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Biomedical subjects

L C Rovati

Publications and source records attributed to L C Rovati.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dose-response efficacy of a new estradiol transdermal matrix patch for 7-day application: a randomized, double-blind, placebo-controlled study. Italian Menopause Research Group.

New estradiol (E2) transdermal matrix patches developed for once-a-week application, releasing 25 micrograms E2 (7D-25) or 50 micrograms E2 (7D-50) daily, were investigated in comparison with a placebo patch and the twice-weekly parent patch releasing 50 micrograms E2 (Derm-50) daily. Three hundred and eleven postmenopausal patients suffering at least seven hot flushes daily were randomly assigned to the four parallel groups and treated continuously for 12 weeks without progestin opposition. The daily number of hot flushes significantly decreased in all groups. At the 12th week the decrease from a base-line average of eight to nine episodes per day was 78% with 7D-25, 93% and 97% respectively with 7D-50 and Derm-50, and significantly (p < 0.001) lower with placebo (59%). Comparable efficacy was observed in terms of severity of hot flushes, Kupperman Index and patient self-rated overall efficacy. Minor systemic adverse events occurred in 10.0%, 8.8%, 16.9% and 13.5% patients in the placebo, 7D-25, 7D-50 and Derm-50 groups respectively. Occasional mild and transient itching and/or erythema at the site of application was reported by a few patients, with no difference between groups or between once-weekly or twice-weekly application. In conclusion all E2 patches were significantly more effective than placebo in relieving climacteric symptoms in a dose-dependent fashion and all were well tolerated.

Administration, Cutaneous↗
PubMed1999

Radiographic assessment. Introduction: existing methodology.

Plain radiograph is the most accepted imaging technique to assess structural changes of osteoarthritis and it is proposed as 'surrogate' of outcome of the disease process. The existing radiographic methodology is well standardized with respect to its technique for investigation of hip, knee and hand joints, including advice on the most appropriate views, patient positioning, X-ray beam alignment, quality control. Quantitation of joint space narrowing is currently proposed as the primary variable in studies of disease progression for hip and knee, while semi-quantitation of this same parameter or of bone changes by published atlases have to be intended as secondary variables, or outcomes in hand studies. Unfortunately, the review of studies that evaluated the longitudinal rate of joint space narrowing indicates that the yearly change may be very small (<0.1mm/year) and of doubtful clinical significance. This underlines the need for further refinement in the definition of the radiographic outcome in prospective clinical trials.

Decision Making↗
PubMed1999

Estradiol and estrone plasma levels during application of three strengths of a 7-day estradiol transdermal patch.

BACKGROUND: A new estradiol transdermal patch was developed for a once weekly application, with the aim to achieve an optimum practicability and to improve long-term compliance with estrogen replacement therapy. The pharmacokinetics of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) during a 7-day application of the new patch is reported in this publication. METHODS: Unconjugated estradiol and estrone were assayed in plasma in a three-way crossover study on 18 postmenopausal women during and after a 7-day application of 3 strengths of the new patch, with daily release rates of 25, 50 and 75 micrograms of estradiol. RESULTS: During the 7-day application of the transdermal patches the concentration in plasma of unconjugated estradiol increased from less than 5 pg/ml, typical of postmenopause, to average concentrations of 26, 49 and 66 pg/ml under the patches with the release rates of 25, 50 and 75 micrograms/day of estradiol, respectively. The increases were linearly related and proportional to the strength of the patches. Upon removal of the patches, the estradiol concentrations returned to the basal postmenopausal values in 8-24 h. Retarded with regard to estradiol, there was also an increase of unconjugated estrone, from basal concentrations of 24 pg/ml to average concentrations of 39, 54 and 62 pg/ml, respectively. Estrone returned to its basal concentrations 24-48 h after removal of the patches. The estradiol/estrone ratio from the low pre-treatment values of 0.15-0.21 typical of postmenopause increased to average values of 0.51, 0.92 and respectively 1.09 during the application of the patches with the three strengths. The ratios are in the range of those of unconjugated hormones during the fertile age of women. The patches were well tolerated by the skin, with rare mild and transient reactions that disappeared spontaneously and did not cause interruption of treatment. Also the systemic tolerability was good, with occasional mild or moderate side effects typical of estradiol found especially under the application of the two higher strengths, i.e. with release of 50 and 75 micrograms/day of estradiol. CONCLUSIONS: The effective pharmacokinetic performance over the 7-day application, combined with the good general and local tolerability and the need to apply the patches only once weekly confer to the new patches a favorable practicability for the long-term estrogen replacement therapy needed to control the most severe postmenopausal disorders.

Administration, Cutaneous↗
PubMed1999

Efficacy on climacteric symptoms of a new estradiol transdermal patch with active matrix in comparison with a reference reservoir patch. Two long-term randomized multicenter parallel-group studies.

METHODS: Two randomized prospective multicentre parallel group studies were performed (one in Germany and the other in Italy) in symptomatic postmenopausal women. The goal was to assess the efficacy on climacteric symptoms and the safety of a new estradiol (CAS 50-28-2) transdermal patch with solid active matrix (SAM) in comparison to a conventional liquid reservoir (LR) type estradiol transdermal patch. Both patches released 50 micrograms/day estradiol. One group of patients received the SAM patch and the other the LR patch in 4-week cycles, with a twice-weekly application of the patches for 3 weeks, followed by one week without patches. Progestin opposition was achieved with medroxyprogesterone acetate 5 mg/day orally in the last 11 days of patch application in the German study and with 10 mg/day in the last 12 days of patch application in the Italian study. Both studies were divided into two Parts: Part 1 with three 4-week cycles for a total of 12 weeks and Part 2 for other ten 4-weeks cycles in which the patches could be applied also continuously. The total duration of the study was therefore 52 weeks. RESULTS: Germany study. 133 patients resulted randomized to the SAM group and 129 to the LR group. Both estradiol patches quickly relieved climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the Kupperman Index. At the end of Part 1, in the SAM group 91% and in the LR group 96% of patients reported relief from climacteric symptoms. At the end of Part 2 the percentages were 98% and 95%, respectively. The two patches were therapeutically equivalent with a power greater than 99.7%. Both patches were systemically fairly well tolerated. Only 4.5% of patients in the SAM group and 3.9% in the LR group discontinued prematurely for possible adverse reactions related to estradiol. There was no significant difference between the two patches with regard to systemic tolerability. Conversely, with regard to local skin reactions, the SAM patch was significantly (p < 0.01) better tolerated than the LR patch. The adhesion to the skin of the SAM patches was better than that of the LR patches. RESULTS. Italian study. 139 patients resulted randomized to the SAM patch and 128 to the LR patch. Also in this study both types of patches relieved the climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the visual analogue scale (VAS) recordings of severity of hot flushes and of sweats. At the end of Part 1 both patches relieved 95% of patients from climacteric symptoms. At the end of Part 2, i.e. after 52 weeks, 100% of patients were relieved from climacteric symptoms. Of these, 72% in the SAM group and 78% in the LR group reported complete disappearance of symptoms. Also in the Italian study, therefore, the two patches were found therapeutically equivalent. Both patches stopped or even reversed bone mineral loss in L2-L4 and had some favorable effects on lipid metabolism. Both patches were systemically equally fairly well tolerated with premature discontinuations for systemic adverse drug reactions in only 5.0% of patients in the SAM group and 3.9% in the LR group. Conversely, as in the German study, the SAM patches were significantly better tolerated by the skin (p < 0.0001). CONCLUSIONS: The two types of estradiol transdermal patches were equivalent in providing an effective and rapid relief from climacteric symptoms. Systemically both patches were fairly well tolerated. The SAM patches were significantly better tolerated by the skin. The better local tolerability combined with better adhesion and cosmetic properties render the SAM patches very patient friendly and improve the compliance in the long term estrogen replacement therapy required to reduce osteoporosis and cardiovascular risks.

Adhesiveness↗
PubMed1998

The effect of sodium monofluorophosphate plus calcium on vertebral fracture rate in postmenopausal women with moderate osteoporosis. A randomized, controlled trial.

BACKGROUND: Fluoride is effective in increasing trabecular bone mineral density (BMD) in the spine, but its efficacy in reducing vertebral fracture rates and its effect on BMD at cortical sites are controversial. OBJECTIVE: To study the effect of low-dose fluoride (sodium monofluorophosphate [MFP]) plus a calcium supplement over 4 years on vertebral fractures and BMD at the lumbar spine and total hip in postmenopausal women with moderately low BMD of the spine. DESIGN: Randomized, double-blind, controlled clinical trial. SETTING: Outpatient clinic for osteoporosis at a university medical center. PATIENTS: 200 postmenopausal women with osteoporosis (according to the World Health Organization definition) and a T-score less than -2.5 for BMD of the spine. INTERVENTION: Women were randomly assigned (100 patients per group) to continuous daily treatment for 4 years with 1) oral MFP (20 mg of equivalent fluoride) plus 1000 mg of calcium (as calcium carbonate) or 2) calcium only. MEASUREMENTS: Lateral spine radiographs were taken at enrollment and at each year of follow-up for detection of new vertebral fractures (defined as a reduction > or =20% and > or =4 mm from baseline in any of the heights of a vertebral body). Nonvertebral fractures were also recorded. All analyses were done with the intention-to-treat approach. RESULTS: Radiologic follow-up was possible for 164 of 200 patients (82%). The rate of new vertebral fractures during the 4 years of the study was lower in the MFP-plus-calcium group (2 of 84 patients; 2.4% [95% CI, 0.3% to 8.3%]) than in the calcium-only group (8 of 80 patients; 10% [CI, 4.4% to 18.8%]). The difference between the groups was 7.6 percentage points (CI, 0.3 to 15 percentage points) (P = 0.05). A moderate but progressive increase in BMD of the spine (10.0% +/- 1.5% at 4 years) was found for MFP plus calcium compared with calcium only (P < 0.001), whereas the more modest increase in BMD of the total hip seen with MFP plus calcium (1.8% +/- 0.6%) did not differ from the increase seen with calcium only. CONCLUSIONS: Low-dose fluoride (20 mg/d) given continuously with calcium for prolonged periods can decrease vertebral fracture rates compared with calcium alone in patients with mild to moderate osteoporosis.

Aged↗
PubMed1998

Avoidance of vertebral fractures in men with idiopathic osteoporosis by a three year therapy with calcium and low-dose intermittent monofluorophosphate.

There are currently no trial-based recommendations for the treatment of idiopathic osteoporosis in men. A prospective, controlled, randomized 3-year study was conducted to evaluate the effects of intermittent, low-dose fluoride combined with continuous calcium supplementation on bone mass and future fracture events in men with this disease. Sixty-four men with idiopathic osteoporosis (mean age 53 years; mean T-score at L2-4, -2.75) and no previous vertebral fractures were randomly assigned to two treatment groups. Group A received intermittent (3 months on, 1 month off) treatment with monofluorophosphate 114 mg/day (i.e. 15 mg fluoride ions) plus continuous calcium supplementation (950-1000 mg/day). Group B received continuous calcium (1000 mg/day) alone. Bone mineral density was measured at the lumbar spine, hip and radius at 6-months intervals; thoracic and lumbar spine radiographs were obtained every 12 months. In group A bone density increased at all sites (by between +1.2% and +8.8%), while group B showed moderate decreases (by between -1.4% and -5.2%). After 36 months, bone densities at all sites in group A were significantly higher than those of group B. Three patients (10%) in group A suffered a total of 4 vertebral fractures versus 12 patients (40%) with 17 fractures in group B (p = 0.008). Non-vertebral fractures occurred in 3 patients in group A versus 11 in group B, though this difference was not significant. Back pain was significantly reduced in group A and unchanged in group B (after 3 years p = 0.0003). All side-effects were mild and transient. Early treatment of idiopathic osteoporosis in the male using the fluoride-calcium regimen we tested can improve cancellous and cortical bone density, reduce the incidence of vertebral fractures and attenuate back pain.

Adult↗
PubMed1998

Pharmacokinetics of estradiol and of estrone during application of a new 7-day estradiol transdermal patch with active matrix.

The pharmacokinetic patterns of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) were investigated in 18 women in natural or surgical menopause during the application of a new estradiol transdermal patch with active matrix and without absorption enhancers designed for epicutaneous applications of 7 days (hereinafter called "patch 7D"). The study was made with randomized and balanced sequences of applications in cross-over of either patch 7D or of an authorized estradiol transdermal patch with a nominal release rate of 50 micrograms/day estradiol designed for a twice-a-week epicutaneous application (hereinafter called "patch 50"). The sequences consisted of applications for 3 weeks either of 3 patches 7D or of 6 patches 50. The patches were applied on the skin of the hips or upper buttocks. The serum samples were obtained during the 1st and during the last week of application of the patches. Estradiol (E2) was assayed in serum by a double-antibody RIA method selective for free estradiol. Estrone (E1) was assayed in serum using a 3H-estrone RIA method. The steady state with regard to E2 and E1 was achieved already during the application of the 2nd patch. Patch 7D provided within 6 h an increase of the E2 concentrations in serum from the basal postmenopausal level of less than 3 pg/ml to therapeutically effective concentrations. The Cmax of E2 of 45 pg/ml was reached on average after 25 h, the concentrations of E2 remaining at sustained and therapeutically effective levels during the whole application of patch 7D. At steady state, during the 3rd week of application, the Cav was on average 31 pg/ml. With a small delay, E1 also increased from the basal 15 pg/ml to a Cmax of 41 pg/ml after 44 h. At steady state, during the 3rd week of application, the Cav was on average 38 pg/ml. Patch 7D provided a similar bioavailability as patch 50 with regard to the rate and the extent of absorption of E2, as shown by the AUCs during the 7-day applications of one patch 7D compared to those during the 7-day applications of 2 patches 50. The release of E2 from patch 7D is therefore similar to that of patch 50, i.e. on an average of 50 micrograms/day over a 7-day period of application. The E2/E1 ratio increased from the postmenopausal values lower than 0.2 found before the application of patch 7D to average values of 0.67, i.e., to values that are normally found during the fertile life of the woman. The improvement of the E2/E1 ratio occurred already in the first 6-12 h of application of patch 7D. The E2/E1 ratio returned rapidly to the initial low postmenopausal levels after removal of the patch. Patch 7D was well tolerated by the skin, probably because it does not contain absorption enhancers. It provoked, however, some systemic adverse reactions typical of E2 overdosing. In the therapeutic practice these adverse reactions can easily be avoided using patches 7D of lower strength. No drop-out due to systemic or local intolerance occurred. The adhesion of patch 7D on the skin was good. During the application of a total of 54 patches, only in one occasion one patch became partially detached (about 40% of the total area) from the 3rd to the 7th day during the first 7-day period of application.

Administration, Cutaneous↗
PubMed1998

Bioavailability and pharmacokinetic characteristics of two monofluorophosphate preparations with calcium supplement.

Two studies on the rate and extent of bioavailability of fluoride from a single dose of oral preparations of sodium monofluorophosphate (Na2FPO3) combined with calcium supplement were conducted according to a cross-over design on 18 (Study 1) and 20 (Study 2) male healthy volunteers, respectively. Evaluated were: a) tablets containing 76 mg Na2FPO3 (Ref1); b) chewable tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 1); c) effervescent tablets containing 76 mg Na2FPO and 3240 mg calcium lactogluconate/carbonate (Ref 2); d) effervescent tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 2). In all preparations Na2FPO3 was equivalent to 10 mg elemental F. The calcium supplement was equivalent to 500 mg elemental Ca. Fluoride was assayed in serum and in urine by a gas chromatographic method with a limit of quantitation of 10 ng/ml. Test 1 was found equivalent to Ref1 with regard to rate and extent of bioavailability of fluoride in serum. Test 2 (effervescent tablets resulting in an oral solution of Na2FPO3 and calcium salts) was found bioequivalent in rate and extent to Ref2 (effervescent tablets authorized for marketing with the same content in F and Ca equivalents as Test 2). The pharmacokinetics of fluoride from all investigated preparations was characterized by a short lag time, a rapid absorption, a Cmax of fluoride of 291-351 ng/ml (without significant differences between preparations) reached 30-75 min after administration, and a terminal t1/2 of 6-14 h. About 50% of the absorbed fluoride was eliminated with the urine (from 0 to infinity time). The kur.el was 0.06 h-1. The renal clearance 65 ml/min. The preparations were well tolerated by the subjects. In conclusion, Test1 and Test2 represent combinations of Na2FPO3 with calcium supplement which are well tolerated and provide a rapid, reliable and practically complete bioavailability of fluoride. They are therefore suitable for the bone-forming therapy of osteoporosis.

Adolescent↗
PubMed1997

Bone effects of transdermal hormone replacement therapy in postmenopausal women as evaluated by means of ultrasound: an open one-year prospective study.

OBJECTIVES: To evaluate the effectiveness of transdermal oestrogen replacement therapy plus medrogestone (HRT) in postmenopausal bone loss prevention by means of US. METHODS: We enrolled 112 healthy postmenopausal women in an open, prospective study. These women, after a gynaecological evaluation and an US assessment of the skeletal status, were advised to take cyclic sequential oestrogen/progestagen therapy: 50 microg/day of transdermal 17beta-oestradiol (Rotta Research Laboratorium) plus 5 mg/day of medrogestone, for 12 days per cycle (Wyeth-Ayerst). After 1 year we recalled these women: only 32 of them were taking HRT, while 49 had declined HRT without taking alternative therapies. The remaining women were excluded from the study as they were either unavailable for the check-up or they were taking prohibited therapies. We used DBM Sonic 1200 (Igea, Italy) to assess US parameter changes at phalanxes at enrollment and after 1 year. This device enabled us to evaluate US transmission velocity (AD-SoS) and US attenuation pattern (UBPS). In a previous study we had evaluated the intra- and inter-observer reproducibility of AD-SoS measurements (0.4 and 1.0% respectively). Using the same data we evaluated the intra- and inter-observer precision of UBPS. RESULTS: The UBPS intra-operator reproducibilities were 5.3% and 6.1% (for the 1st and the 2nd operator, respectively), while inter-observer precision was 8.8%. Both AD-SoS and UBPS significantly decreased in the non-user group(-0.7%, P < 0.001 and -14.3%, P < 0.001 respectively). In the user group AD-SoS showed a significant increase (+0.7%, P < 0.01), while a slight but significant decrease was observed for UBPS (-2.8%, P < 0.05). CONCLUSIONS: Our findings show that the effectiveness of transdermal HRT in slowing or even arresting postmenopausal bone loss can be monitored by quantitative US studies. The trend difference observed between AD-SoS and UBPS with and without therapy is at least partially explained by a different response to HRT with regard to bone density as well as structure.

Administration, Cutaneous↗
PubMed1997

Neurophysiological evaluation with multimodality evoked potentials in craniostenosis and craniofacial stenosis.

Multimodality evoked potentials (somatosensory and acoustic) have been recorded before surgery in children selected for surgical treatment for different kinds of craniostenosis and craniofacial stenosis. Evoked potentials were found to be deranged on at least one recording in 50% of cases, suggesting a significant incidence of neurophysiological alterations in these patients. No correlation was found between evoked potentials' derangements and clinical status, radiological findings, or different kinds of craniostenosis; moreover, a significant correlation was found between neurophysiological alterations and the age of the children. These preliminary data might define the possible role of neurophysiological tests in the presurgical evaluation of craniostenosis and craniofacial stenosis.

Aging↗
PubMed1997

A delayed complication with steel wire osteosynthesis.

We treated a 6-year-old child for hyperteleorbitism. We performed a facial bipartition steel wire osteosynthesis of the frontal bone. After 7 years we observed two episodes of pneumococcal meningitis, which were treated with intravenous antibiotic, resulting in a prompt recovery. The computed tomographic scan and nuclear magnetic resonance image showed the steel wire included in the frontal sinus and in contact with the dura mater. Removal of the wire and suture of the dura allowed prompt recovery.

Adolescent↗
PubMed1997

Effect of cholecystokinin-A receptor blockade on lipid-induced gastric relaxation in humans.

The purpose of this study was to assess the role of endogenous cholecystokinin (CCK) in regulating fat-induced changes in human gastric relaxation. Proximal gastric pressure-volume relationships were determined in 12 healthy volunteers during a series of gastric distensions, both fasting and after intragastric instillation of 250 ml of 10% Intralipid. All subjects were studied twice, in a randomized, double-blind study, during intravenous infusion of either loxiglumide (CCK-A antagonist) or saline. For each distension, intragastric pressure and compliance were determined together with perception intensity. During saline infusion, Intralipid reduced intragastric pressure (prelipid, 11.7 +/- 0.8; postlipid, 9.7 +/- 0.6 mmHg; P = 0.002) and increased compliance (pressure-volume slope values: prelipid, 87.6 +/- 9.7; postlipid, 47.2 +/- 7; P < 0.01). Loxiglumide infusion during fasting exerted no effect on either intragastric pressure or compliance. After lipid, however, loxiglumide abolished the expected postlipid reduction in intragastric pressure (prelipid, 12.1 +/- 0.7; postlipid, 11.5 +/- 0.8 mmHg; P = 0.4) but did not consistently abolish the postlipid increase in compliance. Loxiglumide exerted no effect on the cumulative perception score or on the volume at perception threshold, although it prevented the fat-induced reduction in pressure at perception threshold [control: prelipid, 15.4 +/- 1.1; postlipid, 10.7 +/- 0.5 (P < 0.05); loxiglumide: prelipid, 13.8 +/- 1.5; postlipid, 12.2 +/- 0.9 (P > 0.05)]. Endogenous CCK or CCK-A receptors therefore play a role in the fat-induced reduction of intragastric pressure and might also modulate gastric perception after lipid.

Adult↗
PubMed1997

Cholecystokinin-A receptor antagonists: therapies for gastrointestinal disorders.

Cholecystokinin (CCK) is a peptide that exerts several regulatory functions in the periphery, as well as in the brain. The biological functions attributed to CCK are mediated by two receptor subtypes, termed CCKA and CCKB, located predominantly in the gastrointestinal (GI) tract and in the brain, respectively. Several selective and potent non-petide CCKA receptor antagonists have been synthesised and fully characterised in preclinical studies. A few of them have been, and continue to be tested in humans. This paper focuses on the data available on the effect of CCKA receptor antagonist administration in humans, and shows how, in addition to allowing a more exact definition of the role of CCK in the regulation of some GI functions, these drugs may also possess therapeutic potential in GI disorders.

Journal Article↗
PubMed1997

Pharmacokinetics of estradiol and of estrone during application of three strengths of an estradiol transdermal patch with active matrix.

The pharmacokinetic pattern of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) during and after application of three strengths of a new transdermal estradiol patch (Dermestril) with active matrix was investigated in a cross-over study in 24 women in natural or surgical menopause. Free estradiol and estrone were assayed by GC-MS on plasma samples obtained during a 4-day application on the upper buttocks of the patches with 3 strengths and release rates of 25, 50 and 100 micrograms/day estradiol. The estradiol concentrations in plasma increased from 0-10 pg/ml typical of menopause to average concentrations of 23, 40 and 79 pg/ml during the application of the new estradiol transdermal patches with the three strengths. The concentrations of estradiol are in the range of those during the early follicular phase in women in fertile age. The increases were linearly related with the strength of the patches. Upon removal of the patches the estradiol concentrations returned to the basal low values in 8-24 h. Retarded with regard to estradiol, there was also an increase of estrone, from basal average concentrations of 22-32 pg/ml up to 31, 39 and 60 pg/ml. The increase of estrone was less pronounced than that of estradiol. Also estrone returned to its basal concentrations 24 h after removal of the patches. The estradiol/ estrone ratio from very low values typical of postmenopause increased to values of about 1, i.e. in the range of those found during the fertile age of woman. The adhesion of the patches was satisfying, provided that direct rough frictions were avoided. The patches were locally well tolerated, with rare mild and transient irritating effects on the skin. Also the systemic tolerability was good, with occasional mild or moderate side effects typical of estradiol (headache, mastodynia and pelvic heaviness) which in the practical use can be easily avoided by the application of patches of lower strength.

Administration, Cutaneous↗
PubMed1997

The role of cholecystokinin and the cholinergic system in intravenous amino acid-induced gallbladder emptying.

BACKGROUND: Recent studies have demonstrated that separate intravenous infusion of amino acids (IVAA) at high doses induces gallbladder emptying. However, little is known about the mechanisms mediating IVAA-induced gallbladder contraction. OBJECTIVE AND METHODS: To investigate whether the effect of IVAA on gallbladder motility is mediated by the cholinergic system and/or cholecystokinin (CCK), the major hormonal stimulus for gallbladder contraction. Six healthy male volunteers were studied in random order on five occasions using: (a) IVAA, (b) loxiglumide (CR 1505, a selective CCK-A receptor antagonist), (c) IVAA plus loxiglumide, (d) atropine and (e) IVAA plus atropine. Gallbladder volumes (ultrasonography) and plasma CCK levels (radioimmunoassay) were determined every 15 min for 60 min before and for 120 min during intravenous infusion of amino acids (Vamin 18EF; 250 mg protein/kg/h) and/or loxiglumide (10 mg/kg/h) and/or atropine (0.005 mg/kg/h). RESULTS: IVAA significantly (P < 0.05) reduced gallbladder volume from 32 +/- 5 ml to 17 +/- 2 ml but induced only a small and transient increase in plasma CCK levels. Loxiglumide given alone significantly (P < 0.05) increased fasting gallbladder volume to 190% of the basal value. IVAA-induced gallbladder emptying was completely abolished by loxiglumide. Maximal gallbladder relaxation during IVAA plus loxiglumide was not significantly different compared to loxiglumide given alone. Concomitant administration of atropine also significantly (P < 0.05) inhibited IVAA-induced gallbladder emptying. CONCLUSION: In healthy volunteers intravenous infusion of high doses of amino acids results in a significant gallbladder contraction, which is inhibited by CCK-A receptor blockade and by atropine.

Adult↗
PubMed1996

Bioavailability of estradiol from two transdermal patches.

The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.

Administration, Cutaneous↗
PubMed1996

Pharmacokinetics of estradiol and of estrone during repeated transdermal or oral administration of estradiol.

The estradiol (CAS 50-28-2, E2) and estrone (CAS 53-16-7, E1) concentrations in blood were investigated during a 3-week twice weekly application of an E2 transdermal patch, or daily oral administration of E2 tablets. The transdermal patch (Dermestril 50, hereinafter called "Patch") contains 4 mg E2 and delivers daily 50 micrograms E2. The E2 tablets (hereinafter called "Tablet") contains 2 mg micronized E2. The study was performed on 32 healthy postmenopausal women randomly assigned to two parallel groups, each of 16 subjects, one treated with Patch and the other with Tablet. During the first transdermal Patch application, E2 reached effective concentrations of 30 pg/ml of more 12 h after application. During the following 5 applications the concentrations of E2 remained rather constant (fluctuation = 0.65). The study state was reached with the second Patch, with an average concentration (Cav) of 35 pg/ml. After removal of the last Patch, the E2 concentrations returned to the basal levels within 12 h. The E1 concentrations reached the maximum concentration (Cmax) of 48 pg/ml 41 h after the first Patch application and then remained rather constant (fluctuation = 0.28), with a Cav at steady state of 47 pg/ml. During the oral administration of the first Tablet, E2 reached the peak of 1084 pg/ml 49 min after administration and then decreased rapidly in the following 3 h. There was a progressive cumulation of E2 until steady state, which was reached after the 5th Tablets with a Cav of 418 pg/ml i.e. 12.0 times greater than during Patch, and very large pulses of E2 (fluctuation = 3.68). The E1 concentrations reached the peak of 334 pg/ml 4.28 h after the first administration. The steady was reached with the 14th daily administration. There were Large pulses of E1 (fluctuation = 1.15). The Cav was 441 pg/ml, i.e. 9.4 times greater than during Patch. In conclusion the twice weekly application of the transdermal Patch elicits rather constant and therapeutically effective blood concentrations of E2 and E1. In contrast, the daily oral administration of E2 Tablets elicits large pulses of E2 and E1, and exposes the subjects to high concentrations of E2 and of E1, which are 12.0 and 9.4 times greater, respectively, than those elicited by the Patch. Both treatments were fairly well tolerated, and no withdrawal of the medications during the study was necessary.

Administration, Cutaneous↗