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Biomedical subjects

L C Rovati

Publications and source records attributed to L C Rovati.

At least 19 recordsLinked to original sources
PubMed2006

Assessment of joint space narrowing with conventional standing antero-posterior radiographs: relief in mild-to-moderate pain is not a confounder in recent osteoarthritis structure-modifying drug trials.

OBJECTIVE: Knee pain relief has been suggested to potentially alter radioanatomic positioning in conventional standing antero-posterior knee radiographs. This study was performed to determine whether this is always the case and in particular if it applied to two recent randomised, placebo-controlled trials showing both symptom- and structure-modification with glucosamine sulfate in knee osteoarthritis. DESIGN: Patients in the two studies were selected if they completed the 3-year evaluations and, irrespectively of treatment, (1) were pain-improvers in that they underwent Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (WOMAC) pain decrease at least equal to the mean improvement observed with glucosamine sulfate, or (2) if their baseline standing knee pain (item #5 of the WOMAC pain scale) was "severe" or "extreme" and improved by any degree at the end of the trials. Changes in minimum joint space width were then compared between treatments. RESULTS: Knee pain was of mild-to-moderate severity in the two original studies and in all patient subsets identified here. Obviously, there were more pain-improvers in the glucosamine sulfate than in the placebo subsets (N=76 vs 57 in pooling the two studies), but WOMAC pain scores improved to the same extent (over 50% relative to baseline). Notwithstanding such a major pain relief, patients in the placebo subsets of both studies suffered a definite mean (SE) joint space narrowing, that was of -0.22 (0.15)mm in the pooled analysis, and that was not observed with glucosamine sulfate: +0.15 (0.07)mm; P=0.003. Similar evidence was found in the smaller subsets with at least severe baseline standing knee pain improving after 3 years. CONCLUSIONS: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials, possibly due to the mild-to-moderate patient characteristics. Consensus deliverables should acknowledge that the potential limitations of conventional standing antero-posterior radiographs should not be overestimated since they may not apply to all patient populations and to all studies using this gold standard technique.

Administration, Oral↗
PubMed2005

Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man.

OBJECTIVE: Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man. METHODS: Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1,500, and 3,000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state. RESULTS: Endogenous plasma levels of glucosamine were detected (10.4-204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750-1,500 mg, but not at 3,000 mg, where the plasma concentration-time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 microM with the standard 1,500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h. CONCLUSIONS: Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1,500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available.

Administration, Oral↗
PubMed2005

Efficacy of etidronate and sequential monofluorophosphate in severe postmenopausal osteoporosis: a pilot study.

In a three-year pilot study on 52 women with severe postmenopausal osteoporosis, treatment with etidronate followed by calcium and vitamin D (ECaD) was compared to etidronate followed by monofluorophosphate, calcium and vitamin D (EFCaD). BMD in lumbar spine, total hip and femoral neck increased significantly more with EFCaD than with ECaD. Pain-mobility score decreased significantly more with EFCaD than with ECaD (p=0.006). New vertebral fractures occurred in three patients under EFCaD (12%) and in nine under ECaD (35%), (p=0.048). Three patients under EFCaD (12%) and 15 under ECaD (58%) did not respond to therapy (p of difference=0.001). Mild or moderate adverse reactions were reported by 25 patients, with no significant difference between the two groups. The pilot study suggests that etidronate, sequentially followed by monofluorophosphate, could be a safe, effective and relatively inexpensive therapy in severe postmenopausal osteoporosis.

Absorptiometry, Photon↗
PubMed2003

Relief in mild-to-moderate pain is not a confounder in joint space narrowing assessment of full extension knee radiographs in recent osteoarthritis structure-modifying drug trials.

OBJECTIVE: To assess whether improvement in knee pain biased the determination of the structure-modifying effect reported for glucosamine sulfate in two recent 3-year, randomised, placebo-controlled clinical trials, in which conventional standing antero-posterior full extension knee radiographs were used for the measurement of joint space narrowing, and in which pain relief might have improved knee full extension. DESIGN: Patients completing the 3-year treatment course were selected based on a WOMAC pain decrease at least equal to the mean improvement in the glucosamine sulfate arms in either of the original studies, irrespective of treatment with glucosamine sulfate or placebo (drug responders or placebo responders). In a second approach, 3-year completers were selected if their baseline standing knee pain (item #5 of the WOMAC pain scale) was 'severe' or 'extreme' and improved by any degree at the end of the trials. In both cases, changes in minimum joint space width were compared between treatment groups. RESULTS: Global knee pain was mild-to-moderate in the two study populations and in all patient subsets identified. There were obviously more pain improvers in the glucosamine sulfate subsets (N=76 in the two studies combined) than in the placebo subsets (N=57), but WOMAC pain scores improved to the same extent, which was as large as over 50% relative to baseline. Nevertheless, the placebo subsets in both studies underwent an evident mean (SD) joint space narrowing, which in the pooled analysis of both studies was -0.22 (0.80) mm, and was not observed with glucosamine sulfate: +0.15 (0.60) mm (P=0.003 vs placebo). Similar results were found in the smaller subsets with > or = severe baseline standing knee pain that improved after 3 years, with a joint space narrowing nevertheless of -0.28 (0.76) mm with placebo (N=26), not observed with glucosamine sulfate: +0.21 (0.68) mm (N=31; P=0.014 vs placebo). CONCLUSIONS: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials using conventional standing antero-posterior radiographs, possibly due to the mild-to-moderate patient characteristics.

Female↗
PubMed2003

Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate.

OBJECTIVE: To investigate the relationship between baseline radiographic severity of knee osteoarthritis (OA) and the importance of long-term joint space narrowing. DESIGN: Sub-analysis from a three-year randomized, placebo-controlled, prospective study, of 212 patients with knee OA, recruited in an osteoarthritic outpatient clinic and having been part of a study evaluating the effect of glucosamine sulfate on symptom and structure modification in knee OA. MATERIAL AND METHODS: Measurements of mean joint space width (JSW), assessed by a computer-assisted method, were performed at baseline and after 3 years, on weightbearing anteroposterior knee radiographs. RESULTS: In the placebo group, baseline JSW was significantly and negatively correlated with the joint space narrowing observed after 3 years (r=-0.34, P=0.003). In the lowest quartile of baseline mean JSW (<4.5mm), the JSW increased after 3 years by (mean (S.D.)) 3.8% (23.8) in the placebo group and 6.2% (17.5) in the glucosamine sulfate group. The difference between the two groups in these patients with the most severe OA at baseline was not statistically significant (P=0.70). In the highest quartile of baseline mean JSW (>6.2mm), a joint space narrowing of 14.9% (17.9) occurred in the placebo group after 3 years while patients from the glucosamine sulfate group only experienced a narrowing of 6.0% (15.1). Patients with the most severe OA at baseline had a RR of 0.42 (0.17-1.01) to experience a 0.5mm joint space narrowing over 3 years, compared to those with the less affected joint. In patients with mild OA, i.e. in the highest quartile of baseline mean JSW, glucosamine sulfate use was associated with a trend (P=0.10) towards a significant reduction in joint space narrowing. CONCLUSION: These results suggest that patients with the less severe radiographic knee OA will experience, over 3 years, the most dramatic disease progression in terms of joint space narrowing. Such patients may be particularly responsive to structure-modifying drugs.

Aged↗
PubMed2003

Pharmacokinetics and metabolism of the cholecystokinin antagonist dexloxiglumide in male human subjects.

1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.

Administration, Oral↗
PubMed2002

Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males.

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. RESULTS: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. CONCLUSIONS: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.

Administration, Oral↗
PubMed2001

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

BACKGROUND: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. METHODS: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. FINDINGS: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. INTERPRETATION: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

Administration, Oral↗
PubMed2001

Pharmacokinetics of andolast after administration of single escalating doses by inhalation in mild asthmatic patients.

The pharmacokinetics of andolast, a new tetrazolyl-benzamido derivative with antiallergic, antiinflammatory, mucosal protective and antisecretive activities, have been investigated in patients suffering from mild asthma (FEV(1) > or =70% of predicted) in whom obstruction was reversible (FEV(1) increase > or =15% of initial) after the administration of 0.2 mg of salbutamol by inhalation. Twelve out-patients (seven males and five females) were enrolled in the present study and were treated with a single dose of andolast of 2, 4 and 8 mg by inhalation using the MIAT Monohaler device according to a randomised crossover design. Plasma samples were collected before drug administration and up to 540 min after dosing. Andolast plasma concentrations were determined using a validated LC-MS/MS method with a limit of quantitation of 0.2 ng ml(-1). Pharmacokinetic analysis was carried out using standard non-compartmental methods. In addition, andolast safety and tolerability were evaluated by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence of adverse events throughout the study period. Andolast was absorbed after inhalation and was available to the systemic circulation. The mean peak plasma concentrations were 6.3, 10.9 and 30.5 ng ml(-1) at the three doses, respectively, and occurred at 30, 52.5 and 30 min (median t(max)). The mean AUC(t) values were 1852, 2889 and 7677 ng min ml(-1). The apparent plasma clearance (CL/F) and volume of distribution (V(z)/F) were, respectively, 1168 ml min(-1) and 430 l at the dose of 2 mg, 1143 ml min(-1) and 468 l at the dose of 4 mg, and 1141 ml min(-1) and 486 l at the dose of 8 mg. The apparent elimination half-life averaged 4.5, 5.0 and 4.6 h at the three doses, respectively. Even though the small number of subjects participating in the present study reduced the power of the statistical test, there was no statistically significant evidence of non-proportionality for all the andolast pharmacokinetic parameters calculated at the three doses. Thus, the data obtained as a whole suggest that andolast pharmacokinetics are dose-independent in the dose range investigated. Finally, the safety and tolerabilty of the drug administered to mild asthmatic patients was good up to the maximum investigated dose of 8 mg.

Administration, Inhalation↗
PubMed2001

Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates.

Alendronate has been approved as a first antiresorptive drug for treatment of osteoporosis in men. Except for fluoride, in some countries so far there has been no approved anabolic substance for the treatment of male osteoporosis. From small studies in men and male patients included in studies on postmenopausal osteoporosis there is sufficient evidence that fluoride has the same osteoblast-stimulating potency in men and women. In our own study on 64 men with idiopathic osteoporosis without prevalent fractures, a low-dose intermittent fluoride regimen (15 mg fluoride ions 3 months on, 1 month off) resulted in an average gain of lumbar spine BMD of 3% per year and a lower rate of incident fractures as compared with patients treated with calcium only. A combination of fluoride with an antiresorptive drug may improve the therapeutic results in terms of pattern of biochemical marker response and gain in BMD. This was shown for postemopausal osteoporosis in several studies using fluoride and hormone replacement therapy (HRT). Encouraged by a Dutch study using etidronate/fluoride in corticoid-induced osteoporosis, we performed a pilot study in 33 men with severe established primary osteoporosis giving cyclically etidronate for 14 days followed by fluoride plus calcium/vitamin D for 76 days. This combined regimen resulted in significantly higher increases of BMD than fluoride or etidronate alone. In an ongoing trial we are studying a continuous, combined treatment of alendronate and fluoride plus calcium/vitamin D in established idiopathic osteoporosis in men. The results of a preliminary evaluation look very promising. A large study with a bisphosphonate plus fluoride, taking fractures as the primary endpoint and bone biopsies to assess safety, would be very valuable.

Alendronate↗
PubMed2001

Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation.

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.

Adult↗
PubMed2001

Assessment of skin safety of a new glyceryl trinitrate transdermal patch. Animal and human studies.

The experimental models and the studies in man employed to assess the skin and general safety of a newly developed glyceryl trinitrate (GTN, CAS 55-63-0) transdermal patch, hereinafter coded EPI, are described. EPI was found well tolerated by the skin after single or 28-day repeated epicutaneous application on the rabbit, devoid of phototoxicity in the mouse, devoid of skin sensitizing potential in the guinea pig and devoid of photosensitizing effects in the guinea pig. Tested were also, with negative results, the cytotoxic, hemolytic and genotoxic potential, the presence of bacterial endotoxins, the systemic and intracutaneous toxicity, and the possible conjunctival irritant effects. The application of EPI for 14 consecutive days on the thoracic skin of 28 healthy volunteers did not provoke subjective discomfort such as itching, burning or pain, or objective skin lesions. On the application site a light and transient erythema was often found demonstrating the transcutaneous absorption of the vasodilating GTN from the patch. The 14-day application was followed after two weeks by the application of a challenge EPI patch to detect a possible skin sensitization by EPI. No skin reaction was elicited, showing that also in man EPI is devoid of skin sensitizing potential. During the 14-day application of EPI several GTN commonly induced systemic adverse reactions were observed, particularly headache, confirming the systemic bioavailability of GTN from the patch. Headache rapidly disappeared after removal of the patch, in parallel with the decrease of the blood concentrations of GTN and of its active metabolites, consistently with the previous pharmacokinetic findings. This is an advantage of the administration of GTN with the transdermal patch because, in the case of unbearable headache, the patient is relieved by the simple removal of the patch.

Adhesives↗
PubMed2001

Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review.

This article reviews the literature related to the absorption, distribution, metabolism and excretion (ADME) of glucosamine (Gl) in man and in animals after administration of crystalline glucosamine sulfate (CGS). Intravenous administration of CGS In man, after single bolus intravenous (i.v.) injection of 1005 mg CGS (628 mg Gl), the parent Gl disappears from plasma with an apparent half life of 1.11 h. Investigations with uniformly 14C labeled Gl (14C-Gl) administered with 502 mg CGS indicate that the disappearance of Gl is due to an incorporation into the plasma globulins that occurs with a lag time of 0.45 h and a rate of 0.26 h-1. The radioactivity reaches a peak after 10 h and is eliminated with a t1/2 of 95 h. After single i.v. doses of 502 mg CGS traced with 14C-Gl, the urinary excretion in 120 h accounted for 29% of the administered dose. Consistent results are obtained in rat and dogs, in which radioactivity rapidly appears in liver, kidneys and other tissues, including the articular cartilage. In man, after i.v. bolus injection of 1005 mg CGS, the urinary excretion in 24 h of Gl determined with ion exchange chromatography was 38% of the administered dose, mostly in the first 8 h after administration. Similar results were obtained tracing CGS with 14C-Gl. Consistent results of urinary excretion were obtained in rats and dogs tracing CGS with 14C-Gl. The excretion of radioactivity in feces was small. The elimination of radioactivity with the expired air as 14CO2 measured in rats amounted to 49% of the administered dose in the 144 h following the administration, 16% of which occurred in the first 6 h. Intramuscular administration of CGS In man, a single intramuscular injection of 502 mg CGS traced with 14C-Gl, gave results similar to those after i.v. administration. Oral administration of CGS In man, after a single dose of 7.5 g CGS, Gl in plasma was below the limit of quantitation (3 micrograms/ml) of the ion exchange chromatography method. After a single dose of 314 mg CGS traced with 14C-Gl, radioactivity appeared incorporated in plasma globulins with a lag time of 1.5 h and increasing with a rate of 0.24 h-1. The peak was reached at the 9th h after administration. The radioactivity then was eliminated with a t1/2 of 58 h. The absolute oral bioavailability evaluated on the AUCs of the globulin-incorporated radioactivity was 44%. The fecal excretion in 120 h was 11.3% of the administered dose showing that at least 88.7% of the administered dose was absorbed through the gastrointestinal tract. The difference of 45% is probably due to a hepatic first-pass effect. Investigated in the rat with doses from 126 to 3768 mg CGS traced with 14C-Gl, a linear relationship was found with the AUCs as well as between doses and the Cmax of radioactivity in total and in deproteinized plasma. The urinary elimination in man of the parent Gl in 24 h determined with ion exchange chromatography after a single dose of 7.5 g of CGS was 1.19% of the administered dose, occurring mostly in the first 8 h after administration. After administration of 1884 mg repeated for 7 days the daily urinary excretion of Gl increased from 1.60% of the daily dose during the first 24 h to 2.22% of the daily dose in the last 24 h. The steady state was reached after the second day. The urinary excretion at steady state during repeated administration allowed to conclude that daily 1884 CGS administered either t.i.d. in sugar coated tablets or once a day in oral solution were bioequivalent. The elimination of radioactivity with the expired as 14CO2 measured in rats was 82% of the administered dose in the 144 h following the administration, 61% of which occur in the first 6 h. Interaction of Gl with the ADME of glucose The ADME of glucose was investigated in the rat administering i.v. or orally 14C uniformly labeled glucose. The kinetic in plasma and the tissue distribution of glucose differed totally from those of Gl, pointing out that exogenous glucose provides the energy for biochemical processes, whereas exogenous Gl acts mainly as substrate for the biosynthesis of mucopolysaccharides and of biopolymers of the articulations and bones. There was no evidence of interaction by Gl orally administered with the ADME of glucose.

Animals↗
PubMed2000

Efficacy on climacteric symptoms and safety of low dose estradiol transdermal matrix patches. A randomized, double-blind placebo-controlled study.

Two estradiol (E2) transdermal patches releasing 25 micrograms/day E2 (D-25) or 37.5 micrograms/day E2 (D-37.5) were compared to a placebo patch on 156 patients in natural or surgical menopause suffering from at least 5 hot flushes per day, randomly and blindly assigned to three parallel groups of 52 patients each, to be treated continuously for 12 weeks, without progestin opposition. "Responders" (patients with less than 3 hot flushes per day at the end of treatment), were 82% and 90% under D-25 or D-37.5, respectively, both significantly (p < 0.001) more than under placebo (44%). Comparable efficacy was observed on severity of hot flushes, Kupperman Index and on the self-rated efficacy. Systemic adverse events occurred in 10%, 10% and 8% of patients, respectively, under D-25, D-37.5 or placebo. Occasional mild and transient itching and/or erythema on the site of application was reported by few patients and did never require discontinuation of application. In conclusion D-25 and D-37.5 were significantly more effective than placebo in relieving climacteric symptoms and were systemically and locally as well tolerated as placebo. D-25 (Demestril 25) releasing 25 micrograms/day E2 can therefore be recommended for low-dosed estrogen replacement therapy.

Administration, Cutaneous↗
PubMed2000

Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study.

In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective.

Adult↗
PubMed2000

Bioavailability and pharmacokinetic profile of glyceryl trinitrate and of glyceryl dinitrates during application of a new glyceryl trinitrate transdermal patch.

The pharmacokinetics and bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolites, i.e. 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0), were compared during a single 24-h application of a new GTN transdermal patch (Epinitril 10, hereinafter called EPI-10) or a reference patch (hereinafter called ND-10) releasing 10 mg GTN in 24 h. The study was an open, randomized balanced cross-over study on 24 healthy male volunteers to whom the patches were applied to the antero-lateral part of the thorax in two periods separated by a 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and at 0.5, 2 and 3 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope-labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). The ratios of the AUCs of GTN, 1,2-GDN and 1,3-GDN measured during application of EPI-10 or of ND-10 were within the 0.85-1.25 limits required to assess equivalence of the extent of bioavailability. The ratios of the Cmax were within said limits for the signal metabolite 1,2-GDN and only slightly below (0.78-1.16) for the parent GTN. EPI-10 can therefore be considered equivalent to ND-10 also with regard to the rate of bioavailability. Under both patches GTN reached steady-state levels after 3-6 h of patch application and remained on sustained levels during the whole 24-h application. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h. Both patches were well tolerated at the application site. For its small size, thinness and transparency, EPI-10 is very patient friendly, a quality that improves compliance with the therapeutic regimen.

Adhesiveness↗
PubMed2000

Plasma levels of glyceryl trinitrate and dinitrates during application of three strengths of a new glyceryl trinitrate transdermal patch.

The pharmacokinetic characteristics and the bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolities 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0) during a single 24-h application of three strengths of a newly developed GTN transdermal patch (Epinitril) were investigated. The three strengths coded in this paper EPI-5, EPI-10 and EPI-15 have a nominal release rate of GTN of 5, 10 and 15 mg, respectively, in 24 h. The study was an open, randomized balanced cross-over study on 18 healthy male volunteers, to whom the patches were applied for 24 h to the antero-lateral part of the thorax in three periods, separated by an at least 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and 1, 3 and 6 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). GTN and its two metabolites reached the plateau already 3 h after application of the patches and remained on extended and fairly constant levels during the whole 24-h application. The plasma levels of the three nitrates were proportional to the strengths of the patches. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h, an important property when an intermittent GTN therapy is needed in order to avoid tolerance to the drug. The patches were well tolerated at the application site. For their good tolerability, small size and transparency, the new GTN patches are very patient friendly, a quality that improves compliance with the therapeutic regimen.

Adhesiveness↗