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ZusammenfassungInnerhalb einer dreijährigen Pilotstudie an 52 Frauen mit schwerer postmenopausaler Osteoporose wurden die Behandlungen mit Etidronat und anschließender Gabe von Kalzium und Vitamin D (ECaD) einerseits bzw. mit Etidronat und anschließender Verabreichung von Monofluorphosphat plus Kalzium und Vitamin D (EFCaD) andererseits miteinander verglichen. Die Knochenmineraldichte (BMD) von Lendenwirbelsäule, Gesamthüfte und Schenkelhals nahm mit dem EFCaD-Regime signifikant stärker zu als mit dem ECaD-Regime. Der Score für Schmerzen/Mobilität ging mit EFCaD signifikant stärker zurück als mit ECaD (p=0,006).Neue vertebrale Frakturen traten beidrei Patientinnen unter EFCaD (12%) bzw. neun Patientinnen unter ECaD (35%) auf (p = 0,048). Bei drei Patientinnen unter EFCaD (12%) bzw. 15 Patientinnen unter ECaD (58%) war kein Ansprechen (Response) auf die Therapie zu verzeichnen (p-Wert des Unterschieds = 0,001). Bei 25 Patientinnen wurde über leichte bis mittelschwere unerwünschte Ereignisse berichtet, wobei zwischen den beiden Behandlungsgruppen keine signifikanten Unterschiede zu beobachten waren. Die Pilotstudie deutet darauf hin, dass Etidronat, sequenziell gefolgt von Monofluorphosphat, eine sichere, wirksame und relativ kostengünstige Therapie bei schwerer postmenopausaler Osteoporose darstellen könnte.

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.

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.

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 (p0.001) 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.

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 (p0.001) 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.

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.

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.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 (p0.01) 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 (p0.0001).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.

A double-blind therapeutic investigation was performed on 178 Chinese patients suffering from osteoarthritis of the knee randomized into two groups, one treated for 4 weeks with glucosamine sulfate (GS, CAS 29031-19-4, Viartril-S) at the daily dose of 1,500 mg and the other with ibuprofen (IBU, CAS 15687-27-1) at the daily dose of 1,200 mg. Knee pain at rest, at movement and at pressure, knee swelling, improvement and therapeutic utility as well as adverse events and drop-outs were recorded after 2 and 4 weeks of treatment. The variables were recorded also after 2 weeks of treatment discontinuation in order to appreciate the remnant therapeutic effect. Both GS and IBU significantly reduced the symptoms of osteoarthritis with the trend of GS to be more effective. After 2 weeks of drug discontinuation there was a remnant therapeutic effect in both groups, with the trend to be more pronounced in the GS group. GS was significantly better tolerated than IBU, as shown by the adverse drug reactions (6% in the patients of the GS group and 16% in the IBU group--p = 0.02) and by the drug-related drop-outs (0% of the patients in the GS group and 10% in the IBU group--p = 0.0017). The better tolerability of GS is explained by its mode of action, because GS specifically curbs the pathogenic mechanisms of osteoarthritis and does not inhibit the cyclo-oxygenases as the non-steroidal anti-inflammatory drugs (NSAIDs) do, with the consequent anti-inflammatory analgesic activities but also with the several adverse reactions due to this not targeted effect. The present study confirms that GS is a selective drug for osteoarthritis, as effective on the symptoms of the disease as NSAIDs but significantly better tolerated. For these properties GS seems particularly indicated in the long-term treatments needed in osteoarthritis.

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.

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.

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.

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.

Glucosamine sulfate (Dona, CAS 29031-19-4) is a drug used in the treatment of osteoarthritis. When orally given, it is more effective than placebo and at least as effective as non-steroidal anti-inflammatory drugs in relieving osteoarthritis symptoms. The aim of this multicentre, randomised, placebo-controlled, double-blind, parallel-group study was to assess the efficacy and safety of glucosamine sulfate intramuscularly given on the same parameters. 155 out-patients with knee osteoarthritis (Lequesne's criteria), radiological stage between I and III, Lequesne's severity index of at least 4 points and symptoms for at least 6 months, were treated with i.m. glucosamine sulfate (or placebo) 400 mg twice a week for 6 weeks. Clinic visits were performed at enrollment, after a 2-week baseline, at weekly intervals during treatment and 2 weeks after drug discontinuation. Responders to treatment were considered those patients with a reduction of at least 3 points in the Lequesne index, together with a positive overall judgement by the investigator. The Lequesne index was slightly over 10 points in average in both groups at the beginning of treatment. A significant decrease in the index was observed for glucosamine compared to placebo (3.3 vs. 2.0 points in average, respectively; p0.05, Student's t-test). The responder rate in the evaluable patients was 55% with glucosamine (n = 73) and only 33% (n = 69) with placebo (p = 0.012, Fisher's Exact Test). According to the intention-to-treat approach, considering also drop-outs, these proportions were 51% vs. 30% (p = 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of glucosamine sulfate (CAS 29031-19-4) was investigated in 6 healthy male volunteers (2 per administration route) using 14C uniformly labelled glucosamine sulfate and administering it in single dose by intravenous (i.v.), intramuscular (i.m.) or oral route. The results show that after i.v. administration the radioactivity due to glucosamine appears in plasma and is rapidly eliminated, with an initial t1/2 of 0.28 h. 1-2 h after administration the radioactivity due to glucosamine disappears almost completely and is replaced by a radioactivity originating from plasma proteins, in which glucosamine or its metabolites are incorporated. This radioactivity reaches a peak after 8-10 h and then declines with a t1/2 of 70 h. About 28% of the administered radioactivity is recovered in the urine of the 120 h following the administration and less than 1% is recovered in the feces. After i.m. administration similar pharmacokinetic patterns are observed. After oral administration a proportion close to 90% of glucosamine sulfate is absorbed. Free glucosamine is not detectable in plasma. The radioactivity incorporated in the plasma proteins follows pharmacokinetic patterns which are similar to those after i.v. or i.m. administration, but its concentration in plasma is about 5 times smaller than that after parenteral administration. The AUC after oral administration is 26% of that after i.v., or i.m. administration. The smaller plasma levels of radioactivity after oral administration are probably due to a first pass effect in the liver which metabolizes a notable proportion of glucosamine into smaller molecules and ultimately to CO2, water and urea.(ABSTRACT TRUNCATED AT 250 WORDS)

A two-way cross-over study was conducted on 12 Caucasian male healthy volunteers aged between 25 and 38 years in order to determine the bioavailability and pharmacokinetics of fluoride after single oral administration in fasting conditions of two products (tablets and powder for oral use) of L-glutamine monofluorophosphate (G-MFP, CAS 116420-36-1). The two products contained the equivalent of 10 mg F and the equivalent of 300 mg CA as calcium gluconate and calcium citrate. The two products were found bioequivalent with regard to the release of fluoride, both on the basis of the AUC and Cmax of fluoride in plasma and of the urinary excretion of fluoride during the 48 h following the administration. The pharmacokinetics of fluoride in plasma is characterized by a short lag time (6 min), a rapid absorption, a peak which is reached 0.5-1.0 h after administration, followed by a biphasic elimination. The first phase with a k alpha of 1.8 h-1 is followed by a slower phase with a K beta of 0.14 h-1. Probably the terminal elimination rate is slower, about 0.05 h-1. The urinary excretion of fluoride during the 48 h after administration accounted for 40-50% of the administered dose of fluoride. The results are consistent with those found in previous studies after administration in fasting conditions of sodium fluoride or sodium monofluorophosphate alone or in combination with calcium salts.

A two-treatment cross-over study was conducted on 8 Caucasian male healthy volunteers aged between 26 and 32 years in order to determine the influence of a standard meal on the bioavailability and pharmacokinetics of fluoride after a single oral administration of tablets containing the equivalent of 10 mg fluoride as sodium monofluorophosphate (Na-MFP, CAS 10163-15-2) in a fixed combination with 300 mg Ca as calcium gluconate and calcium citrate. The meal provoked a significant delay of the appearance of fluoride in blood (from 4 to 11 min), a slowing of the absorption rate, a prolongation of tmax (from 34 to 146 min), a decrease of Cmax (from 369 to 122 ng/ml) and a prolongation of the Mean Residence Time (from 7.1 to 9.1 h). However, the amount of fluoride entering in the systemic circulation was not affected by the meal, as shown by the ANOVA on the AUC and on the cumulated urinary excretion of fluoride in the 48 h following the administration of Na-MFP. It is concluded that appropriate meals do not influence the amount of absorbed fluoride from Na-MFP, and that they modify the rate of absorption with pattern that may improve the safety and possibly also the efficacy of Na-MFP.

8 Reduction in estimated 10-years cardiovascular disease risk in dyslipidaemic hypertensive subjects in monotherapy with ACE-inhibitors (ACE-Is) or Calcium Channel Blockers (CCBs) by the use of a combined nutraceutical A.F.G. Cicero1, B. Gerocarni1, I. Setnikar2, C. Benvenuti2, L. Rovati2. 1Internal medicine, Aging and Kidney Disease Dept., University of Bologna, Italy; 2Rottapharm-Madaus SpA, Monza, Italy E-mail: afgcicero@cardionet.it

In a randomized double-blind study with two parallel groups of 10 male healthy volunteers each the response of gastric mucosa after a 7 days ingestion of sodium fluoride tablets (NaF) or sodium monofluorophosphate tablets (MFP) was compared. Gastroscopic evaluations were performed before treatment, day 1 and day 7. Simultaneously blood samples were collected for determination of laboratory data and serum fluoride values. In the MFP-group no severe gastric lesions were observed, whereas in the NaF-group in 7 of the 10 subjects significant gastric mucosal lesions including acute hemorrhages and free blood in the gastric lumen were found. The differences of the lesions scores in both groups were statistically significant (p = 0.0015). The serum fluoride content was comparable in both treatment groups. Possible adverse drug reactions were reported in 4 subjects with NaF and in 1 subject with MFP. In summary, under the experimental conditions used MFP is well tolerated by the stomach while NaF produces significant gastric mucosal lesions.

The medicinal therapy of osteoarthritis is based on the use of analgesics, NSAIDs and corticosteroids to relieve pain and inflammation. In addition, "chondroprotective" agents (CPA) are used to stop the evolution of the disease. In this review the biochemical and pharmacological activities of some of the most widely used CPAs are described. All of these show more or less marked antiinflammatory activities, which for some of them are the result of an inhibition of cyclo-oxygenase and of prostaglandin biosynthesis, in which case they should be more properly classified as mild NSAIDs. Only two of the CPAs reviewed, diacerein and D-glucosamine sulfate, elicit antiinflammatory and antireactive effects without significant inhibition of the prostaglandin biosynthesis. These agents have also remarkable chondroprotective effects, and only these two agents should be classified as true CPAs. In particular glucosamine sulfate, which naturally occurs in the human body and is almost devoid of toxicity, is suitable for long-term therapeutic use. This, with its chondrometabolic, antireactive and antiarthritic properties, represents the pharmacological rationale for the use of glucosamine sulfate as a disease-modifying agent in osteoarthritis.

The antireactive activity of glucosamine sulfate (GS) (CAS 29031-19-4) was tested in the rat in experimental models of subacute inflammation (sponge granuloma and croton oil granuloma), on subacute mechanical arthritis (kaolin arthritis) and in immunological-reactive arthritis and generalized inflammation (adjuvant arthritis). On these models GS was found effective in oral daily doses of 50-800 mg/kg. Tne potency of GS in comparison of that of indometacin used in the same tests as reference substance was found 50-300 times lower. Since, however, the toxicity of indometacin in chronic toxicity experiments is 1000-4000 times larger, the therapeutic margin with regard to prolonged treatments of inflammatory disorders results 10-30 times more favourable for GS than for indometacin. GS can therefore be considered as a drug of choice for prolonged oral treatment of rheumatic disorders.

The study was conducted in a triple cross-over on 12 healthy Caucasian volunteers (4 males and 8 females) of an age between 23 and 44 years. The following products were given in a single oral dose in fasting state. 1. Solution of 29.18 mg of sodium fluoride in 80 ml of water (reference NaF solution). 2. Solution of 100 mg sodium monofluorophosphate (CAS 10163-15-2) in 80 ml of water (Na2FPO3 solution). 3. Tablets with 100 mg sodium monofluorophosphate and 1250 mg calcium carbonate (Na2FPO3 + Ca tablets). The three products were equivalent in fluorine content (13.2 mg). The bioavailability of fluorine was evaluated on the basis of the plasma levels and of the urinary excretion of fluoride. After administration of the products, fluoride appeared in blood with a lag time smaller than 0.05 h and invaded the blood with a t1/2 from 0.07 to 0.12 h. The Cmax of fluoride in plasma was 412-466 ng/ml at a tmax of 0.5-0.7 h. The AUCs of fluoride after Na2FPO3 solution and after Na2FPO3 tablets were within the 0.80-1.20 bioequivalence limits with regard to the AUC after NaF solution. The three products can therefore be considered bioequivalent according to the Westlake criteria. In the 24 h following the administration, the urinary excretion of fluoride accounted for 51 +/- 10%, 46 +/- 6% and 47 +/- 8% of the administered dose, respectively for NaF solution, Na2FPO3 solution and Na2FPO3 + Ca tablets. The difference between the three products was statistically not significant and confirms their bioequivalence.(ABSTRACT TRUNCATED AT 250 WORDS)

The study was conducted on 12 healthy male Caucasian volunteers of an average age of 27.8 +/- 4.0 years with single oral doses of the following products: 1. sodium monofluorophosphate tablets (MFP-tablets, Mono-Tridin); 2. aqueous solution of 23.2 mg of sodium fluoride (NaF solution-reference); 3. aqueous solution of sodium monofluorophosphate (MFP solution). The three products were equivalent in fluorine content with 10.5 mg F. The bioavailability was evaluated on the basis of the plasma levels and of the urinary excretion of fluoride. The study was designed as a triple latin-square crossover and each subject received the three products in three different periods, at empty stomach. After administration of the products, fluoride appeared quickly in blood (lag time between 0.07 and 0.13 h) and invaded rapidly the blood (invasion t1/2 from 0.04 to 0.15 h). The Cmax of fluoride in plasma was 439 ng/ml at tmax of 1.08 h after MFP tablets, 430 ng/ml at a tmax of 0.51 h after NaF solution and 403 ng/ml at tmax of 0.62 h after MFP solution. The differences for the Cmax were not statistically significant. The relative bioavailability of fluoride from MFP tablets, estimated from the AUC, was 1.35, and significantly larger than that from the reference NaF solution. Fluoride was eliminated from plasma with an initial fast rate (t1/2 from 0.68 to 1.03 h) and a terminal slower rate (t1/2 from 4.71 to 7.37 h). The plasma levels of fluoride were consistent with a two-compartment open pharmacokinetic model after extravascular administration. In the 24 h following the administration the urinary excretion of fluoride accounted for 50-53% of the administered dose, without significant difference between the three products. The three products were well tolerated and no systemic or gastric adverse reaction was recorded.

Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS)

Experiments on rabbit isolated colon show that a carbachol-induced contraction is accompanied by a decrease in cAMP content of the smooth muscle. (±)-α-(Benzoylamino)-4-[2-(diethylamino)-ethoxy]-NN-di-propylbenzen-propanamid (tiropramide, CR 605), a new tyrosine derivative with antispastic properties, increases cAMP concentrations within the same dose range that produces smooth muscle relaxation with or without carbachol (0·1 μm). These effects are potentiated by 1 mM theophylline, a phosphodiesterase inhibitor. In a purified microsomal preparation from rabbit colon smooth muscle, corresponding to sarcoplasmic reticulum, tiropramide induced a dose-dependent increase Ca2+ binding in the presence of ATP and Mg2+. Tiropramide inhibited phosphodiesterase activity in rabbit colon homogenates in a range of doses about ten times that producing relaxation, cAMP content enhancement and increase Ca2+ binding to sarcoplasmic reticulum. The effects of tiropramide on the carbachol-stimulated rabbit colon in the presence of theophylline, indomethacin or PGE1 are more in agreement with an action of tiropramide as inhibitor of cAMP catabolism than as a result of a prostaglandin-mediated effect. These observations suggest that the smooth muscle relaxant activity of tiropramide arises from drug-induced increase of cAMP concentrations possibly because of inhibition of cAMP catabolism. This effect is accompanied by the binding to the sarcoplasmic reticulum of Ca2+, preventing its interaction with the contractile proteins of the smooth muscle. A direct effect of tiropramide-enhanced cAMP content on contractile proteins in the smooth muscle cannot be excluded.

The metabolites of tiropramide were extracted from the urine of healthy volunteers given tiropramide hydrochloride orally. Eight metabolites of tiropramide were found by gas chromatography/mass spectrometry. Three were identified on the basis of their mass spectra, retention times and comparison with synthetic standards. For the others a probable structure is proposed on the basis of their mass spectra.

Iproniazid was found to inhibit formalin-induced oedema of the foot, dextran-induced oedema and cotton-pellet-induced granulomatous tissue in the rat. The presence of the adrenals was essential for the antiphlogistic activity. The antiphlogistic action was not accompanied by any antipyretic effect. Inhibition of formalin-induced oedema was also observed with phenylbutazone and with salicylamide.

Tiropramide hydrochloride and some of its metabolites were studied in vivo for their antispasmodic activities on the following models: gastric emptying in the mouse retarded by cholecystokinin octapeptide (CCK-8) or morphine, progression of intestinal contents in the mouse, spontaneous motility of the colon in the anesthetized rabbit, diarrhea induced by castor oil in the rat, spasm of the sphincter of Oddi provoked by morphine in the guinea pig, contractions of the urinary bladder in the anesthetized rat. On these models tiropramide had an antispasmodic activity at doses of 4-40 mg/kg i.p. or i.v. and of 50-90 mg/kg orally. The potency was greater on "pathological" contractions or spasms and smaller on "physiological" movements. Tiropramide may therefore be regarded as a "eukinetic" antispasmodic agent. Tiropramide in general was more potent than reference agents such as papaverine or flavoxate and was active also after oral administration. The metabolites of tiropramide, i.e. CR 1034, CR 1098 and CR 1166 showed similar pharmacodynamic effects, but their potency was smaller than that of tiropramide. Large doses of tiropramide have depressive actions on the cardiovascular system, which can be seen especially if tiropramide is administered i.v. and are less pronounced after oral administration. The circulatory effects are therefore probably the limiting factor for increasing the parenteral doses of tiropramide in human therapy. Tiropramide was found less toxic than papaverine (LD50). The metabolites of tiropramide were less toxic than the parent compound. The toxicity of the chiralic forms of tiropramide does not differ significantly from that of the racemic substance.

The plasma levels, the urinary excretion and the biliary excretion of piperidinoethyl-3-methylflavone-8-carboxylate (flavoxate, F) were studied in rats after i.v. and after oral administration. Parallel experiments were made with 3-methyl-flavone-8-carboxylic acid (M), the main metabolite of F. The substances are found in blood and are excreted in the urine and in the bile. The quantities excreted in the urine after oral administration are similar to those excreted after i.v. administration, showing that the enteric availability of the drugs is almost complete. The end product in urine and in bile is represented by a substance which yields M after a strong acid hydrolysis. There are marked pharmacokinetic differences between F and M, probably related to their physical properties.

Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists. The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini. In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein). It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis. Lorglumide is therefore a useful pharmacological tool to study the functions of CCK. For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.

The anticholecystokinin activities of loxiglumide, (D,L-4-(3,4-dichloro-benzoylamino)-5-(N-3-methoxypropyl-pentylamino++ +)-5-oxo- pentanoic acid, CR 1505) are described. Loxiglumide antagonizes in vivo the contractions of the gall bladder of guinea pig induced or mediated by cholecystokinin-8 (CCK-8) (i.v. ED50 = 0.24 mumol/kg), the emptying of the gall bladder of the mouse induced by CCK-8 (i.v. ED50 = 29 mumol/kg, oral ED50 = 42 mumol/kg), the retardation of gastric emptying of the rat induced by CCK-8 (i.p. ED50 = 13 mumol/kg), the retardation of the pyloric transit in the mouse induced by CCK-8 (i.v. ED50 = 3.7 mumol/kg, oral ED50 = 11 mumol/kg), the hypermotility of the ileum of the rabbit induced by CCK-8 (i.v. ED50 = 1.2 mumol/kg) and the contractions of the gall bladder of the non-anesthetized dog induced by caerulein (i.v. ED50 ca. 11 mumol/kg). Loxiglumide also antagonizes the satiety behaviour of the rat elicited by CCK-8 (i.p. ED50 = 0.65 mumol/kg) and the exocrine pancreatic hypersecretion in the anaesthetized dog induced by CCK-8 (i.v. ED50 ca. 0.35 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and is active after parenteral and after oral administration.

New glutaramic acid derivatives were evaluated for anti-cholecystokinin (CCK) activity in vitro on guinea pig gallbladder. The compounds are competitive and specific CCK-antagonists, causing a parallel right shift of the cumulative dose-response curve of the agonist. The affinity for the binding site of the CCK-receptor for some of these compounds was hundreds of times higher than that of pro-glumide, the model compound.

The pharmacokinetics, organ distribution, metabolism and excretion of glucosamine were studied in the dog giving uniformly labelled [14C]-glucosamine (sulfate), i.v. or orally, in single doses. Immediately after i.v. administration, the radioactivity in plasma is due to glucosamine, and freely diffuses into organs and tissues. This radioactivity disappears quickly from plasma (initial t1/2 = 13 min, terminal t1/2 = 118 min). After 30-60 min the radioactivity in plasma is no longer due to glucosamine, but is incorporated into alpha- and beta-globulins. The protein-incorporated radioactivity is found already 20-30 min after i.v. administration, reaches a peak after 8 h and then slowly disappears, with a t1/2 = 2.9 days. Of the administered radioactivity, more than 34% is excreted in the urine, mainly as glucosamine, and 1.7% is excreted in the feces. Radioactivity is excreted also as [14C]-CO2 in the expired air. The radioactivity, after i.v. administration, diffuses rapidly from blood into the body. Some organs show an active uptake of radioactivity, e.g. the liver and the kidney. Other tissues, such as the articular cartilage, also have an active uptake. In most other organs the radioactivity found can be explained by passive diffusion processes from plasma. After oral administration of a single dose of [14C]-glucosamine the radioactivity is quickly and almost completely absorbed from the gastrointestinal tract. The pattern of disappearance, metabolic transformation, tissue distribution and excretion of the radioactivity are consistent with those found after i.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacological activities of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropylglutaramate(+/-)dimaleate (protacine, CR 604), a new indolyl derivative with strong anti-inflammatory, analgesic and antipyretic activities, are described. The dose-dependent activity of protacine on inflammation has been shown both in short-term experiments, like the hind paw edema induced by carrageenin and several other irritants, and long-term tests, like the aminoacetonitrile-induced osteolathyrism, the adjuvant-induced arthritis and the cotton pellet-induced granuloma. The analgesic activity of the drug has been evidenced in the phenylquinone-induced writhing and the Randall-Selitto tests, and the antipyretic effects in the yeast-induced hyperthermia in rats. Other general pharmacological effects have been studied, too. Contrarily to several other anti-inflammatory drugs, including indometacin, showing advers effects at doses which are in the same range of those active on experimental inflammation, protacine shows these effects to a minor degree and at doses which are much larger than those pharmacologically active. The therapeutic index of protacine therefore is superior to that of other anti-inflammatory drugs.

The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. The substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 16 rats (8 males and 8 females) and in single peroral (p.o.) doses of 10 mg/kg to other 16 rats (8 males and 8 females). The radioactivity in plasma, in several organs and tissues and in gastrointestinal contents was measured by scintillometry. After i.v. administration the radioactivity is rapidly found in all investigated organs and tissues and also in the stomach contents. The radioactivity is concentrated in the liver and kidney, and also in other organs, as the pancreas and the salivary glands. After 120 h the radioactivity is small in the organs but still appreciably present in the colon content. The radioactivity crosses the blood-brain barrier. Deep compartments were not found. After p.o. administration the radioactivity is rapidly found in the organs and is particularly concentrated in the liver, showing a rapid absorption from the gastrointestinal tract. Besides the obvious higher concentration of radioactivity in the stomach and small intestine in the initial times after p.o. administration, the distribution and elimination pattern from the organs do not substantially differ from those found after i.v. administration. The distribution pattern found using the scintillographic method were confirmed by an autoradiographic study made on 12 non-pregnant rats (10 males and 2 females) and on 7 rats at the 13th day of pregnancy and 7 rats at the 18th day of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

A study was made on possible interferences of several drugs on the urinary excretion of nifurpipone and of nitrofurantoin orally administered to rats. Phenobarbital, a microsomial enzyme inducer, SKF 525 A, a microsomial enzyme inhibitor, probenecid, an inhibitor of the tubular acid secretory system, quanine, an inhibitor of the tubular alkaline secretory system, and hydrochlorothiazide, a diuretic, were studied. None of these treatments altered in an important way the urinary excretion of nifurpipone or of nitrofurantoin.

The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. For the study of pulmonary, urinary and fecal excretion the substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 4 rats (2 males and 2 females) and in single peroral (p.o.) doses of 10 mg/kg to other 4 rats (2 males and 2 females). For the study of biliary excretion 4 mg/kg of 14C-tiropramide hydrochloride were administered in single i.v. doses to 4 rats (2 males and 2 females) anesthetized with urethane and the bile was collected from the choledocus in the 8 h following administration. The radioactivity in the expired CO2, urine feces and bile was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. The following results were obtained. Radioactivity in the expired CO2: No radioactivity was found, either after i.v. or p.o. administration. Radioactivity in urine: In the 48 h after administration 37% of the i.v. administered radioactivity and 31% of the p.o. administered radioactivity was recovered in the urine. Six basic substances could be identified. In order of decreasing abundance these were CR 1166, CR 1098, tiropramide, CR 1034, CR 1919 and CR 1938. Radioactivity in feces: In the 120 h after administration 60% of the i.v. administered radioactivity and 56% of the p.o. administered radioactivity was recovered in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)

The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg of loxiglumide (CR 1505). The pharmacokinetics of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 +/- 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 +/- 5.1 mg/l at tmax of 2.3 +/- 0.8 h, a mean residence time (MRT) of 6.9 +/- 1.1 h and an AUC of 60.6 +/- 16.3 (mg/l) x h. After the last dose of 400 mg the lag time was 17 +/- 6 min, the Cmax 12.7 +/- 3.8 mg/l at tmax of 2.1 +/- 0.8 h, a MRT of 11.0 +/- 1.9 h and an AUC of 109.8 +/- 39.9 (mg/l) x h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

A series of substituted 2-(2,3,5,6-tetramethylbenzyl)imidazolines and related compounds have been synthesized to study the steric and hydrophobic effects on the vasoactivity of the introduction of four methyl groups on the phenyl moiety. The 2-(2,3,5,6-tetramethylbenzyl)imidazoline (I) showed a high hypertensive activity, whereas the 2-benzylimidazoline possesses an adrenolytic activity. The 2-(2,3,5,6-tetramethylphenoxy)methylimidazoline (XVII) retained the hypertensive activity, whereas the corresponding thioether (XIX) was inactive. Some structure-activity relationships with regard to the presence of substituents in the 4-position of the phenyl moiety and on the benzylic CH2 are reported.

Si descrivono la sintesi, le caratteristiche fisico-chimiche e le proprieta antimicrobiche del thiabenzazonio, un nuovo derivato ammonico quaternario della 1,5-benzodiazepina. Il thiabenzazonio e dotato di una spiccata attivita batteriostatica e battericida su alcune specie microbiche Gram-positive, che spesso sono responsabili di infenzioni del cavo orofaringeo.