Accumulation of fluconazole in sebum.

Concentrations of fluconazole in sebum and plasma were determined in 2 parallel groups, each consisting of 8 healthy subjects. Group 1 received a 150 mg fluconazole capsule once weekly over a period of 4 weeks, Group 2 was administered 2 capsules/week, corresponding to 300 mg fluconazole/week for 4 weeks. Sampling was performed immediately before and 5 hours after dosing, and at intervals up to 2 weeks after the last dose. Fluconazole concentrations were determined by a specific and highly sensitive gas chromatographic method. Both treatments were well tolerated. Maximum fluconazole concentrations (mean +/- SD) in plasma were 3.5 +/- 1.0 microg/ml (Group 1) and 5.5 +/- 1.0 microg/ml (Group 2); maximum sebum concentrations were 11.0 +/- 8.4 microg/g (Group 1) and 48.4 +/- 37.0 microg/g (Group 2). Significant accumulation of fluconazole in sebum relative to plasma was observed. Sebum/plasma ratios ranged from 1.6 to 6.5 (Group 1) and from 4.3 to 27.9 (Group 2), with median ratios of 2.4 and 9.1, respectively. The overall accumulation factor was 7. The findings may be of particular relevance for the treatment of dermal mycoses involving the sebaceous glands, especially those associated with hair, such as tinea capitis.

The pharmacokinetics of extended-release formulations of calcium antagonists and of amlodipine in subjects with different gastrointestinal transit times.

The influence of gastrointestinal (GI) transit times on the pharmacokinetics (PK) of three calcium channel blockers (CCBs), recommended for once-daily dosing, was investigated. In a three-way crossover design, the single-dose PK of a controlled-delivery formulation of 240 mg diltiazem (DIL), an extended-release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AML) were compared in two groups of healthy subjects, with either slow (> 35 h) or rapid (< 15 h) GI transit, as assessed by the metal detector method (EAS II). GI transit significantly affected the PK of DIL. Mean PK parameters in the rapid versus slow transit group were the following: trough levels (C24 h): 22.8 +/- 8.3 versus 49.5 +/- 35.7 ng/ml, p < 0.05; AUC 1134.4 +/- 512.7 versus 1704.7 +/- 1185.6 hng/ml, p < 0.05 (one-sided). Neither AUC nor trough levels of FEL and AML were significantly influenced by transit times, nor was Cmax after any of the three treatments. Variations in PK parameters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times were significantly lower for AML compared to DIL and FEL (7% vs. 30% and 17%, p < 0.001 and p < 0.002, respectively). Peak-to-trough ratios (Cmax/C24 h mean) were 1.8 +/- 0.9 for DIL, 7.6 +/- 3.5 for FEL, and 1.7 +/- 0.2 for AML. In conclusion, the predictability of pharmacokinetic behavior both in conditions of rapid or slow GI transit is optimized in drugs with intrinsically slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation-based once-a-day characteristics are sensitive to GI transit if these processes are rapid enough to interfere with the formulation-specific release profile.

The uptake of fluconazole in finger and toe nails.

OBJECTIVE: The uptake of the antimycotic agent fluconazole in finger and toe nail following various treatment schedules was investigated in order to characterize the pharmacokinetic basis for the systemic treatment of onychomycosis with fluconazole. SUBJECTS: Between 8 and 12 healthy, male and female Caucasian subjects were included in four separate studies. Mean age of the subjects in the single studies ranged between 34 years (study 4, group 2; n = 4 male and 4 female) and 38 years (study 4, group 1; n = 4 male and 4 female). METHODS: Fluconazole was administered orally over 4 weeks in all studies. The treatment schedules were 150 mg once weekly (study 1), 300 mg once weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once weekly in a parallel group study (study 4). At fixed times samples of blood, nail cuttings and nail dust were taken, up to two months after end of treatment. Fluconazole was analyzed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. RESULTS: High concentrations of fluconazole were found in distal nail clippings with all three treatments. Mean maximum concentrations which occurred in the third or fourth week of treatment amounted to 2.1 microg/g (150 mg/w), 5.4 microg/g (300 mg/w) and 6.5 microg/g (50 mg/d) in finger nails and to 9.6 microg/g (150 mg/w), 12.3 microg/g (300 mg/w) and 12.2 microg/g (50 mg/d) in toe nails. The nail concentrations were 1-2 times (finger) and 2-3 times (toe) higher than the corresponding fluconazole plasma levels and were within the MIC range for dermatophytes and yeasts occurring commonly in onychomycosis. The residence times of fluconazole in the nail plate after the end of treatment was long, with approximate half-lives of 33 days in finger nail and 30 days in toe nail. In pharmacokinetic terms there was no evidence of advantages of the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazole was found to penetrate into both finger and toe nails at a very fast rate. On the first two days of the 150 mg/w and 300 mg/w treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amounted to 50-80% of the later observed peak levels. The initial concentrations in the upper dorsal plate were particularly high, with mean peak concentrations of 11.9 microg/g (150 mg) and 33.7 microg/g (300 mg) in finger nails and 5.7 microg/g (150 mg) and 24.4 microg/g (300 mg) in toe nails. CONCLUSIONS: Fluconazole is rapidly and highly distributed into finger and foot nail, reaching there higher concentrations than in the plasma. The rapid initial uptake of fluconazole in nail, which is unlike the uptake of other antifungal agents, suggests the existence of special routes of access to the nail for fluconazole, possibly based on high diffusion rates.

Determination of azithromycin in gastric biopsy samples.

OBJECTIVES: To measure the concentration of azithromycin in gastric biopsy samples of gastritis patients undergoing Heliobacter pylori eradication treatment with azithromycin as one antibiotic constituent of the medication. PATIENTS: Seven male outpatients, non-smokers, non-alcoholics, aged 25-40 years (mean 32 years), suffering from gastritis with involvement of H. pylori. METHODS: The patients received a 5-day treatment with azithromycin (1 x 500 mg on day 1 and 1 x 250 mg on days 2-5), 40 mg pantoprazole once daily and 2 x 400 mg metronidazole once daily. Samples of gastric tissue were obtained from 5 patients and of gastric juice from 2 patients, at the occasion of gastroscopic interventions. The gastric samples were subject to analysis of azithromycin, using a highly sensitive and specific HPLC method with electrochemical detection. RESULTS: The median concentrations of azithromycin in gastric tissue amounted to 7.5 microg/g on day 2 and to 9.7 microg/g on day 5 of the treatment. Four days after the end of treatment, median concentrations were still at 3.9 microg/g. In all tissue samples, azithromycin concentrations were well above the MIC for H. pylori (0.25 microg/ml). The well-known tissue affinity of azithromycin was underlined by the lack of detectable levels in gastricjuice. CONCLUSION: The high concentrations of azithromycin observed in gastric tissue of patients with gastritis on a 5-day dosage regimen point to a favorable pharmacokinetic basis for a role of azithromycin as a component of the eradication therapy of Heliobacter pylori.

Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells.

Multidrug resistance is expressed not only by bacteria, but also by tumor cells and by some normal cells of the body. It enables eukaryotic cells to exclude not only cytostatic drugs but also non-cytostatic antibiotics. This was demonstrated in genetically engineered multidrug resistant (MDR) cells infected with the facultative intracellular bacterium Listeria monocytogenes for all macrolide antibiotics tested (azithromycin, clarithromycin, erythromycin, josamycin, roxithromycin and spiramycin). In these cells and in conventionally selected MDR cells higher concentrations of the macrolides were necessary to inhibit the growth of L. monocytogenes than in the respective parental cells. This effect was due to a reduced intracellular accumulation, which was shown with a biological assay for all macrolides tested. For azithromycin, the results of this test were confirmed by measurement of the intracellular concentrations with high-performance liquid chromatography (HPLC). Besides the macrolides, MDR cells excluded also antibiotics of other chemical groups which was shown for ciprofloxacin, clindamycin, rifampicin and the streptogramin derivative RP 59500. In addition, in conventionally selected cells higher concentrations of chloramphenicol, doxycyclin, ofloxacin and trimethoprim than in the respective parental cells were necessary to inhibit the growth of L. monocytogenes. In contrast, when using genetically engineered cells, no significant differences were found for these antibiotics. These differences might be due to a higher expression of multidrug resistance in the conventionally selected cells because these cells were also more effective in excluding rhodamine 123 in a flow cytometric assay. In conclusion, expression of multidrug resistance by eukaryotic cells leads to a reduced concentration of macrolides and other antibiotics in these cells and to an impairment of activity against intracellular bacteria.

Accumulation of fluconazole in scalp hair.

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1-cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 micrograms/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 micrograms/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150-mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 micrograms/g.

Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility.

Fluconazole shows good penetration into the tissues and body fluids examined and a rapid equilibrium is achieved between the concentrations in the various compartments. The pharmacokinetics of fluconazole after intravenous or oral administration are proportional to the dose. This finding, together with the slow elimination of the triazole (t1/2 30 h), makes it easier to forecast the therapeutically effective dosage. Measurements of fluconazole concentration in blood can be used to predict levels in some tissues (lung, brain, gynaecological samples), body fluids (sputum, saliva, vaginal secretions) or exudates. Concentrations in cerebrospinal fluid and vitreous humour of the eye reach approximately 80% of the levels found in blood. A very high proportion of fluconazole is excreted unchanged in the urine, where concentrations of the drug are 10-20-fold higher than in blood. Whilst this pharmacokinetic profile is valuable in the treatment of fungal infections of the urinary tract, it also means that the dosage may need to be decreased in patients with renal impairment. The susceptibility of fungi to fluconazole in vitro and in vivo correlates well with the concentrations of the drug measured in various compartments of the body.

Pharmacokinetic and pharmacodynamic interaction study between midazolam and the macrolide antibiotics, erythromycin, clarithromycin, and the azalide azithromycin.

This report includes a recalculation of the pooled data of 2 pharmacokinetic and pharmacodynamic studies of the interaction between the hypnotic midazolam and the antibiotics erythromycin, clarithromycin (macrolides), and azithromycin (an azalide). Erythromycin and clarithromycin similarly and strikingly impaired the metabolism of midazolam and enhanced its pharmacodynamic activity; little or no effect was found with azithromycin. It was concluded that coadministration of midazolam and azithromycin involves less clinical risk than with the 2 macrolides.

Interaction between midazolam and clarithromycin: comparison with azithromycin.

A comparative pharmacokinetic and pharmacodynamic investigation was carried out on the interaction between the hypnotic midazolam and 2 different macrolide-type antibiotics, clarithromycin and azithromycin. In an open randomized crossover study of 3 phases 12 healthy volunteers received either clarithromycin (250 mg twice a day for 5 days), azithromycin (500 mg once a day for 3 days) or no pretreatment. On the last day of antibiotic treatment they ingested 15 mg midazolam. Plasma samples were collected for midazolam analysis up to 24 h and pharmacodynamic performance measured by a series of tests up to 12 h. Pretreatment with clarithromycin caused large and statistically significant changes in both the pharmacokinetic and pharmacodynamic parameters of midazolam compared to control. For example, the AUC was increased from 248.84-888.75 hng/ml (factor of 3.57, p < 0.0001) and the mean duration of sleep increased from 135.4 min to 281.3 min (p < 0.05). No statistically significant effect was found with azithromycin in any test. It is concluded that a drug interaction exists between midazolam and clarithromycin which could be of clinical importance. No such effect is present with azithromycin.

Screening for cytochrome P450 3A in man: studies with midazolam and nifedipine.

This report describes work directed towards the development of a screening technique for cytochrome P450 3A activity which should be valid for a variety of drugs metabolized by this enzyme. A significant correlation (P < 0.01) was found between the ratio of the plasma concentration of nifedipine to that of its oxidized metabolite and the area under the time curve for the plasma concentration of midazolam. It is suggested that the nifedipine: metabolite ratio might have general predictive value for the metabolism of orally administered cytochrome P450 3A substrates.

A new pharmaceutical concept for the treatment of oropharyngeal and oesophageal candidosis with fluconazole.

Administration of fluconazole in capsule form has proved effective in the prophylaxis and treatment of mucosal candidosis, particularly in immunosuppressed patients. An additional topical effect in oropharyngeal and oesophageal candidosis might be expected with a fluconazole suspension. This hypothesis was therefore tested in a crossover study in 12 healthy volunteers in whom the concentrations of the antimycotic were measured in saliva and plasma after oral administration of 100 mg fluconazole as either a capsule or a suspension. The time courses of the fluconazole concentrations were very similar with the two formulations in plasma, but significantly different in saliva. Thus, the mean Cmax for fluconazole in saliva of 551 micrograms ml-1 was reached 5 min after ingestion of the suspension, compared with a value of 3 micrograms ml-1 some 4 h after taking the capsule. The mean concentration of the antimycotic in saliva over the observation period (0-96 h) was more than 80% higher with the suspension than with the capsule.

Levels of fluconazole in normal and diseased nails during and after treatment of onychomycoses in toe-nails with fluconazole 150 mg once weekly.

Thirty-six patients with onychomycoses of their toe-nails were included in a double-blind, parallel-group comparative study of fluconazole 150 mg once weekly and griseofulvin 1,000 mg once daily for 12 months, or earlier if cured. Every month during treatment and in cured patients 3 and 6 months after stop of treatment one toe-nail was clipped and serum samples were taken. In patients treated with fluconazole the concentration of fluconazole was measured in serum and nails. We found a very high concentration of fluconazole in nails (peak 8.54 micrograms/g) and the nail concentration was statistically significantly higher than serum concentrations (p < 0.001). In cured patients fluconazole was still present in high concentrations 3 (1.7 micrograms/g) and 6 (1.4 micrograms/g) months after stop of treatment. These results indicate that fluconazole should be effective in the treatment of onychomycosis in a dose of 150 mg once weekly. The results also indicate that the treatment period could be shortened because fluconazole is still present in high concentrations 6 months after stop of therapy. The concentration of fluconazole found in nails is much higher than that found in the case of terbinafine and itraconazole, indicating that fluconazole should be at least as effective as these drugs in the treatment of tinea unguium.

Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam.

The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h.ng.ml-1 vs. (E) 662.7 h.ng.ml-1*+ and (A) 220.0 h.ng.ml-1; concentration maxima (C) 67.2 ng.ml-1 vs. (E) 182.3 ng.ml-1*+ and (A) 86.7 ng.ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h* and (A) 2.41 h (* p < 0.05 vs. (C), +p < 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.

Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions.

The concentrations of azithromycin in polymorphonuclear leukocytes (PMNLs), monocytes, erythrocytes, and plasma were measured in six healthy volunteers after the last treatment of a 3-day regimen of 500 mg once daily. Marked enrichment of azithromycin was found in PMNLs and monocytes. The drug concentrations after the last dose amounted to 114 +/- 43 (mean +/- standard deviation) mg/liter at 12 h in PMNLs and 34 +/- 17 mg/liter at 6 h in monocytes. Fourteen days thereafter, azithromycin was still detectable in the PMNLs at 53 +/- 34 mg/liter and in the monocytes at 1 +/- 2 mg/liter, although the drug was no longer detectable in plasma (< 0.02 mg/liter). Maximum drug concentrations for azithromycin in plasma (0.40 +/- 0.30 mg/liter) and erythrocytes (0.15 +/- 0.05 mg/liter) at 3 h after the last administration were much lower and occurred earlier than those observed in the phagocytic cells. The mean enrichment factors (cellular/extracellular ratios) of azithromycin in phagocytes relative to plasma came to 231 +/- 150 and 3,924 +/- 584 at 3 and 120 h, respectively, for PMNLs and 83 +/- 55 and 523 +/- 285 at 3 and 120 h for monocytes, respectively, after the last dose. The phagocytosis tests with PMNLs separated from the blood of volunteers at various times after the last treatment confirmed the enhanced intracellular activity of these cells against staphylococci.

[A new pharmaceutical concept for the therapy of oropharyngeal and esophageal candidiasis with fluconazole]. / Ein neues pharmazeutisches Konzept für die Therapie der oropharyngealen und oesophagealen Candidose mit Fluconazol.

Administration of fluconazole capsules is of proven worth in the treatment of candidosis of the mucous membranes, particularly in immunocompromised patients. An additional topical effect on the course of oropharyngeal and oesophageal candidosis can be expected when fluconazole is administered as a suspension. For this reason a crossover pharmacokinetic study with 12 healthy volunteers was carried out, in which the concentrations of the antimycotic were measured in saliva and plasma, after oral administration of 100 mg fluconazole as either a capsule or as a suspension. The time-courses of the concentration of fluconazole after the two formulations were very similar in plasma, but significantly different in saliva. The mean Cmax for fluconazole in saliva was 551 micrograms/ml 5 min after ingestion of the suspension and 3 micrograms/ml 4 h after taking the capsule. Over the observation time (0-96 h) the concentration of the antimycotic in saliva was more than 80% higher with the suspension than with the capsule.

[Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility of yeasts]. / Fluconazol: Vergleich von Pharmakokinetik, Therapie und Empfindlichkeit der Sprosspilze in vitro.

Fluconazole penetrates well into the tissues and body fluids which were examined and achieves rapid equilibration between the different compartments. The pharmacokinetics of fluconazole are independent of the dose after oral or intravenous administration. This finding, together with the drug's slow elimination (t1/2 30 h) facilitate the estimation of the therapeutically effective dosage. The concentrations of fluconazole measured in blood can be extrapolated to the concentrations in tissue (lung, brain, gynecological tissues), body fluids (sputum, saliva, vaginal secretions) and exudates. The concentration of fluconazole in cerebrospinal fluid and in the vitreous humour of the eye is ca. 80% of that in blood. Fluconazole is predominantly excreted in the urine in the unchanged form, which explains the 10 to 20 fold higher concentration of the drug in urine relative to blood. Although this pharmacokinetic profile favours the use of fluconazole in mycotic infections of the urinary tract it also means that the dose of the drug may have to be adapted to lower regimens in the systemic treatment of patients with restricted kidney function. The in vitro and in vivo susceptibility of the yeasts correlates with the concentrations of fluconazole measured in the different compartments of the body.

Relative bioavailability of carbinoxamine and phenylephrine from a retard capsule after single and repeated dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylephrine (PE, CAS 59-42-7) after single dose administration of a retard capsule (Rhinopront) containing 20 mg PE hydrochloride and 4 mg CA maleate, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects according to a standard crossover design with a one-week wash-out. The pharmacokinetic profile of the active ingredients of the retard capsule was also investigated in the same subjects under repeated dosing conditions (one capsule b.i.d. during 4 days). Blood samples were collected before each administration and up to 36 h after the first and last doses. CA and total PE (free + conjugated) were assayed in the plasma samples by HPLC with coulometric detection and by gas chromatography with electron-capture detection, respectively. The pharmacokinetic parameters obtained after single dose administration indicated an effective slow release of PE and CA with the retard capsule, compared to the solution. Significantly dampened Cmax, delayed tmax and prolonged plateau time were observed. Despite the clear decrease in absorption rate, the two formulations yielded a similar extent of absorption for CA (90% confidence interval of AUC ratio: 61-111%), but not for PE (90% confidence interval of AUC ratio: 56-69%). At steady-state, accumulation of the two active principles apparently followed simple superposition (accumulation index R = 1.6 for PE and 3.9 for CA). The slow absorption pattern of the formulation was maintained at steady-state with tmax and plateau time similar to single dose conditions.

Intracutaneous transport of orally administered fluconazole to the stratum corneum.

Fluconazole administered at 150 mg/week for 1-5 weeks is effective orally against dermatophytes and yeast in stratum corneum. Clinical and mycological cure rates approach 90%, but the precise distribution of the drug within various layers of skin is uncertain. We administered fluconazole at 150 mg/week for 2 weeks to 5 volunteers. Distribution of fluconazole in biopsies of skin was imaged by energy dispersive analysis of X-rays (EDX) and transmission electron microscopy, and in cells by electron energy-loss spectroscopy (EELS). Eight hours after a second dose, EDX showed fluconazole highest and homogeneously distributed in stratum corneum, lower in the rest of the epidermis, and lowest in dermis. The highest fluconazole levels detected by EELS were in cytoplasmic inclusions of sweat and sebaceous glands and less in keratinocytes and dermal collagen. We conclude that fluconazole delivered to stratum corneum by direct diffusion from capillaries and in sweat is also in all likelihood transported in sebum.

Comparative pharmacokinetics of fluconazole and of itraconazole in Japanese and in German subjects.

In separate but identically designed studies the oral pharmacokinetics of 100 mg doses of the 2 antimycotics fluconazole and itraconazole were examined in Japanese and German subjects (both n = 12), both fasting and concomitant to a heavy breakfast. The results with the 2 races were compared. With fasting subjects no significant difference was found with either antimycotic for any parameter. With fluconazole the pharmacokinetic parameters after food were essentially the same for the 2 races. The only significant difference, a delay of 1.5 h in the median tmax in the Japanese relative to the Germans, should not be of practical importance. In contrast, the mean AUC for itraconazole in Japanese subjects after the meal was only 54.9% of the value with Germans (p < 0.05); the corresponding Cmax was only 54.7% (p < 0.01). As itraconazole is normally administered together with food, this suggests that there is a possibility of underdosage in Japanese subjects. There appears to be no such problem with fluconazole.

Serial gadolinium-enhanced magnetic resonance imaging in patients with multiple sclerosis treated with mitoxantrone.

Serial gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) was used to monitor the effect of mitoxantrone in ten patients with rapidly deteriorating multiple sclerosis (MS). MRI was performed as a baseline and thereafter at 1, 3, 6, 9, 12 and 24 months. The total number of Gd-enhancing lesions diminished from 169 at baseline to 10 after 1 year and to 5 after 2 years. This reduction and the percentage of follow-up MRI studies showing no Gd enhancement were more pronounced than in other MRI studies of the natural course of MS. Measured with quantitative neurological scales, only one patient showed deterioration after 2 years; nevertheless, the changes in MRI were much more marked than those observed clinically. Serial Gd-MRI therefore, seems necessary for documenting efficacy in future therapeutic trials.