflorescence Necrosis in Pinot noir Grapevines

The effect of 60% shading and nitrogen (N) source on growth, tissue NH₄⁺ and NO₃^- concentrations, and inflorescence necrosis (IN) was investigated in one- and two-year-old potted Pinot noir grapevines. New growth of the vines was significantly reduced by shading and NH₄⁺ feeding resulted in less new growth compared to NO₃^- feeding. The shaded two-year-old vines developed 26.6% IN compared to only 0.6% on unshaded vines. No IN was induced by either NH₄⁺ or NO₃^- feeding treatments. Shading increased tissue NH₄⁺ concentration in most tissues of one-year-old vines with few exceptions and in laminas, petioles, and rachis of two-year-old vines. Two-year-old vines fed NH₄⁺ and/or NO₃^- had a higher rachis, petiole, stem, and young root NH₄⁺ concentration at post-anthesis, compared to the no N control. The NH₄⁺-fed vines had a higher NH₄⁺ concentration than that of NO₃^##-fed vines only in stems at post-anthesis and young roots pre-anthesis, anthesis, and post-anthesis. Tissue NO₃^- concentration of laminas, petioles, stems, and young roots was proportional to the amount of NO₃^--fed to the vines in the root medium. Elevated tissue NH₄⁺ concentration in the rachis of shaded vines and increased incidence of IN suggest that IN is associated with elevated tissue NH₄⁺ levels. NH₄⁺ and/or NO₃^- in culture media is not a source of elevated NH₄⁺ level for IN development.

Trace element accumulation in three seabird species from Horn�ya, Norway

Soft tissues and body feathers of Common Guillemots (Uria aalge), Brunnich's Guillemots (Uria lomvia), and Kittiwakes (Rissa tridactyla) collected at Hornoya (northern Norway) were analyzed for total mercury, selenium, cadmium, zinc, and copper. Kittiwakes revealed highest cadmium and mercury concentrations in most tissues compared to both guillemot species, whereas interspecific differences in concentrations of essential elements were less obvious. The results are discussed in relation to feeding habits and migration patterns of the different seabird species. Age-dependent accumulation of selenium, mercury, and cadmium was clearly recognizable when comparing trace element contents in fully-fledged Kittiwakes to adult specimens. There was no evidence that the analyzed birds suffered from acute toxicities of heavy metals.

Tissue vitamin E status is compromised by dietary protein insufficiency in young growing rats.

In vitro erythrocyte hemolysis previously has been found to be significantly elevated in rats fed a low protein diet. To investigate the effects of dietary protein insufficiency on tissue vitamin E status, four groups of male weanling Long-Evans rats were given free access to either an 8% (wt/wt) lactalbumin diet containing 50 (L50) or 500 (L500) mg/kg diet of all-rac-alpha-tocopheryl acetate, or a 20% (wt/wt) lactalbumin diet containing 50 (N50) or 500 (N500) mg/kg of all-rac-alpha-tocopheryl acetate for 6 wk. A fifth group (P50) was pair-fed to the L50 group with the N50 diet. The L50 and L500 groups showed signs of protein malnutrition such as growth retardation as well as lower hematocrit and plasma protein and albumin concentrations. The alpha-tocopherol concentrations of plasma, heart, lung, kidney and muscle were significantly lower in the L50 group compared with the N50 group. The L500 group showed significantly less alpha-tocopherol in heart, kidney, muscle, brain and adipose tissue compared with the N500 group. The alpha-tocopherol concentrations in liver, testis, spleen and adrenal gland did not significantly differ either between the L50 and N50 groups or between the L500 and N500 groups. Supplementation with 500 mg/kg diet of all-rac-alpha-tocopheryl acetate resulted in significantly higher tissue alpha-tocopherol concentration in all tissues except muscle. The tissue alpha-tocopherol concentrations of the P50 group were not significantly different from those of the N50 group. The results indicated that protein insufficiency resulted in significantly lower alpha-tocopherol concentrations in most tissues in young growing rats.

Tissue Vitamin E Status Is Compromised by Dietary Protein Insufficiency in Young Growing Rats ,

Abstract In vitro erythrocyte hemolysis previously has been found to be significantly elevated in rats fed a low protein diet. To investigate the effects of dietary protein insufficiency on tissue vitamin E status, four groups of male weanling Long-Evans rats were given free access to either an 8% (wt/wt) lactalbumin diet containing 50 (L50) or 500 (L500) mg/kg diet of all-rac-α-tocopheryl acetate, or a 20% (wt/wt) lactalbumin diet containing 50 (N50) or 500 (N500) mg/kg of all-rac-α-tocopheryl acetate for 6 wk. A fifth group (P50) was pair-fed to the L50 group with the N50 diet. The L50 and L500 groups showed signs of protein malnutrition such as growth retardation as well as lower hematocrit and plasma protein and albumin concentrations. The α-tocopherol concentrations of plasma, heart, lung, kidney and muscle were significantly lower in the L50 group compared with the N50 group. The L500 group showed significantly less α-tocopherol in heart, kidney, muscle, brain and adipose tissue compared with the N500 group. The α-tocopherol concentrations in liver, testis, spleen and adrenal gland did not significantly differ either between the L50 and N50 groups or between the L500 and N500 groups. Supplementation with 500 mg/kg diet of all-rac-α-tocopheryl acetate resulted in significantly higher tissue α-tocopherol concentration in all tissues except muscle. The tissue α-tocopherol concentrations of the P50 group were not significantly different from those of the N50 group. The results indicated that protein insufficiency resulted in significantly lower α-tocopherol concentrations in most tissues in young growing rats.

Ciprofloxacin

Ciprofloxacin belongs to the fluoroquinolone class of antimicrobial agents which primarily inhibit bacterial DNA gyrase. It is effective after oral or intravenous administration, demonstrating potent antibacterial activity against most Gram-negative, and many Gram-positive bacteria. Although most bacterial strains have remained susceptible to the drug, low rates of resistance have been observed in some strains of Pseudomonas aeruginosa and enterococci and higher rates in methicillin-resistant Staphylococcus aureus. Ciprofloxacin attains concentrations in most tissues and body fluids sufficient to inhibit the majority of susceptible pathogens. Its pharmacokinetic profile in the elderly (> or = 65 years) is broadly similar to that reported in younger persons, although plasma concentrations are higher, and renal clearance is decreased in elderly persons. Ciprofloxacin is an effective treatment for those infections most common in elderly patients, including infections of the urinary tract, lower respiratory tract, skin and soft-tissues, and bone and joints, and is an effective agent for prophylaxis in transurethral surgery. Orally administered ciprofloxacin appeared to be at least as effective as alternative orally administered antimicrobial agents (trimethoprim, cotrimoxazole [trimethoprim/sulfamethoxazole], amoxicillin, amoxicillin/clavulanic acid) and also as effective as various parenteral agents (ceftriaxone, cefamandole, ceftazidime, cefotaxime) in a small number of comparative clinical trials. However, further studies are needed to clarify the comparative efficacy of ciprofloxacin with that of other oral and parenteral agents in the elderly. Initial trials have also indicated therapeutic efficacy of oral ciprofloxacin in malignant external otitis and bacterial prostatitis. Nevertheless, with its good tolerability profile and potent antimicrobial activity following oral administration, ciprofloxacin appears to offer a valuable alternative for treating various acute and chronic infections in elderly patients. Causative pathogens are frequently multiresistant in this patient group, and ciprofloxacin avoids or minimises the need for parenteral therapy.

Plasma pharmacokinetics, tissue disposition, excretion and metabolism of vinorelbine in mice as determined by high performance liquid chromatography.

We have investigated the pharmacokinetics of the investigational semi-synthetic vinca alkaloid vinorelbine (navelbine, NVB). The analyses have been performed by using a sensitive and selective method based on ion-exchange normal phase high-performance liquid chromatography with fluorescence detection combined with liquid-liquid extraction for sample clean-up. Pharmacokinetic studies were performed in male FVB mice receiving 12 mg/kg NVB through intravenous injection. The results have been compared to those obtained for vinblastine (VBL). The plasma pharmacokinetics of NVB can be described by a three compartment model. The elimination half-life is significantly longer and the plasma AUC values higher for NVB compared to VBL. This is reflected in tissues, where, 24 hr after drug administration, the concentration of NVB is 5 to 10-fold higher compared to VBL. Qualitatively, the tissue distribution and retention of the drugs is very similar. The drug concentrations in most tissues decline parallel with the circulating plasma levels, whereas prolonged retention is found in tissues of lymphatic and testicular origin. Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for NVB. This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and faeces (41%) as NVB or DNVB. No other metabolites have been detected.

Oral glutathione increases tissue glutathione in vivo

Mice were given an oral dose of glutathione (GSH) (100 mg/kg) and concentrations of GSH were measured at 30, 45 and 60 min in blood plasma and after 1 h in liver, kidney, heart, lung, brain, small intestine and skin. In control mice, GSH concentrations in plasma increased from 30 μM to 75 μM within 30 min of oral GSH administration, consistent with a rapid flux of GSH from the intestinal lumen to plasma. Under these GSH-sufficient conditions, no increases over control values were obtained in GSH concentrations in most tissues except lung over the same time course. Mice pretreated for 5 days with the GSH synthesis inhibitor, l-buthionine- S, R-sulfoximine (BSO, 80 μmol/day) had substantially decreased tissue concentrations of GSH. Oral administration of GSH to these GSH-deficient animals gave statistically significant increases in GSH concentrations in kidney, heart, lung, brain, small intestine and skin but not in the liver. Administration of the equivalent amount of the constituent amino acids, glutamate, cysteine, and glycine, resulted in little change in GSH concentrations in all tissues in GSH-deficient animals. Thus, the results show that oral GSH can increase GSH concentrations in several tissues following GSH depletion, such as can occur in toxicological and pathological conditions in which GSH homeostasis is compromised.

Clinical Pharmacokinetics of Teicoplanin

Teicoplanin is a recently introduced glycopeptide antibiotic for the treatment of a variety of aerobic and anaerobic Gram-positive infections. It is a mixture of 5 closely related components, of similar polarity and biological activity, and 1 or more polar hydrolysis products. Teicoplanin is rapidly and extensively absorbed from muscle and the peritoneal cavity but very poorly absorbed from the gastrointestinal tract. Following intravenous administration, the disposition kinetics are best described by a tri-exponential equation, and the majority of drug is excreted unchanged, by glomerular filtration. In patients with normal renal function, the half-lives of the first, second and terminal phases are 35 minutes, 10 hours and 87 hours, respectively. The initial volume of distribution is 0.089 L/kg, the volume of distribution at steady-state is 0.86 L/kg, clearance is 0.0114 L/h/kg and renal clearance is 0.0083 L/h/kg. Teicoplanin is highly bound in plasma to albumin (fraction unbound = 0.1) and in tissues. The pharmacokinetics are linear over a wide dose range (2 to 26 mg/kg). The minor differences in the pharmacokinetics of the components of teicoplanin can be accounted for by differences in lipophilicity. The events following multiple dosing are predicted from single dose data; renal clearance decreases in patients with renal insufficiency in a predictable manner. Negligible drug is lost during haemodialysis. As expected, clearance per kilogram is higher in children than in adults, and lower in the elderly, associated with a decrease in glomerular filtration rate with advancing years. Tissue distribution data are limited. Concentrations, relative to those in plasma, are high in lung and bone tissue and low in fat. Animal data show high concentrations in most tissues, and particularly high in liver and kidneys. Teicoplanin penetrates slowly and poorly into cerebrospinal fluid, but relatively rapidly and effectively in synovial and pleural fluids and in soft tissue. The manufacturer's recommended intravenous or intramuscular dosage regimens rapidly achieve and maintain adequate plasma concentrations of teicoplanin; the dosing interval is usually 1 day. The maintenance dosing rate, but not the loading dose (if needed), must be reduced in patients with poor renal function and in the elderly. For those patients on continuous ambulatory peritoneal dialysis, the peritoneal cavity offers a convenient alternative route of drug administration.

Roxithromycin. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy.

Roxithromycin is an acid-stable orally administered antibacterial macrolide structurally related to erythromycin. It has an in vitro antibacterial profile similar to that of erythromycin, with activity against Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, S. pyogenes, Branhamella catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia trachomatis, Gardnerella vaginalis, Haemophilus ducreyi, some anaerobes and other less common pathogens. Roxithromycin has a pharmacokinetic profile that is characterised by excellent enteral absorption achieving high concentrations in most tissues and body fluids. The results of clinical studies with roxithromycin have confirmed the potential for its use in a variety of infections, which was suggested by its antibacterial activity in vitro and pharmacokinetic profile. Clinical efficacy has been confirmed in the treatment of respiratory tract infections, including community-acquired and atypical pneumonias, ear, nose and throat infections, genitourinary tract infections, and skin and soft tissue infections. In a relatively small number of patients roxithromycin has generally been shown to be as effective as erythromycin and other appropriate antibacterial drugs in some of the above indications. Roxithromycin is well tolerated and has less potential than erythromycin to produce clinically significant drug interactions. Thus, roxithromycin is an orally active drug which should prove a useful alternative when selecting antibacterial therapy for indications where macrolides are appropriate.

Tissue concentrations of MPTP and MPP+ in relation to catecholamine depletion after the oral or subcutaneous administration of MPTP to mice

One hour after MPTP was given to mice at a dose of 30 mg/kg s.c., its concentration in tissues varied in the order kidney>liver> lung>brain>heart. When the same dose of MPTP was given orally, concentrations in most tissues were much lower at 1 hr than after s.c. administration, although the MPTP concentration in liver was only slightly lower. The concentrations of MPP+ (a metabolite of MPTP) at 1 hr were as high or higher than those of MPTP in all tissues except kidney, and MPP+ disappeared from the various tissues with half-lives from 3–20 hrs. The highest concentrations of MPP+, both absolute and relative to MPTP, were in heart. After oral administration of MPTP, no MPP+ was found in brain, and MPP+ concentrations in other tissues were lower than those after s.c. dosing. The depletion of heart norepinephrine was similar after MPTP administration by either route of administration even though MPTP and MPP+ concentrations in heart were lower after oral administration, suggesting that other metabolites of MPTP might also contribute to heart norepinephrine depletion.