Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin.

Oxidative stress plays an important role in the development of fibrotic responses in the lung. However, it is not clear whether inhibiting oxidative stress with antioxidants can attenuate fibrotic processes in the lung. The objective of these studies was to test whether the catalytic antioxidant porphyrin manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) could protect mice against bleomycin-induced lung fibrosis. A 10 mg/kg intraperitoneal dose of MnTBAP was established as safe and had a serum and lung half-life of 9.5 h in mice. Based on this data, four groups of mice were given one dose of bleomycin (3.2 U/kg, intratracheal) or saline and MnTBAP (5 mg/kg, intraperitoneal) or saline twice daily for 14 d. Lung fibrosis was assessed by measuring (1) lung hydroxyproline content as an index of collagen accumulation, (2) airway dysfunction by whole body plethysmography, and (3) histopathology. Bleomycin produced a 20% loss in body weight that was only 10% in the bleomycin/MnTBAP group. Bleomycin produced a twofold increase in hydroxyproline content that was decreased 23% by MnTBAP. Bleomycin produced a twofold increase in airway dysfunction that was also attenuated 30% by MnTBAP. Histopathologic analysis of the lungs of mice treated with bleomycin demonstrated a severe fibrotic response that was attenuated 28% by MnTBAP. Future studies on the oxidant mechanisms that MnTBAP is affecting in this bleomycin model of lung fibrosis may shed light on potential new therapeutic approaches for treating interstitial lung diseases.

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis.

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.

Pharmacokinetic study of azithromycin with fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole) in healthy volunteers.

BACKGROUND: Azithromycin, fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole; TMP/SMX) are all agents that are utilised for the treatment and/or prophylaxis of opportunistic infections in patients with AIDS. OBJECTIVE: To characterise the potential for an interaction when azithromycin is coadministered with cotrimoxazole or with fluconazole. DESIGN: Two separate nonblind randomised studies were conducted in healthy volunteers. During the fluconazole study the potential for fluconazole to adversely affect the pharmacokinetics of azithromycin was also studied. PARTICIPANTS: 24 (cotrimoxazole) and 18 (fluconazole) healthy male and female volunteers. RESULTS: The results of both studies indicated that neither the peak concentrations of nor the exposures (area under the concentration-time curve) to the test drugs were changed when azithromycin was coadministered. In addition, fluconazole did not significantly alter the pharmacokinetic parameters of azithromycin. CONCLUSIONS: Azithromycin does not alter the bioavailability of either cotrimoxazole or fluconazole.

An overview of health risks and benefits of alcohol consumption.

This article provides an overview of the most recent evidence on health risks and benefits of alcohol consumption. Not only different types of dose-response curves but also other factors are important to consider when balancing health risks and benefits of alcohol consumption. The association between alcohol exposure and the risk of developing alcohol-related harm is multifactorial; there is a considerable individual variation in risk and a particular female susceptibility. Guidelines on drinking published over the last decade have become successively more restrictive. Whereas guidelines in the 1980s referred to "sensible drinking" or "responsible drinking," more recent guidelines refer to "low-risk drinking." For an increasing number of groups, the recommendation is to avoid alcohol entirely. The need to consider individual risk factors and specific risk situations is increasingly emphasized. The possible net beneficial health effects of moderate drinking may be achieved in less risky ways by refraining from smoking, eating less dietary fat, and doing regular exercise. A number of health risks of moderate drinking have been demonstrated. Yet, for the moderate drinker, various psychosocial problems--especially in the area of productivity and relations--are more likely to develop than organ damage. Also, the risks involved in giving general guidelines on drinking have been widely discussed. If these guidelines were generally accepted and followed, it could have negative consequences on public health.

[How can primary health care influence patients' alcohol drinking habits. "Simple intervention" results in a new therapeutic perspective]. / Så kan primärvården påverka patientens alkoholvanor. "Enkel intervention" ger nytt perspektiv på behandlingen.

A review of findings in randomised trials with at least one-year follow-up suggests that primary care physicians can intervene briefly and successfully for patients manifesting symptoms of excessive drinking but no serious dependence. The risk level can be assessed by summing the preceding week's intake of spirits, wine and beer in standard measures and then convert it into grams of pure alcohol. Denial is minimised by using a non-judgmental lifestyle approach, and defining problems in terms of lifestyle habits and its consequences. Nervous problems, hypertension and dyspepsia are the most common diagnoses in the target group. Measurement of biochemical markers can be used, the serum gamma-glutamyl transpeptidase (GGT) level being still the most useful. Questionnaires are of limited value as they are associated with high false-positive rates. To motivate patients to reduce alcohol consumption, an intervention strategy with feedback is proposed, mainly based on the monitoring of symptoms and clinical findings including biochemical markers, and a self-help pamphlet is recommended. It is emphasised that the goal should be realistic to the patient, and that controlled drinking is an acceptable goal even in cases of mild dependence.

Why is it so difficult for general practitioners to discuss alcohol with patients?

If general practitioners are to take an active role in the secondary prevention of problems connected with alcohol, they must be able to discuss the subject in an adequate fashion. Interviews from a trial study showed that the greatest difficulties were lack of time and fear of spoiling the relationship with the patient. Earlier studies indicate that the latter problem may have several causes, in part arising from a desire not to infringe upon the integrity of the patient, and partly due to condemnation of excessive drinkers. In other words, the root cause is often contradictory conceptions of alcohol problems on the part of the physician. In order to ensure effective alcohol counselling in primary care, such conceptions must be dealt with in future training courses.

Stereo-specific analysis of a novel protein kinase C inhibitor.

SPC-100270 drug substance ((2S,3S)-2-aminooctadecane-1,3-diol) is a synthetic sphingosine analogue possessing limited ultraviolet absorbance (UV) and two chiral centres. Analytical methodology employing derivatization of SPC-100270 with o-phthaldialdehyde (OPA) and a chiral thiol, N-acetyl-D-penicillamine, was developed to assess the isomeric purity of SPC-100270 in the presence of two of its three stereoisomers. Separation of the isoindole derivatives was achieved with isocratic reversed-phase column chromatography with detection at 330 nm. Under the conditions studied, the derivatization was complete within 3 h at 50 degrees C. The standard and derivatized solutions were stable for 7 days under refrigerated conditions. The limit of detection was 0.036 micrograms SPC-100270 per ml and the limit of quantitation was 0.237 micrograms SPC-100270 per ml. The assay response was linear over a concentration range of 4.7-376 micrograms SPC-100270 per ml with a coefficient of determination of greater than 0.9999. The precision, ruggedness and specificity of the assay were acceptable for determination of SPC-100270 in the presence of its stereoisomers and under forced degradation conditions. The method has been applied successfully in two independent laboratories for quality control release and stability assessment of SPC-100270 drug substance for early clinical studies.

The electrocardiographic effects of cetirizine in normal subjects.

OBJECTIVE: To establish whether the antihistamine cetirizine has the potential to prolong the QTc interval in normal volunteers at up to six times the usual recommended dose. METHODS: Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTc prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. RESULTS: Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTc compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. CONCLUSION: In healthy volunteers, cetirizine does not prolong the QTc interval at doses of up to six times the usual recommended dose.

Comparative bioavailability and steady state fluctuations of Tegretol commercial and carbamazepine OROS tablets in adult and pediatric epileptic patients.

The comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24-h treatment interval.

Effect of food and relative bioavailability following single doses of diclofenac 150 mg hydrogel bead (HGB) capsules in healthy humans.

The effect of food on the bioavailability of diclofenac from a 150 mg diclofenac hydrogel bead (HGB) capsule was evaluated in 12 healthy male subjects in a fed and fasted state. Additionally, the fasting bioavailability of diclofenac from a 150 mg diclofenac HGB capsule relative to diclofenac sodium in buffered aqueous solution was evaluated in these same 12 subjects. The study was designed as an open-label, randomized, single-dose, 3 x 3 Latin-square crossover trial balanced for residual effects. A 2-week washout period was maintained between treatments. Blood samples were collected at frequent intervals over a 24-h period with plasma being separated and analyzed for diclofenac using a validated HPLC method. The administration of the 150 mg diclofenac HGB capsule dose within 30 min following a standardized breakfast minimally affected the bioavailability of diclofenac relative to administration under fasted conditions (7 per cent decrease in AUC(0-24), p greater than 0.05). There was, however, a 38 per cent decrease (p less than 0.05) in the Cmax and a three-fold increase (p less than 0.05) in Tmax for the fed HGB capsule administration. Under fasted conditions, significant differences in mean pharmacokinetic parameters were found between the 150 mg diclofenac HGB capsule and diclofenac sodium in buffered aqueous solution. The extent of availability of diclofenac from the HGB capsule was only 59 per cent relative to that from the solution (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerin absorption from transdermal systems: formulation effects and metabolite concentrations.

We recently compared plasma concentrations of nitroglycerin and its two dinitrate metabolites in 16 healthy male subjects after application of two controlled-release transdermal formulations of the drug. Analysis of the resulting plasma concentration-time curves indicated that the two formulations did not produce equivalent concentrations of parent drug or either of the dinitrate metabolites during the initial period of dosing. In addition, both formulations produced concentrations of the two dinitrate metabolites that exceeded the concentration of the parent drug by severalfold. Even if the pharmacologic effect of the dinitrate metabolites is low compared to that of nitroglycerin, these higher concentrations may contribute to the effect of nitroglycerin. Scrutiny of the ratio of 1,2-glyceryl dinitrate to 1,3-glyceryl dinitrate in the 16 subjects confirmed previous observations that preferential formation of the 1,2-glycerol dinitrate metabolite may occur depending on the route of administration. This ratio may thus be indicative of the bioavailability of nitroglycerin following transdermal application. Additional data suggesting racial differences in nitroglycerin absorption after transdermal application are presented.

Dosage form and formulation effects on the bioavailability of vitamin E, riboflavin, and vitamin B-6 from multivitamin preparations.

The effects of formulation factors and pharmaceutical dosage form on the bioavailability of RRR-alpha-tocopherol (d-alpha-tocopherol), riboflavin, and pyridoxine hydrochloride were studied after administration of two capsule formulations and a tablet to 12 normal humans. Absorption of RRR-alpha-tocopherol was increased from the Aquabiosorb soft elastic gelatin (SEG) capsule formulation compared with the modified standard-SEG capsule and the commercial tablet. There were no significant differences in bioavailability of riboflavin and pyridoxine hydrochloride between the SEG formulation and the tablet albeit a trend toward consistent absorption was seen from the SEG formulation. The modified-SEG formulation exhibited significantly lower bioavailability for these water-soluble vitamins. The enhanced bioavailability of vitamin E and the trend towards faster and more consistent absorption of riboflavin and vitamin B-6 from the SEG formulation may be related to the surfactant vehicle employed and the attendant wetting properties. The results also suggest ethnic differences in vitamin bioavailability.

Cost containment using cysteine HCl acidification to increase calcium/phosphate solubility in hyperalimentation solutions.

The purpose of this study was to determine if (1) the calcium/phosphate insoluble product was inversely related to pH [when cysteine HC1 (CH) was added as neonatal supplementation at 0.5 mM/kg/day to hyperalimentation (HAL) solutions] and (2) the potential cost savings to the hospital. The pH of the HAL solutions was adjusted by adding various amounts of CH to the HAL solution. HAL solutions containing 27 mEq of calcium/liter and 30 mEq (15 mM) of phosphate/liter were compounded. Ten-milliliter aliquots were analyzed at 0, 12, 24, and 48 hr. All samples (n = 56) were filtered (0.22 mu), viewed with 7-10,000 X magnification scanning electron microscopy, and qualitatively analyzed with a Philips Energy Dispersive X-Ray Analysis System equipped with a SW9100 Microprocessor. Calcium/phosphate insoluble product was present in the 0-, 12-, 24-, and 48-hr samples from the CH-free solutions. The solutions containing 759 mg (4.17 mM)/liter of CH however, remained free of precipitant. This investigation demonstrated that addition of CH to HAL can foster significant cost containment (projected $82,000/yr tangible hospital savings) by the elimination of current calcium/phosphate separation procedures for neonates on parenteral nutrition.

Bacterial endotoxin retention by inline intravenous filters.

Filters used in i.v. administration sets were tested for their ability to retain bacterial endotoxins for up to 96 hours of continuous infusion. Inline filters composed of cellulose ester, polyacrylate, polypropylene, polyethylene, or Posidyne Nylon 66 were used during continuous infusion of 5% dextrose injection at 83 mL/hr. One milliliter of inoculum containing 10(8) Escherichia coli was injected through a port upstream from the filter. A bacterial filter was used to monitor the sterility of effluent from the inline filters. The effluent was tested with limulus amebocyte lysate (LAL) that could detect endotoxin concentrations greater than 50 pg/mL. A control solution was monitored for viability of the bacteria throughout the course of the study, and positive endotoxin controls were used to confirm the sensitivity of the LAL. Samples of effluent were tested at 0, 4, 19, 24, 48, 72, and 96 hours. Effluent from all filters was sterile throughout the study. LAL assay indicated that only the effluent from filters containing Posidyne Nylon 66 was free of endotoxins for 96 hours. Effluent from the other filters contained endotoxins immediately after injection of the E. coli. Of the inline filters tested, only the one composed of Posidyne Nylon 66 was able to retain E. coli endotoxin for 96 hours. Further study is needed with E. coli and other microorganisms that are likely contaminants of i.v. infusions.

Pharmacokinetic-pharmacodynamic modelling and simulation using the electrical circuit simulation program SPICE2.

The use of the electrical circuit simulation program SPICE2 for performing digital computer simulations of linear and non-linear pharmacokinetic-pharmacodynamic models is described. SPICE2 utilizes the principles of network thermodynamics (thermodynamics of electrical circuits). These principles dictate analogy between the conservation laws of chemical reactions and mass transport and Kirchhoff's laws of current and voltage balance, and also prove that Fick's law of diffusion is isomorphous with the conductance form of Ohm's law. Detailed descriptions of program inputs, formats, and options for simulation of linear and non-linear pharmacokinetic-pharmacodynamic systems are provided, with appropriate examples. Single as well as multiple dose simulations (accumulation kinetics and dynamics) are discussed. The advantages of SPICE2 over other available simulation packages, including user-friendliness, ease of operation, versatility, power, and the economy of time and effort afforded, are emphasized. The educational value of SPICE2 as a highly versatile tool for teaching both fundamental and complex pharmacokinetic-pharmacodynamic concepts, as well as its routine usage in elucidating complex research problems, are also discussed.