AimsThe aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (M MX®) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability. MethodsTwo phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of 153 Sm-labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco-scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls. Results153 Sm-labelled tablets reached the ascending colon after a mean ± SD 9.8 ± 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety-six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased C max values from 1429 ± 1014 to 1040 ± 601 pg mL − 1 ( P = 0.028) and AUC values from 14 814 ± 11 254 to 13 486 ± 9369 pg h − 1 mL − 1 ( P = 0.008). Mean residence time and t max increased by 12-29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide. ConclusionsMMX®-budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.

The aim of this study was to investigate the antiandrogenic activity of a new monoester of cortexolone, cortexolone 17alpha-propionate (CAS 19608-29-8, CB-03-01). Although the compound displayed a strong local antiandrogenic activity in hamster's flank organ test, it did not exhibit antiandrogenic activity in rats after subcutaneous injection, nor did it affect gonadotropins hypersecretion when injected to parabiotic rats. As topical antiandrogen, the steroid resulted about 4 times more active than progesterone (CAS 57-83-0) and, when compared to known antiandrogen standards, it was about 3 times more potent than flutamide (CAS 13311-84-7), about 2 times more effective than finasteride (CAS 98319-26-7) and approximately as active as cyproterone acetate (CAS 427-51-0). Its pharmacological activity seemed to be primarily related to its ability to antagonistically compete at androgen receptor level; nevertheless its primary pharmacological target needs to be further investigated. Its topical activity, along with the apparent absence of systemic effects, anticipates this compound to have the potential of representing a novel and safe therapeutic approach for androgen-dependent skin disorders.

SUMMARY BackgroundThe administration of parnaparin sodium as oral colon-release tablets (CB-01-05 MMX Ò ) has been proposed as a novel approach for the treat-

No abstract

Purpose Parenteral administration of lowmolecular-weight heparins (LMWHs) and unfractionated heparin (UFH) resulted effective in improving the symptoms of experimental colitis in rat. Today, there is little information about their activity by intracolonic instillation. The scope of this study was to evaluate the ability of CB-01-05 (a LMWH with a mean molecular weight of about 5,700), compared to a series of other LMWHs and to UFH, directly instilled into the distal colon of the rat, to ameliorate dinitrobenzene (DNB)-induced experimental colitis. Method Adult male Wistar rats underwent colitis induction by intracolonic instillation of DNB. Starting 24 h after colitis induction, CB-01-05 (0.005-0.9 mg), other LMWHs (0.3-0.6 mg), and UFH (0.6 mg) were instilled, by rectal route, into the distal colon once a day for three consecutive days. On the day following the last administration, the animals were sacrificed and the distal colon was isolated, weighed, macroscopically examined, and processed for histology. Additional experiments in rat splenocytes, performed in order to elucidate the anti-inflammatory mechanisms of CB-01-05, were performed. Results Among the tested items, only CB-01-05 at doses ranging from 0.2 to 0.9 mg was significantly effective in reducing colon weight increase and in improving both the mucosal damaged area and the histological score. The other LMWHs resulted far less effective, showing decreasing activity closely related with the decrease of their molecular weight, thus demonstrating their biological nonequivalence. CB-01-05 resulted also more active than UFH. CB-01-05 was shown to interfere with cytokines production by rat splenocytes, mainly inhibiting interferon (IFN)-c expression. Conclusions CB-01-05 instilled into the colon is well tolerated, has strong anti-inflammatory effect on DNBinduced colitis in rat, and is the most effective agent among other LMWHs and UFH. These results suggest that the anti-inflammatory activity of CB-01-05, together with its topical administration, could represent a new approach in the management of ulcerative colitis.

The following error was published in Table 2 of this article. LMWH-A, LMWH-C, and UFH are not properly aligned. This makes it impossible to link the drugs to the correct doses and to the effects, and so the information is greatly misleading. The correct Table 2 appears below.

Rifamycin SV is a broad-spectrum, poorly absorbed antimicrobial agent that, when coupled with MMX technology, is being targeted for the oral treatment of traveler's diarrhea (TD) and Clostridium difficileassociated disease (CDAD). Rifamycin SV was tested for activity against 911 TD-associated enteropathogens and 30 C. difficile isolates collected from several global surveillance studies. Rifamycin SV demonstrated similar antimicrobial activity levels against the Enterobacteriaceae, with MIC 50 values ranging from 32 to 128 g/ml for all but one strain (an enterotoxigenic Escherichia coli at >512 g/ml). For non-Enterobacteriaceae strains, MIC 50 values ranged from 2 to 8 g/ml, with the exception of Campylobacter spp., for which all strains had MIC values of >512 g/ml. Rifamycin SV also demonstrated excellent activity (MIC 50 of <0.03 g/ml) against most C. difficile strains (including one hypervirulent NAP1 strain), and this activity was even superior to the potency observed for vancomycin, metronidazole, and rifaximin. In mutational passaging studies, rifamycin SV induced stable resistance and showed a mutation frequency in E. coli similar to that of rifampin. This study presents the potency of rifamycin SV for enteropathogens commonly recovered from patients with TD and CDAD. Additional in vitro and in vivo studies appear necessary to determine the utility of rifamycin SV as an oral agent for the prevention and treatment of TD and CDAD.Rifamycin SV is a broad-spectrum semisynthetic antimicrobial agent of the rifamycin group with limited oral absorption that is active against Gram-positive bacteria and moderately active against . Coupled with the proprietary drug delivery system MMX (Cosmo Technologies Ltd., Dublin, Ireland), designed to release the antibiotic in the colonic lumen, rifamycin SV has been formulated as a tablet for treatment of colonic bacterial infections, including traveler's diarrhea (TD) and Clostridium difficile-associated disease (CDAD). As with all members of the rifamycin group, rifamycin SV inhibits DNA transcription by interfering with bacterial RNA polymerases (2,22).TD is the most common gastrointestinal (GI) illness contracted by persons from developed countries when they visit resource-poor countries; annually, it is estimated that 100 million persons travel internationally, with an estimated 30 to 40% of them developing TD and approximately 3% progressing to postinfectious irritable bowel syndrome (15,19). The most common bacterial etiologies of TD, accounting for nearly 60 to 80% of the cases, are pathogenic Escherichia coli, Salmonella spp., Shigella spp., and Campylobacter spp. although pathogenspecific prevalence rates do vary by geographic region (19).Current travel medicine treatment guidelines recommend the use of antimicrobials for TD, in addition to fluid replacement and antimotility drugs, especially for severe disease (10). These guidelines recommend the use of a fluoroquinolone (FQ) or azithromycin for most travelers worldwide although regional pockets have significant lev...

A series of new cortexolone-related derivatives has been synthesized and investigated for potential anti-androgenic activity. Among the steroids evaluated, 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04) was the most promising one. The compound displayed a strong local antiandrogenic activity in hamster's flank organ test, and it was also found to be effective in the rat after subcutaneous injection. When compared to other well known androgen antagonists, the rank order of topical anti-androgenic activity in that test was: cyproterone acetate (CAS 427-51-0) > or = CB-03-04 > finasteride (CAS 98319-26-7) > flutamide (CAS 13311-84-7). In addition, the steroid had selective antigonadotropic activity, when injected into parabiotic rats, and was about as active as progesterone. The activity of CB-03-04 was ascribed mainly to its ability to compete with the stimulating effects of testosterone and dihydrotestosterone and, concurrently, to inhibit the gonadotropins hypersecretion. This bimodal mechanism of action could be predictive for the clinical usefulness of the steroid in the treatment of prostate cancer and benign prostate hypertrophy.