Single and repealed dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue districution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3).Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations. but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen.Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations.Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose.Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer.The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low while rifampicin had a little higher urine concentrations.

Several studies have shown that treatment with bisphosphonates can reduce the pain associated with different painful diseases. In a previous study we demonstrated that in mice two bisphosponates, clodronate and pamidronate, had an antinociceptive effect under acute conditions not related to bone processes, after in vein (iv) or intracerebroventricular (icv) injection. The present study tested the time-dependent antinociceptive action of clodronate and pamidronate in comparison with that of acetylsalicylic acid (ASA) and morphine after iv and icv injection using the tail-flick test in acute and chronic treatment. The effects of clodronate on other measures of animal behaviour were also evaluated. In the tail-flick test, administration of clodronate iv produced an antinociceptive effect that was greater than that of ASA and statistically significant up to 16 h; pamidronate iv showed a significant antinociceptive effect for only 6 h. Clodronate and pamidronate icv showed an increase in tail-flick latency time that was significant and lasted for 16 and 6 h, respectively, while morphine produced an antinociceptive effect for 24 h. In the test we found significant differences between male and female mice in the latency time values but not in the length of the analgesic effect. In the chronic treatment paradigm, clodronate produced a significant increase of the tail-flick latency after the first injection. The analgesic effect increased up to 50% after 5 days of treatment. Significant analgesic effects were still present after 3, 7, and 14 days from the end of treatment. Clodronate did not produce any significant behavioural effects in the Rota-rod test, pentobarbital-induced sleeping time, and locomotor activity cage. These data indicate that clodronate presents a central and peripheral prolonged antinociceptive effect, without any behavioural side effects.

UNLABELLED:We determined the analgesic and antiinflammatory actions and the related acute mucosal gastric damage from the active S(+)-isomer ibuprofen (dexibuprofen), in comparison with those of the standard racemic formulation of ibuprofen in rodents. The antinociception was evaluated by hot-plate and tail-flick methods after IV and oral (PO) administration in mice and after PO administration in rats. S(+)-Ibuprofen was at least twice more potent than the ibuprofen racemic formulation. The antiinflammatory action of the test compound, assessed with the abdominal constriction test in mice (IV and PO) and with hind paw edema in rats (IV and PO), was found to be significantly more potent than that of ibuprofen after IV treatment in mice and PO administration in rats. Moreover, the test compound caused significantly less mucosal gastric damage than the racemic formulation administered at identical doses (50 mg/kg PO in rats). In conclusion, the S(+)-ibuprofen isomer was found to be more potent than the racemic formulation in analgesic and antiinflammatory tests and presented fewer gastric toxic effects. On the basis of the results of this work, we suggest that the administration of chemical entities, such as R(-)-ibuprofen, should be avoided if they are not essential for the anticipated therapeutic activity. IMPLICATIONS:Ibuprofen is a nonsteroidal antiinflammatory drug often prescribed as a racemic formulation. We studied the analgesic and antiinflammatory effects of the active S(+)-isomer. The S(+)-ibuprofen was found to be more potent than the racemic formulation and produced less acute gastric damage.

A single-dose trial in mice (1.25 mg/kg SPA-S-753 or 1 mg/kg amphotericin B [AmB] by intravenous route) was performed to study the pharmacokinetics, tissue distribution, and urinary excretion of a new polyene, SPA-S-753 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate), in comparison with AmB. Antibiotic concentrations were determined by microbiological assay (agar diffusion method). The elimination half-lives in serum were 15.1 and 19.8 h, respectively, for SPA-S-753 and AmB; the area under the curve from 0 to infinity values were 49.3 for SPA-S-753 and 23.6 microg. h/mL for AmB, because of the higher serum levels of SPA-S-753 found just after administration. The tissue concentrations of SPA-S-753 were lower than those of AmB in liver and lungs but higher in the kidneys. The urine concentrations of SPA-S-753 and the percent of the administered dose recovered from the urine were quite low in mice, whereas those of AmB were higher.

Venous tolerance of a new water soluble polyene antibiotic, SPK-843, in 5% glucose solution for infusion is low in laboratory animals. The use of Intralipid 10% emulsion was therefore proposed, in which the antibiotic remained chemically stable for at least 2 h in a mildly acid or nearly neutral environment and at concentrations of 0.1-0.5 mg/mL, producing no alterations in the emulsion structure. Tolerance was assessed through repeated infusions in the ear marginal vein of rabbits and was found much more satisfactory than the tolerance observed when the vehicle used was 5% glucose solution. The study of the effect of some variables (concentration, volume infused, dose per kg) on venous toxicity offered the possibility to plan optimal administration conditions of presumed therapeutic doses.

Single- and multiple-administration trials in rats were performed in this study to assess the serum and tissue concentrations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure. A dose of 1.25 mg/kg (roughly 1 mg/kg of free base) by intravenous route was used both for the single- and multiple-administration trials. The single-administration trial was carried out in comparison with amphotericin B (AmB) at intravenous doses of 1 mg/kg. Plasma samples were drawn at intervals from 15 min to 96 h after injection. The elimination half-lives were 22.15 and 18.15 h, and the area under the curve to infinity (AUC0–∞) values were 35.52 and 10.33 µg·h·ml–1, respectively, for SPK-843 and AmB. Both drugs showed an extensive tissue distribution, with higher uptake by the kidneys, followed by the liver, spleen and lungs for SPK-843, and higher uptake by the spleen, followed by the lungs, liver and kidneys for AmB. The multiple-administration trial (1.25 mg/kg/day for 7 days) led to sustained serum and tissue concentrations. On the seventh day, the rats were bled at intervals from 5 min to 96 h after dosing. The serum elimination half-life and AUC0–∞ values were roughly twice those of the single-dose study (41.4 h and 72.1 µg·h·ml–1, respectively). Also, the half-lifes and AUCs from 0 to ∞ of tissues were greater than those in the single-dose trial.

The pharmacokinetics and tissue distribution of three preparations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure, were compared in rats after a single 1.25 mg/kg intravenous administration. Blood and tissue samples were obtained at 0.25-96 h after injection. The serum pharmacokinetics of the three dosage forms of the antibiotic, A (5% glucose solution), B (10% lipid emulsion at pH 5.3) and C (10% lipid emulsion at pH 7.5), did not show large differences, the half-lives being 22.2, 26.5 and 23.2 h and the AUC(0-infinity) 35.5, 40 and 44.8 microg.h.ml(-1) for preparations A, B and C, respectively. The tissue uptake of the two lipid-based preparations, particularly the spleen uptake, was greater than that of the glucose preparation, suggesting an active role of the lipid vehicle in tissue distribution.

The effects induced by oral administration of 0, 5 and 20 mg of meparticin kg(-1)of body weight for 28 days (group 1, 2 and 3, respectively) upon prostatic estrogen, androgen, alpha(1)- and beta-adrenergic receptor concentrations and on estradiol and testosterone serum levels in adult male rats were studied. The effects produced by mepartricin treatments on the weight and dimension of the gland were investigated. Both mepartricin dosages induced significant decreases (P< 0.05) of the absolute and relative weights and of the dimensions of the prostate. A significant dose-dependent decrease (P< 0.05) in estradiol serum levels was observed in treated rats, whereas no significant modifications were found in testosterone serum levels. As far as prostatic steroid receptor concentrations were concerned, a significant (P< 0.05) decrease in estrogen receptor number was observed in both treated groups, whilst a significant increase (P< 0.05) of androgen receptor concentrations was recorded only in rats treated with 20 mg mepartricin kg(-1). Conversely, a dose-dependent up-regulation of both prostatic alpha(1)- and beta-AR was found. Data obtained suggest that the prostatic alpha(1)-AR expression may be strongly influenced by estrogen deprivation (mepartricin treatment), therefore the combination of estrogen suppression (mepartricin) and adrenergic suppression (alpha(1)-AR blockers) may be suggested as a possible pharmacotherapeutic strategy for the treatment of benign prostatic hyperplasia.

Pharmacokinetics of a new semisynthetic polyene antibiotic (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide) in the form of its diaspartate salt (code SPA-S-753) was studied in rats and mice following intravenous injection and in rats following oral administration at different dose levels. In rats the urinary and biliary recovery after intravenous administration was also determined. Rats and mice received a single intravenous injection of 1.25 and 2.5 mg/kg of SPA-S-753 (about 1–2 mg/kg of free base) or 1 mg/kg of amphotericin B as reference drug. Blood samples were obtained at 5 min to 96 h after injection. The half-lives at the elimination phase in serum were 21.3, 26.5, 10.8 h in rats and 11.7, 13.7, 19.8 h in mice, respectively, for 1.25 and 2.5 mg/kg of SPA-S-753 and 1 mg/kg of amphotericin B. The values of AUC0–∞ for SPA-S-753 were about 5 times higher in rats and twice higher in mice than those for amphotericin B. Rats received also a single oral dose of 200 or 500 mg/kg of SPA-S-753. Serum samples were obtained at 0.5–96 h after dosing. The compound is poorly absorbed by the oral route. The mean cumulative urinary recovery of SPA-S-753 at 48 h after intravenous injection of 1.25 mg/kg in rats accounts only for 0.5% of the dose, while the cumulative recovery from the bile at 10 h after 2.5 mg/kg i.v. administration in rats accounts for 5.5% of the dose.

Use of bisphosphonate in the preparation of pharmaceutical forms intended for intramuscular use. the use of pharmaceutical substances from the class of bisphosphonates in the preparation of pharmaceutical forms to be administered intramuscularly, in the treatment of diseases of the skeletal system is described. Bisphosphonates to be used include, among others, alendronic acid, clodronic acid, etidronic acid, medronico acid, pamidronic acid and its salts, acceptable from a pharmacological and pharmaceutically. Dosage forms in question are particularly characterized by the presence of benzyl alcohol.

The racemates and several enantiomers of 2-phenoxypropionic acids, bearing alkyl, acetyl, benzyl, benzoyl, phenyl, difluorophenyl, Cl, NO2 groups on the aromatic moiety, were investigated as potential analgesic-antiinflammatory drugs. The enantiomers, whose absolute configuration has been previously determined by us, were prepared by chiral resolution of the diastereoisomeric salts of the racemates with cynchonidine. The enantiomeric excess was determined by chiral chromatography. The chiroptical properties of the dextroisomers were investigated by CD. The pharmacological properties of the racemates and the enantiomers were monitored by analgesic-antiinflammatory activity tests as well as by gastrotolerability and acute toxicity tests. Some compounds were shown to be superior to ASA and ketoprofen because they have higher or similar analgesic properties, with less gastroulcerogenetic activity. Furthermore low acute toxicity was found for the compounds with high values of ED50. Correlations between the configuration of the enantiomers and their activity are not evident. For the most active compounds, the activity of one of the enantiomers is superior to that of the racemates. This is particularly true for (S)-3, (R)-15 and (S)-18.

A series of partricin A amides were synthesized using the active ester method by reaction with several amines on the carboxy group and then with some acids on the mycosamine group of partricin A. Most of the derivatives are more potent antifungals than the known reference standards, including amphotericin B, and a few are also less toxic and less hemolytic. Amides substituted with basic groups may give hydrosoluble salts, useful for injectable formulations, and two derivatives were selected for further development, namely, partricin A 2-dimethylaminoethyl amide (10, SPA-S-710) and N-dimethylaminoacetyl-partricin A 2-dimethylaminoethyl amide (22, SPA-S-752).

The presynaptic actions of GABA and (±)baclofen on the stratum radiatum in the CA1 region of guinea-pig hippocampal slices were investigated using a modified grease-gap recording technique. D.c. potential shifts were recorded in response to varying concentrations of GABA and (±)baclofen. In Ca2+-free media containing tetrodotoxin, bath applications of GABA (2.5 μM to 20mM) produced depolarizations which were concentration-dependent. Maximum depolarization was attained with 10 mM GABA. Superfusion of (±)baclofen (0.125–500 μM) produced a concentration-dependent hyperpolarization which peaked at a concentration of 250μM. The GABA-induced depolarization but not the (±)baclofen-induced hyperpolarization was depressed by the GABAA antagonists bicuculline and picrotoxinin. The (±)baclofen-induced hyperpolarization but not the GABA-induced depolarization was suppressed by CGP 35 348, a GABAB antagonist. In the presence of bicuculline, GABA (0.5–5.0 mM) occasionally caused a hyperpolarization which could be blocked by CGP 35 348. These results indicate that the primary presynaptic action of GABA on the d.c. potential in the CA1 region of the hippocampus is to produce a GABAA receptor-mediated depolarization, while (±)baclofen induces a GABAB receptor-mediated hyperpolarization.The grease-gap d.c. potential recording technique, described in this paper, is expected to be useful in examining changes in the membrane potentials of presynaptic terminals.

The attractive feature of Service Oriented Architecture (SOA) is that pieces of software conceived and developed by independent organizations can be dynamically composed to provide richer functionality. The same reasons that enable flexible compositions, however, also prevent the application of some traditional testing approaches, making SOA validation challenging and costly. Web services usually expose just an interface, enough to invoke them and develop some general (black-box) tests, but insufficient for a tester to develop an adequate understanding of the integration quality between the application and the independent web services. To address this lack we propose an approach that makes web services more transparent to testers through the addition of an intermediary service that provides coverage information. The approach, named Service Oriented Coverage Testing (SOCT), provides testers with feedback about how much a service is exercised by their tests without revealing the service internals. In SOCT, testing feedback is offered itself as a service, thus preserving SOA founding principles of loose coupling and implementation neutrality. In this paper we motivate and define the SOCT approach, and implement an instance of it. We also perform a study to asses SOCT feasibility and provide a preliminary evaluation of its viability and value.

A case of tumoral calcinosis of the hand is reported. The lesion was localized at the fifth digit of the right hand and caused pain and disability. The clinical, diagnostic and therapeutic problems of this rare soft tissue disease are discussed.