Microporous material from kanemite for drug inclusion and release.

A microporous material obtained from kanemite, a layered polysilicate, was studied in order to investigate its feasibility of including drugs and then releasing them. Diphenydramine hydrochloride was chosen as a model drug. The preparation of the microporous material and its loading with the drug are described. As kanemite is able to intercalate anions between its layers, the intercalation compound of diphenydramine and kanemite was also prepared. Both the drug-loaded microporous material and the intercalation compound were submitted to dissolution tests at pH 7.5. The drug release profiles from these two different materials and from a physical mixture were compared.

How to improve the readability of the patient package leaflet: a survey on the use of colour, print size and layout.

This paper displays the results of the second part of a survey about patient information and the use of the patient package leaflet. The aim of this research is to investigate the consumers' attitude towards written information. As the formal aspects of the written message are very important in communication, we prepared a questionnaire in order to evaluate the attitude of patients towards some typographical modifications. Patients were invited to give indications about which colours could be used in the different paragraphs of the package leaflet and which print size could be easily read. All people interviewed were asked to choose a colour, from six proposed by us, to be used for 'therapeutic indications', 'side effects', 'how to use', 'paediatric use', 'contraindications', 'use in pregnancy' and 'warnings'. Clear suggestions for the choice of colours for therapeutic indications, side effects and contraindications arose from the survey. In the other cases there was no uniformity of answers. All people complained that the print size used in the package leaflet is too small and suggested 10 and 11 points Didot. Finally, from the survey it emerged that people would appreciate a more detailed package leaflet but information should be given in a schematic and concise way.

Intercalation compounds of hydrotalcite-like anionic clays with antiinflammatory agents--I. Intercalation and in vitro release of ibuprofen.

Hydrotalcite-like compounds are layered solids having positively charged layers and interlayer charge-compensating anions. The synthetic Mg0.67Al0.33(OH)2 Cl0.33.0.6H2O, which is biocompatible, has been used to intercalate a model drug, ibuprofen, in order to prepare a modified release formulation. The intercalation compound was prepared via ion-exchange starting from the chloride form of hydrotalcite and its composition, determined both by elemental microanalysis and thermogravimetric analysis, was Mg0.67Al0.33(OH)2IBU0.33.0.47H2O, drug content 50% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.78 nm (interlayer distance of chloride form) to 2.17 nm. The result of dissolution tests at pH 7.5 showed that the in vitro drug release was modified if compared with that obtained with comparative formulations. The mechanism of modified drug release has been interpreted on the basis of the ion exchange process of the ibuprofen anion intercalated in the lamellar host and phosphates contained in the intestinal fluid buffer.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. XI. Synthesis and biological activity of several naphtho- and quinolino-1,4-thiazine and -1,4-thiazepine derivatives containing the imidazole ring.

Several derivatives of naphthol[1,2-b]imidazo[1',2'-d]-1,4-thiazine and -1,4-thiazepine and imidazo[1',2'-4,5]-1,4-thiazino[3,2-c]quinoline and -1,4-thiazepino[3,2-c] quinoline have been synthesized. These compounds and other imidazo[2,1-d][1,5]benzothiazepine derivatives, previously synthesized, have been tested for their possible pharmacological activities. One of these substances displayed inhibitory activity on CNS, others showed an appreciable antiinflammatory effect. None of the naphtho and quinolino derivatives showed affinity for the benzodiazepine receptor.

Synthesis and antimicrobial activity of some new derivatives of 6,12-dihydroindolo[2,1-b]quinazolin-6,12-dione.

Some derivatives of tryptantrine were prepared in order either to increase solubility and to study structure-activity relationship. All synthesized compounds were tested for antimicrobial activity.

Synthesis and SAR study of imidazo[2,1-b]benzothiazole acids and some related compounds with anti-inflammatory and analgesic activities.

Some (un)substituted imidazo[2,1-b]benzothiazole carboxylic or acetic acids and some related compounds, i.e. imidazo[2,1-b]naphthol[2,1-d]thiazole, 4H-imidazo[2,1-c][1,4]benzothiazine, 4,5-dihydroimidazo[2,1-d][1,5]benzothiazepine carboxylic and acetic acids were synthesized and tested in vivo in order to study the structure-activity relationships (SAR) of their antiinflammatory and analgesic activities. Pharmacological assays confirmed the interest of this class of compounds as potential antiinflammatory and analgesic drugs with low side effects.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. X--Synthesis and inhibition of benzodiazepine receptor binding of new 1,4-thiazine and 1,5-thiazepine polycondensed heterocycles with steroidal structure.

Some naphtho[1,2,-b]-s-triazolo[4,3-d]-1,4-thiazine and 1,5-thiazepine and s-triazolo[4', 3'-4,5]-1,4-thiazino[3,2-c]quinoline derivatives have been synthesized and tested for their ability to displace [3H]RO 15-1788 binding from bovine brain membranes. Several compounds showed moderate binding affinity for the benzodiazepine receptor.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VIII-Synthesis and inhibition of benzodiazepine receptor binding of some derivatives of triazino[3,4-c]-1,4-benzothiazine and triazino[3,4-d]-1,5-benzothiazepine, two new heterocyclic ring systems.

Several series of triazino[3,4-c]-1,4-benzothiazines and triazino[3,4-d]-1,5-benzothiazepines were synthesized. Tentative syntheses performed to obtain 5H-as-triazino[3,4-c]-1,4-benzothiazin-1,2-diones and 5,6-dihydro-as-triazino[3,4-d]-1,5-benzothiazepin-1,2-diones gave rise to s-triazolo derivatives. Only in one case was the reaction successful, affording the 3,5-dihydro-as-triazino[3,4-c]-1,4-benzothiazin-1,2-dione 9a. All the final compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VI. Synthesis and preliminary pharmacological evaluation of 1-alkylaminomethyl-4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepines.

A series of new 1-alkylaminomethyl derivatives of 4,5-dihydro-s- triazolo[3,4-d]-1,5-benzothiazepines has been prepared using chloromethyltriazolobenzothiazepines 4a-g as key intermediates. The 1-alkylaminomethyl derivatives were tested for CNS activity on mice and some of them caused remarkable decrease of spontaneous motor activity.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. VII. Synthesis and inhibition of benzodiazepine receptor binding of some 4,5-dihydro-tetrazolo[5,1-d]-1,5-benzothiazepines and 5-phenyl-s-triazolo[3,4-d]-1,5-benzothiazepines.

The 4,5-dihydro-tetrazolo[5,1-d]-1,5-benzothiazepines 3a-k and the 5-phenyl-s-triazolo[3,4-d]-1,5-benzothiazepines 6a-f and 11a-c have been prepared and tested for their ability to displace [3H] flunitrazepam binding from bovine brain membranes. Some of the triazoloderivatives showed moderate binding affinity for the benzodiazepine receptor.

Synthesis and antimicrobial activity of some new indolo[2,1-b]quinazolin-6(12H)ones.

A series of indolo[2,1-b]quinazolin-6(12H)ones 4a-i was prepared and tested for the antimicrobial activity. The synthesis of the new compounds and the results of the antimicrobial screening are reported.

Synthesis and pharmacological activity of imidazo[2,1-b]benzothiazole acids.

We have prepared twelve imidazo[2,1-b]benzothiazole carboxylic and acetic acids by reaction of substituted 2-aminobenzothiazoles with ethyl bromopyruvate and 4-chloroacetoacetate, respectively. The acids, obtained from esters by hydrolysis, were tested for their antiinflammatory, analgesic and ulcerogenic activities.

Studies on annelated [1,4]benzothiazines and [1,5]benzothiazepines, V. Synthesis and biological activity of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine.

The synthesis of a new series of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine has been accomplished starting from 2,3-dihydro-1,5-benzothiazepin-4(5H)ones and their 2-methyl and 2-aryl derivatives. All the compounds were tested in vitro for their antimicrobial activity, but none of them showed remarkable activity. The tricyclic compounds 7a-j, 8a-j, 9a-j, 10a-j, and 11a-j were also screened for their CNS activity in mice and several of them showed interesting activity.

New Canthin-6-one Alkaloids from Quassia amara.

From the wood of QUASSIA AMARA L. (Simarubaceae) two new canthin-6-one alkaloids have been isolated and their structures determined as 3-methyl-4-methoxy-5-hydroxycanthin-2,6-dione ( 1) and 4-methoxy-5-hydroxycanthin-6-one 3-, N-oxide ( 2) by spectroscopic and chemical methods. 3-Methylcanthin-5,6-dione ( 3) has been also isolated and identified for the first time from this source.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. III--Synthesis and CNS activity of some 1-substituted derivatives of the novel heterocyclic system 4,5-dihydro-s-triazolo [3,4-d]-1,5-benzothiazepine.

A series of new 4,5-dihydro-s-triazolo [3,4-d]-1,5-benzothiazepines has been prepared. All the described compounds are representative of a novel ring system. Some of these compounds were tested for their CNS activity and effects comparable with the ones of diazepam were observed.

Indole Alkaloids from Quassia amara.

Three beta-carboline alkaloids have been isolated for the first time from the wood of QUASSIA AMARA L. (Simarubaceae) and their structures were determined to be 1-vinyl-4,8-dimethoxy-beta-carboline ( 1), 1-methoxycarbonyl-beta-carboline ( 2), and 3-methylcantin-2,6-dione ( 3) by spectral and chemical means.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. II. Synthesis of new series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines and related compounds with potential CNS activity.

New series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines have been prepared. The 1-substituted products were obtained starting from 3-hydrazino-2H-1,4-benzothiazine derivatives (III) by treatment with chloroacethyl chloride followed by cyclization of the resulting chloroacethylderivatives into the chloromethyltriazolobenzothiazines (IV a-e), which were then reacted with the appropriate amines to give the desired compounds (V a-n). Other 1-substituted compounds were prepared by ring closure of (III) with cyanogen bromide, affording 1-amino-4H-s-triazolo [3,4-c]-1,4-benzothiazines (XI a-e). The 2-substituted compounds (VIII) were prepared from 2,4-dihydro-1H-s-triazolo [3,4-c]-1,4-benzothiazin-1-ones (VII), synthesized from (I) by reaction with ethyl carbazate. The aminoalkyl side chain was introduced into (VII) in two steps: first by treatment with 1-bromo-3-chloropropane, then by refluxing the resulting product with the appropriate amine. Some 4H-tetrazolo[5,1-c]-1,4-benzothiazines (XII) were also synthesized from (III). Preliminary pharmacological data on the CNS activity of the synthesized tricyclic compounds are reported.

Synthesis and in vitro cytotoxic activity of semisynthetic derivatives in the santonin series.

The synthesis of two new santonin derivatives namely 3-oxo-6 beta-H-11 beta-phenylselenoeudesm-1,4-dien-6,13-olide and 3-oxo-6 beta H-eudesm-1,4,11-trien-6,13-olide is reported along with the results of a series of santonins tested for activity against the growth of KB cells in vitro, a human epidermoid nasopharynx carcinoma. Select compounds were found to be active at concentrations lower than 5 X 10(-5) M. In particular, the compound 2 alpha-bromo-3 beta-hydroxy-6 beta H-eudesm-11-en-6,13-olide exhibits an extremely low ID50 value at 0.33 X 10(-6) M. Some relationships between chemical structure and cytotoxic activity are suggested, i.e. the alpha-methylene-gamma-lactone moiety appears to be necessary for cytotoxic activity toward KB cells growth in vitro by santonin derivatives.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. I. Synthesis of 4H-s-triazolo[3,4-c]-1,4-benzothiazine and derivatives with potential CNS activity.

As a part of a program toward the synthesis and the pharmacological studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines, a number of 4H-s-triazolo[3,4-c]-1,4-benzothiazine derivatives were prepared and tested for their CNS activity. The syntheses of the new tricyclic compounds (VII) were performed via the 2H-1,4-benzothiazine-3(4H)-thiones (II) which were obtained by Lawesson's thiation of lactams (I). Compounds (II) and their S-methyl-thioethers (III), quantitatively obtained by PTC method, were reacted with acylhydrazines to give the title compounds. Some triazolobenzothiazines (VII) were also prepared from 3-hydrazinoderivatives (IV) by cyclization with either an aliphatic acid or the corresponding orthoesther.