Abamectin.

Monograph number: Title: Abamectin. CAS Registry number: [71751-41- CAS name(s): Avermectin B 1 Additional name(s): 5- O- demethylavermectin A 1a and 5- O- demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)avermectin A 1a (4:1); avermectin B 1a/b Drug code(s): MK-936 Trade name(s): Agri-Mek (Novartis) ; Avid (Novartis) ; Zephyr (Novartis) Literature references: Mixture of avermectins, q.v., containing at least 80% of avermectin B 1a ( C 48 H 72 O 14 ) and not more than 20% of avermectin B 1b ( C 47 H 70 O 14 ). Isoln from Streptomyces avermitilis: G. Albers-Schoumlnberg et al., Ger. pat. 2,717,040; eidem, U.S. pat. 4,310,519 (1977, 1982 both to Merck and Co.). Separation of components: T. W. Miller et al., Antimicrob. Ag. Chemother. 15, 368 (1979); by semi-preparative HPLC: C. C. Ku et al., J. Liq. Chromatog. 7, 2905 (1984). Structure determn: G. Albers-Schoumlnberg et al., J. Am. Chem. Soc. 103, 4216 (1981). Absolute configu ration: J. P. Springer et al., ibid. 4221. Partial synthesis of B 1a : K. C. Nicolaou et al., ibid. 106, 4189 (1984). Total synthesis: S. Hanessian et al., ibid. 108, 2776 (1986). Ant helmintic activity: L. S. Blair, W. C. Campbell, J. Parasitol. 64, 1032 (1978); J. R. Egerton et al., Antimicrob. Ag. Chemother. 15, 372 (1979); K. S. Todd et al., Am. J. Vet. Res. 45, 976 (1984). Pesticidal activity: I. Putter et al., Experientia 37, 963 (1981); R. A. Dybas, A. St. J. Green, Brit. Crop. Prot. Conf. - Pests Dis. 1984, 947. Control of red imported fire ants: J. A. Greenblatt et al., J. Agr. Entomol. 3, 233 (1986). Interaction with GABA receptors: S. S. Pong et al., J. Neurochem. 34, 351 (1980); T. N. Mellin et al., Neuropharmacol. 22, 89 (1983) . Receptor binding studies: S. S. Pong, C. C. Wang, ibid. 19, 311 (1980); G. Drexler, W. Sieghart, Eur. J. Pharmacol. 99, 269 (1984). Fate in soil and plants: D. L. Bull et al., J. Agr. Food Chem. 32, 94 (1984); H. A. Moye et al., ibid. 35, 859 (1987); M. S. Maynard et al., ibid. 37, 178, 184 (1989). Review: J. R. Babu, ACS Symposium Series 380, 91-108 (1988). Reviews of modes of action: C. C. Wang, S. S. Pong, Prog. Clin. Biol. Res. 97, 373-395 (1982); D. J. Wright, Biochem. Soc. Trans. 15, 65-67 (1987); of insecticidal activities and use: L. Strong, T. A. Brown, Bull. Ent. Res. 77, 357-389 (1987). Book: Ivermectin and Abamectin, W. C. Camp bell, Ed. (Springer-Verlag, New York, 1989) 363 pp. Properties: Odorless, off-white to yellow crystals from methanol, mp 150-155degrees (dec) . [alpha] D +55.7degrees plus or minus2degrees (c = 0.87 in CHCl 3 ) . uv max (methanol): 237 , 245 , 253 nm (log epsi 4.48, 4.53, 4.34) . Vapor pressure: 1.5 times 10 minus9 torr. Soly at 21degrees (mug/l): water 10; (mg/ml): acetone 100; n- butanol 10; chloroform 25; cyclohexane 6; ethanol 20; isopropanol 70; kerosene 0.5; methanol 19.5; toluene 350. Hydrolysis does not occur in aq soln at pH 3, 5, 7. LD 50 (technical grade) orally in sesame oil in mouse, rat: 13.5 , 10.0 mg/kg ; dermally in rabbit: >2000 mg/kg . LD 50 in mallard duck, bobwhite quail: 84.6 , >2000 mg/kg . LC 50 (96 hr) in rainbow trout, bluegill: 3.6 , 9.6 mug/l ; LC 50 (48 hr) in Daphnia magna: 0.34 mug/l (Merck Technical Data Sheet) . Melting Point: 150-155degrees UV Maxima: 237; 245; Rotation: +55.7degrees plus or minus2 USE: Acaricide; insecticide. THERAP CAT (VET): Anthelmintic.

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monograph of ephedrine

(Ph Eur monograph 0489)




C10H15NO,½H2O 174.2 50906-05-3
Action and use
Beta-adrenoceptor agonist.
Ph Eur
DEFINITION
Ephedrine hemihydrate contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol, calculated with reference to the anhydrous substance.
CHARACTERS
A white, crystalline powder or colourless crystals, soluble in water, very soluble in alcohol, freely soluble in ether.
It melts at about 42°C, determined without previous drying.
IDENTIFICATION
First identification B, D.
Second identification A, C, D, E.
A. It complies with the test for specific optical rotation (see Tests).
B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with the base isolated from ephedrine hydrochloride CRS. Examine the substances in discs prepared as follows: dissolve 40 mg of the substance to be examined in 1 ml of water R, add 1 ml of dilute sodium hydroxide solution R and 4 ml of chloroform R and shake; dry the organic layer over 0.2 g of anhydrous sodium sulphate R; prepare a blank disc using about 0.3 g of potassium bromide R; apply dropwise to the disc 0.1 ml of the organic layer, allowing the solvent to evaporate between applications; dry the disc at 50°C for 2 min. Repeat the operations using 50 mg of ephedrine hydrochloride CRS.
C. Examine the chromatograms obtained in the test for related substances. The principal spot in the chromatogram obtained with test solution (b) is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a).
D. Dissolve about 10 mg in 1 ml of water R. Add 0.2 ml of strong sodium hydroxide solution R and 0.2 ml of copper sulphate solution R. A violet colour is produced. Add 2 ml of ether R and shake. The ether layer is purple and the aqueous layer blue.
E. It complies with the test for water (see Tests).
TESTS
Appearance of solution
Dissolve 0.25 g in water R and dilute to 10 ml with the same solvent. The solution is clear (2.2.1) and colourless (2.2.2, Method II).
Specific optical rotation (2.2.7)
Dissolve 2.25 g in 15 ml of dilute hydrochloric acid R and dilute to 50.0 ml with water R. The specific optical rotation is -41 to -43, calculated with reference to the anhydrous substance.
Related substances
Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.
Test solution (a) Dissolve 0.2 g of the substance to be examined in methanol R and dilute to 10 ml with the same solvent.
Test solution (b) Dilute 1 ml of test solution (a) to 10 ml with methanol R.
Reference solution (a) Dissolve 25 mg of ephedrine hydrochloride CRS in methanol R and dilute to 10 ml with the same solvent.
Reference solution (b) Dilute 1.0 ml of test solution (a) to 200 ml with methanol R.
Apply separately to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 5 volumes of chloroform R, 15 volumes of concentrated ammonia R and 80 volumes of 2-propanol R. Allow the plate to dry in air and spray with ninhydrin solution R. Heat at 110°C for 5 min. Any spot in the chromatogram obtained with test solution (a), apart from the principal spot, is not more intense than the spot in the chromatogram obtained with reference solution (b) (0.5 per cent). Disregard any spot of lighter colour than the background.
Chlorides
Dissolve 0.18 g in 10 ml of water R. Add 5 ml of dilute nitric acid R and 0.5 ml of silver nitrate solution R1 . Allow to stand for 2 min, protected from bright light. Any opalescence in the solution is not more intense than that in a standard prepared at the same time and in the same manner using 10 ml of chloride standard solution (5 ppm Cl) R, 5 ml of dilute nitric acid R and 0.5 ml of silver nitrate solution R1 (280 ppm).
Water (2.5.12)
4.5 per cent to 5.5 per cent, determined on 0.300 g by the semi-micro determination of water.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.200 g in 5 ml of alcohol R and add 20.0 ml of 0.1 M hydrochloric acid . Using 0.05 ml of methyl red solution R as indicator, titrate with 0.1 M sodium hydroxide until a yellow colour is obtained.
1 ml of 0.1 M hydrochloric acid is equivalent to 16.52 mg of C10H15NO.
STORAGE
Store protected from light.
Ph Eur

monograph of chormephinecol

(Ph Eur monograph 0071)





C11H12Cl2N2O5 323.1 56-75-7
Action and use
Antibacterial.
Preparations
Chloramphenicol Capsules
Chloramphenicol Ear Drops
Chloramphenicol Eye Drops
Chloramphenicol Eye Ointment
Ph Eur
DEFINITION
Chloramphenicol is 2,2-dichloro-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]acetamide, produced by the growth of certain strains of Streptomyces venezuelae in a suitable medium. It is normally prepared by synthesis. It contains not less than 98.0 per cent and not more than the equivalent of 102.0 per cent of C11H12Cl2N2O5, calculated with reference to the dried substance.
CHARACTERS
A white, greyish-white or yellowish-white, fine, crystalline powder or fine crystals, needles or elongated plates, slightly soluble in water, freely soluble in alcohol and in propylene glycol, slightly soluble in ether.
A solution in ethanol is dextrorotatory and a solution in ethyl acetate is laevorotatory.
IDENTIFICATION
First identification A, B.
Second identification A, C, D, E.
A. Melting point (2.2.14): 149°C to 153°C.
B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with chloramphenicol CRS.
C. Examine the chromatograms obtained in the test for related substances. The principal spot in the chromatogram obtained with 1 ml of the test solution is similar in position and size to the principal spot in the chromatogram obtained with reference solution (a).
D. Dissolve about 10 mg in 1 ml of alcohol (50 per cent V/V) R, add 3 ml of a 10 g/l solution of calcium chloride R and 50 mg of zinc powder R and heat on a water-bath for 10 min. Filter the hot solution and allow to cool. Add 0.1 ml of benzoyl chloride R and shake for 1 min. Add 0.5 ml of ferric chloride solution R1 and 2 ml of chloroform R and shake. The aqueous layer is coloured light violet-red to purple.
E. To 50 mg in a porcelain crucible add 0.5 g of anhydrous sodium carbonate R. Heat over an open flame for 10 min. Allow to cool. Take up the residue with 5 ml of dilute nitric acid R and filter. To 1 ml of the filtrate add 1 ml of water R. The solution gives reaction (a) of chlorides (2.3.1).
TESTS
Acidity or alkalinity
To 0.1 g add 20 ml of carbon dioxide-free water R, shake and add 0.1 ml of bromothymol blue solution R1 . Not more than 0.1 ml of 0.02 M hydrochloric acid or 0.02 M sodium hydroxide is required to change the colour of the indicator.
Specific optical rotation (2.2.7)
Dissolve 1.50 g in ethanol R and dilute to 25.0 ml with the same solvent. The specific optical rotation is +18.5° to +20.5°.
Related substances
Examine by thin-layer chromatography (2.2.27), using silica gel GF 254 R as the coating substance.
Test solution Dissolve 0.10 g of the substance to be examined in acetone R and dilute to 10 ml with the same solvent.
Reference solution (a) Dissolve 0.10 g of chloramphenicol CRS in acetone R and dilute to 10 ml with the same solvent.
Reference solution (b) Dilute 0.5 ml of reference solution (a) to 100 ml with acetone R.
Apply separately to the plate 1 ml and 20 ml of the test solution, 1 ml of reference solution (a) and 20 ml of reference solution (b). Develop over a path of 15 cm using a mixture of 1 volume of water R, 10 volumes of methanol R and 90 volumes of chloroform R. Allow the plate to dry in air and examine in ultraviolet light at 254 nm. Any spot in the chromatogram obtained with 20 ml of the test solution, apart from the principal spot, is not more intense than the spot in the chromatogram obtained with reference solution (b) (0.5 per cent).
Chlorides (2.4.4)
To 1.00 g add 20 ml of water R and 10 ml of nitric acid R and shake for 5 min. Filter through a filter paper previously washed by filtering 5 ml portions of water R until 5 ml of filtrate no longer becomes opalescent on addition of 0.1 ml of nitric acid R and 0.1 ml of silver nitrate solution R1 . 15 ml of the filtrate complies with the limit test for chlorides (100 ppm).
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on 1.000 g by drying in an oven at 100°C to 105°C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 2.0 g.
Sterility (2.6.1)
If intended for use in the manufacture of a parenteral or ophthalmic dosage form without a further appropriate sterilisation procedure, it complies with the test for sterility.
Pyrogens (2.6.8)
If intended for use in the manufacture of a parenteral dosage form without a further appropriate procedure for the removal of pyrogens, it complies with the test for pyrogens. Inject per kilogram of the rabbit's mass 2.5 ml of a solution containing per millilitre 2 mg of the substance to be examined.
ASSAY
Dissolve 0.100 g in water R and dilute to 500.0 ml with the same solvent. Dilute 10.0 ml of this solution to 100.0 ml with water R. Measure the absorbance (2.2.25) at the maximum at 278 nm.
Calculate the content of C11H12Cl2N2O5 taking the specific absorbance to be 297.
STORAGE
Store protected from light. If the substance is sterile, store in a sterile, airtight, tamper-proof container .
LABELLING
The label states:
—where applicable, that the substance is sterile,
—where applicable, that the substance is apyrogenic.
Ph Eur

monograph of cetrimide

(Ph Eur monograph 0378)




8044-71-1
Action and use
Antiseptic detergent.
Preparations
Cetrimide Cream
Cetrimide Emulsifying Ointment
Ph Eur
DEFINITION
Cetrimide consists of trimethyltetradecylammonium bromide and may contain smaller amounts of dodecyl- and hexadecyl-trimethylammonium bromides.
Content
96.0 per cent to 101.0 per cent of alkyltrimethylammonium bromides, calculated as C17H38BrN (M r 336.4) (dried substance).
CHARACTERS
Appearance
White or almost white, voluminous, free-flowing powder.
Solubility
Freely soluble in water and in alcohol.
IDENTIFICATION
A. Dissolve 0.25 g in alcohol R and dilute to 25.0 ml with the same solvent. At wavelengths from 260 nm to 280 nm, the absorbance ( 2.2.25 ) of the solution has a maximum of 0.05.
B. Dissolve about 5 mg in 5 ml of buffer solution pH 8.0 R. Add about 10 mg of potassium ferricyanide R. A yellow precipitate is formed. Prepare a blank in the same manner but omitting the substance to be examined: a yellow solution is observed but no precipitate is formed.
C. Solution S (see Tests) froths copiously when shaken.
D. Thin-layer chromatography ( 2.2.27 ).
Test solution. Dissolve 0.10 g of the substance to be examined in water R and dilute to 5 ml with the same solvent.
Reference solution. Dissolve 0.10 g of trimethyltetradecylammonium bromide CRS in water R and dilute to 5 ml with the same solvent.
Plate. TLC silica gel F254 silanised plate R.
Mobile phase. Acetone R, 270 g/l solution of sodium acetate R, methanol R (20:35:45 V/V/V).
Application. 1 ml.
Development. Over a path of 12 cm.
Drying. In a current of hot air.
Detection. Allow to cool; expose the plate to iodine vapour and examine in daylight.
Result. The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.
E. It gives reaction (a) of bromides ( 2.3.1 ).
TESTS
Solution S
Dissolve 2.0 g in carbon dioxide-free water R and dilute to 100 ml with the same solvent.
Appearance of solution
Solution S is clear ( 2.2.1 ) and colourless ( 2.2.2 , Method II).
Acidity or alkalinity
To 50 ml of solution S add 0.1 ml of bromocresol purple solution R. Not more than 0.1 ml of 0.1 M hydrochloric acid or 0.1 M sodium hydroxide is required to change the colour of the indicator.
Amines and amine salts.
Dissolve 5.0 g in 30 ml of a mixture of 1 volume of 1 M hydrochloric acid and 99 volumes of methanol R and add 100 ml of 2-propanol R. Pass a stream of nitrogen R slowly through the solution. Gradually add 15.0 ml of 0.1 M tetrabutylammonium hydroxide and record the potentiometric titration curve ( 2.2.20 ). If the curve shows 2 points of inflexion, the volume of titrant added between the 2 points is not greater than 2.0 ml.
Loss on drying ( 2.2.32 )
Maximum 2.0 per cent, determined on 1.000 g by drying in an oven at 100-105 °C for 2 h.
Sulphated ash ( 2.4.14 )
Maximum 0.5 per cent, determined on 1.0 g.
ASSAY
Dissolve 2.000 g in water R and dilute to 100.0 ml with the same solvent. Transfer 25.0 ml of the solution to a separating funnel, add 25 ml of chloroform R, 10 ml of 0.1 M sodium hydroxide and 10.0 ml of a freshly prepared 50 g/l solution of potassium iodide R. Shake, allow to separate and discard the chloroform layer. Shake the aqueous layer with 3 quantities, each of 10 ml, of chloroform R and discard the chloroform layers. Add 40 ml of hydrochloric acid R, allow to cool and titrate with 0.05 M potassium iodate until the deep brown colour is almost discharged. Add 2 ml of chloroform R and continue the titration, shaking vigorously, until the colour of the chloroform layer no longer changes. Carry out a blank titration on a mixture of 10.0 ml of the freshly prepared 50 g/l solution of potassium iodide R, 20 ml of water R and 40 ml of hydrochloric acid R.
1 ml of 0.05 M potassium iodate is equivalent to 33.64 mg of C17H38BrN.
Ph Eur

monograph of aminophylline

(Ph Eur monograph 0300)








C16H24N10O4 420.4 317-34-0
Action and use
Xanthine bronchodilator.
Preparations
Aminophylline Injection
Aminophylline Tablets
Ph Eur
DEFINITION
Theophylline-ethylenediamine contains not less than 84.0 per cent and not more than the equivalent of 87.4 per cent of theophylline (C7H8N4O2; M r 180.2) and not less than 13.5 per cent and not more than the equivalent of 15.0 per cent of ethylenediamine (C2H8N2; M r 60.1), both calculated with reference to the anhydrous substance.
CHARACTERS
A white or slightly yellowish powder, sometimes granular, freely soluble in water (the solution becomes cloudy through absorption of carbon dioxide), practically insoluble in ethanol.
IDENTIFICATION
First identification B, C, E.
Second identification A, C, D, E, F.
Dissolve 1.0 g in 10 ml of water R and add 2 ml of dilute hydrochloric acid R dropwise with shaking. Filter. Use the precipitate for identification tests A, B, D and F and the filtrate for identification test C.
A. The precipitate, washed with water R and dried at 100°C to 105°C, melts (2.2.14) at 270°C to 274°C.
B. Examine the precipitate, washed with water R and dried at 100°C to 105°C, by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with theophylline CRS.
C. To the filtrate add 0.2 ml of benzoyl chloride R, make alkaline with dilute sodium hydroxide solution R and shake vigorously. Filter the precipitate, wash with 10 ml of water R, dissolve in 5 ml of hot alcohol R and add 5 ml of water R. A precipitate is formed, which when washed and dried at 100°C to 105°C, melts (2.2.14) at 248°C to 252°C.
D. Heat about 10 mg of the precipitate with 1.0 ml of a 360 g/l solution of potassium hydroxide R in a water-bath at 90°C for 3 min, then add 1.0 ml of diazotised sulphanilic acid solution R. A red colour slowly develops. Carry out a blank test.
E. It complies with the test for water (see Tests).
F. The precipitate gives the reaction of xanthines (2.3.1).
TESTS
Appearance of solution
Dissolve 0.5 g with gentle warming in 10 ml of carbon dioxide-free water R. The solution is not more opalescent than reference suspension II (2.2.1) and not more intensely coloured than reference solution GY6 (2.2.2, Method II).
Related substances
Examine by thin-layer chromatography (2.2.27), using as the coating substance a suitable silica gel with a fluorescent indicator having an optimal intensity at 254 nm.
Test solution Dissolve 0.2 g of the substance to be examined in 2 ml of water R with heating and dilute to 10 ml with methanol R.
Reference solution Dilute 0.5 ml of the test solution to 100 ml with methanol R.
Apply to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 10 volumes of concentrated ammonia R, 30 volumes of acetone R, 30 volumes of chloroform R and 40 volumes of butanol R. Allow the plate to dry in air and examine in ultraviolet light at 254 nm. Any spot in the chromatogram obtained with the test solution, apart from the principal spot, is not more intense than the spot in the chromatogram obtained with the reference solution (0.5 per cent).
Heavy metals (2.4.8)
1.0 g complies with limit test C for heavy metals (20 ppm). Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.
Water (2.5.12)
Not more than 1.5 per cent, determined on 2.00 g dissolved in 20 ml of anhydrous pyridine R, by the semi-micro determination of water.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
ASSAY
Ethylenediamine
Dissolve 0.250 g in 30 ml of water R. Add 0.1 ml of bromocresol green solution R. Titrate with 0.1 M hydrochloric acid until a green colour is obtained.
1 ml of 0.1 M hydrochloric acid is equivalent to 3.005 mg of C2H8N2.
Theophylline
Heat 0.200 g to constant mass in an oven at 135°C. Dissolve the residue with heating in 100 ml of water R, allow to cool, add 20 ml of 0.1 M silver nitrate and shake. Add 1 ml of bromothymol blue solution R1 . Titrate with 0.1 M sodium hydroxide .
1 ml of 0.1 M sodium hydroxide is equivalent to 18.02 mg of C7H8N4O2.
STORAGE
Store in airtight container , protected from light.
Ph Eur

monograph of strong ammonium solution

General Notices
(Ph Eur monograph 0877)
Preparation
Dilute Ammonia Solution
Ph Eur
DEFINITION
Concentrated ammonia solution contains not less than 25.0 per cent m/m and not more than 30.0 per cent m/m of ammonia (NH3; M r 17.03).
CHARACTERS
A clear , colourless liquid, very caustic, miscible with water and with alcohol.
IDENTIFICATION
A. Relative density (2.2.5): 0.892 to 0.910.
B. It is strongly alkaline (2.2.4) .
C. To 0.5 ml add 5 ml of water R. Bubble air through the solution and lead the gaseous mixture obtained over the surface of a solution containing 1 ml of 0.1 M hydrochloric acid and 0.05 ml of methyl red solution R. The colour changes from red to yellow. Add 1 ml of sodium cobaltinitrite solution R. A yellow precipitate is formed.
TESTS
Solution S
Evaporate 220 ml almost to dryness on a water-bath. Cool, add 1 ml of dilute acetic R and dilute to 20 ml with distilled water R.
Appearance of solution
To 2 ml add 8 ml of water R. The solution is clear (2.2.1) and colourless (2.2.2, Method II).
Oxidisable substances
Cautiously add, whilst cooling, 8.8 ml to 100 ml of dilute sulphuric acid R. Add 0.75 ml of 0.002 M potassium permanganate . Allow to stand for 5 min. The solution remains faintly pink.
Pyridine and related substances
Measure the absorbance (2.2.25) at 252 nm using water R as the compensation liquid. The absorbance is not greater than 0.06 (2 ppm calculated as pyridine).
Carbonates
To 10 ml in a test-tube with a ground-glass neck add 10 ml of calcium hydroxide solution R. Stopper immediately and mix. Any opalescence in the solution is not more intense than that in a standard prepared at the same time and in the same manner using 10 ml of a 0.1 g/l solution of anhydrous sodium carbonate R (60 ppm).
Chlorides (2.4.4)
Dilute 5 ml of solution S to 15 ml with water R. The solution complies with the limit test for chlorides (1 ppm).
Sulphates (2.4.13)
Dilute 3 ml of solution S to 15 ml with distilled water R. The solution complies with the limit test for sulphates (5 ppm).
Iron (2.4.9)
Dilute 4 ml of solution S to 10 ml with water R. The solution complies with the limit test for iron (0.25 ppm).
Heavy metals (2.4.8)
Dilute 4 ml of solution S to 20 ml with water R. 12 ml of the solution complies with limit test A for heavy metals (1 ppm). Prepare the standard using lead standard solution (2 ppm Pb) R.
Residue on evaporation
Evaporate 50 ml to dryness on a water-bath and dry at 100°C to 105°C for 1 h. The residue weighs not more than 1 mg (0.02 g/l).
ASSAY
Weigh accurately a flask with a ground-glass neck containing 50.0 ml of 1 M hydrochloric acid . Add 2 ml of the substance to be examined and re-weigh. Add 0.1 ml of methyl red solution R as indicator. Titrate with 1 M sodium hydroxide until the colour changes from red to yellow.
1 ml of 1 M hydrochloric acid is equivalent to 17.03 mg of NH3.
STORAGE
Store protected from air, at a temperature not exceeding 20°C.
Ph Eur

monograph of aceclofanec

(Ph Eur monograph 1281)







C16H13Cl2NO4 354.2 89796-99-6
Action and use
Analgesic; anti-inflammatory.
Ph Eur
DEFINITION
[[[2-[(2,6-Dichlorophenyl)amino]phenyl]acetyl]oxy]acetic acid.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Practically insoluble in water, freely soluble in acetone, soluble in alcohol.
IDENTIFICATION
First identification B.
Second identification A, C.
A. Dissolve 50.0 mg in methanol R and dilute to 100.0 ml with the same solvent. Dilute 2.0 ml of the solution to 50.0 ml with methanol R. Examined between 220 nm and 370 nm (2.2.25), the solution shows an absorption maximum at 275 nm. The specific absorbance at the absorption maximum is 320 to 350.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison Ph. Eur. reference spectrum of aceclofenac.
C. Dissolve about 10 mg in 10 ml of alcohol R. To 1 ml of the solution, add 0.2 ml of a mixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassium ferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from light for 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protected from light for 15 min. A blue colour develops and a precipitate is formed.
TESTS
Related substances
Liquid chromatography (2.2.29).
Prepare the solutions immediately before use.
Test solution Dissolve 50.0 mg of the substance to be examined in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 25.0 ml with the same mixture of solvents.
Reference solution (a) Dissolve 21.6 mg of diclofenac sodium CRS in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 50.0 ml with the same mixture of solvents.
Reference solution (b) Dilute 2.0 ml of the test solution to 10.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.
Reference solution (c) Mix 1.0 ml of reference solution (a) and 1.0 ml of reference solution (b) and dilute to 100.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.
Reference solution (d) Dissolve 4.0 mg of aceclofenac impurity F CRS, 2.0 mg of aceclofenac impurity H CRS and 2.0 mg of diclofenac impurity A CRS (aceclofenac impurity I) in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 10.0 ml with the same mixture of solvents.
Reference solution (e) Mix 1.0 ml of reference solution (b) and 1.0 ml of reference solution (d) and dilute to 100.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.
Column:
—size: l = 0.25 m, Ø = 4.6 mm,
—stationary phase: spherical end-capped octadecylsilyl silica gel for chromatography R (5 µm) with a pore size of 10 nm and a carbon loading of 19 per cent,
—temperature: 40 °C.
Mobile phase:
—mobile phase A: 1.12 g/l solution of phosphoric acid R adjusted to pH 7.0 using a 42 g/l solution of sodium hydroxide R,
—mobile phase B: water R, acetonitrile R (1:9 V/V),








Flow rate 1.0 ml/min.
Detection Spectrophotometer at 275 nm.
Injection 10 µl; inject the test solution and reference solutions (c) and (e).
Relative retention with reference to aceclofenac (retention time = about 14 min): impurity A = about 0.8; impurity G = about 1.3; impurity H = about 1.5; impurity I = about 2.3; impurity D = about 2.6; impurity B = about 2.7; impurity E = about 2.8; impurity C = about 3.0; impurity F = about 3.2.
System suitability Reference solution (c):
—resolution: minimum 5.0 between the peaks due to aceclofenac and to impurity A.
Limits:
—impurity A: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (c) (0.2 per cent),
—impurities B, C, D, E, G: for each impurity, not more than the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.2 per cent),
—impurity F: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.2 per cent),
—impurity H: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.1 per cent),
—impurity I: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.1 per cent),
—any other impurity: not more than half the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.1 per cent),
—total: not more than 0.7 per cent,
—disregard limit: 0.1 times the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.02 per cent).
























Heavy metals (2.4.8)
Maximum 10 ppm.
To 2.0 g in a silica crucible, add 2 ml of sulphuric acid R to wet the substance. Heat progressively to ignition and continue heating until an almost white or at most a greyish residue is obtained. Carry out the ignition at a temperature not exceeding 800 °C. Allow to cool. Add 3 ml of hydrochloric acid R and 1 ml of nitric acid R. Heat and evaporate slowly to dryness. Cool and add 1 ml of a 100 g/l solution of hydrochloric acid R and 10.0 ml of distilled water R. Neutralise with a 1.0 g/l solution of ammonia R using 0.1 ml of phenolphthalein solution R as indicator. Add 2.0 ml of a 60 g/l solution of anhydrous acetic acid R and dilute to 20 ml with distilled water R. 12 ml of the solution complies with limit test A. Prepare the standard using lead standard solution (1 ppm Pb) R.
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 °C.
Sulphated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.300 g in 40 ml of methanol R. Titrate with 0.1 M sodium hydroxide , determining the end-point potentiometrically (2.2.20).
1 ml of 0.1 M sodium hydroxide is equivalent to 35.42 mg of C16H13Cl2NO4.
STORAGE
In an airtight container , protected from light.
IMPURITIES













A. R = H: [2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid (diclofenac),
B. R = CH3: methyl [2-[(2,6-dichlorophenyl)amino]phenyl]acetate (methyl ester of diclofenac),
C. R = C2H5: ethyl [2-[(2,6-dichlorophenyl)amino]phenyl]acetate (ethyl ester of diclofenac),








D. R = CH3: methyl [[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetate (methyl ester of aceclofenac),
E. R = C2H5: ethyl [[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetate (ethyl ester of aceclofenac),
F. R = CH2-C6H5: benzyl [[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetate (benzyl ester of aceclofenac),
G. R = CH2-CO2H: [[[[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetyl]oxy]acetic acid (acetic aceclofenac),
H. R=CH2-CO-O-CH2-CO2H: [[[[[[[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]acetyl]oxy]acetyl]oxy]acetic acid (diacetic aceclofenac),






I. 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one.

Ph Eur

acetone

(Ph Eur monograph 0872)




C3H6O 58.08 67-64-1
Ph Eur
DEFINITION
Acetone is propan-2-one.
CHARACTERS
A volatile clear , colourless liquid, miscible with water, with alcohol and with ether. The vapour is flammable.
IDENTIFICATION
A. To 1 ml, add 3 ml of dilute sodium hydroxide solution R and 0.3 ml of a 25 g/l solution of sodium nitroprusside R. An intense red colour is produced which becomes violet with the addition of 3.5 ml of acetic acid R.
B. To 10 ml of a 0.1 per cent V/V solution in alcohol (50 per cent V/V) R, add 1 ml of a 10 g/l solution of nitrobenzaldehyde R in the same solvent and 0.5 ml of strong sodium hydroxide solution R. Allow to stand for about 2 min and acidify with acetic acid R. A greenish-blue colour is produced.
TESTS
Appearance of solution
To 10 ml add 10 ml of water R. The solution is clear (2.2.1) and colourless (2.2.2, Method II).
Acidity or alkalinity
To 5 ml add 5 ml of carbon dioxide-free water R, 0.15 ml of phenolphthalein solution R and 0.5 ml of 0.01 M sodium hydroxide . The solution is pink. Add 0.7 ml of 0.01 M hydrochloric acid and 0.05 ml of methyl red solution R. The solution is red or orange.
Relative density (2.2.5)
0.790 to 0.793.
Related substances
Examine by gas chromatography (2.2.28).
Test solution The substance to be examined.
Reference solution To 0.5 ml of methanol R add 0.5 ml of 2-propanol R and dilute to 100.0 ml with the test solution. Dilute 1.0 ml to 10.0 ml with the test solution.
The chromatographic procedure may be carried out using:
—a fused-silica column 50 m long and 0.3 mm in internal diameter coated with a film (0.5 mm) of macrogol 20 000 R,
— helium for chromatography R as the carrier gas with a split ratio of about 50:1 and at a linear flow of 21 cm/s,
—a flame-ionisation detector,
maintaining the temperature of the column at 45°C until injection, then raising the temperature at a rate of 5°C per minute to 100°C and maintaining the temperature of the injection port at 150°C and that of the detector at 250°C.
Inject 1 ml of the test solution and 1 ml of the reference solution.
When the chromatograms are recorded in the conditions described above, the substances are eluted in the following order: acetone, methanol, 2-propanol.
Continue the chromatography for three times the retention time of acetone (which is about 5.3 min).
The test is not valid unless, in the chromatogram obtained with the reference solution, the resolution between the peaks corresponding to methanol and 2-propanol is at least 1.0.
In the chromatogram obtained with the test solution: the area of any peak corresponding to methanol or 2-propanol is not greater than the difference between the areas of the corresponding peaks in the chromatogram obtained with the reference solution and the areas of the corresponding peaks in the chromatogram obtained with the test solution (0.05 per cent V/V for each impurity); the area of any peak, apart from the principal peak and any peaks corresponding to methanol and 2-propanol, is not greater than the difference between the area of the methanol peak in the chromatogram obtained with the reference solution and the area of the corresponding peak in the chromatogram obtained with the test solution (0.05 per cent V/V for each of the additional impurities).
Matter insoluble in water
To 1 ml add 19 ml of water R. The solution is clear (2.2.1).
Reducing substances
To 30 ml add 0.1 ml of 0.02 M potassium permanganate and allow to stand in the dark for 2 h. The mixture is not completely decolourised.
Residue on evaporation
Evaporate 20.0 g to dryness on a water-bath and dry at 100°C to 105°C. The residue weighs not more than 1 mg (50 ppm).
Water (2.5.12)
Not more than 3 g/l, determined on 10.0 ml by the semi-micro determination of water. Use 20 ml of anhydrous pyridine R as solvent.
STORAGE
Store protected from light.
IMPURITIES
A. CH3-OH: methanol,
B. propan-2-ol.

Ph Eur

monograph for acacia

General Notices
(Ph Eur monograph 0307)
Action and use
Bulk-forming laxative; pharmaceutical aid.
When Powdered Acacia is prescribed or demanded, material complying with the requirements below with the exception of Identification test A shall be dispensed or supplied.
Ph Eur
DEFINITION
Acacia is the air-hardened, gummy exudate flowing naturally from or obtained by incision of the trunk and branches of Acacia senegal L. Willdenow, other species of Acacia of African origin and Acacia seyal Del.
CHARACTERS
Acacia is almost completely but very slowly soluble, after about 2 h, in twice its mass of water leaving only a very small residue of vegetable particles; the liquid obtained is colourless or yellowish, dense, viscous, adhesive, translucent and weakly acid to blue litmus paper. Acacia is practically insoluble in alcohol.
It has the macroscopic and microscopic characters described under identification tests A and B.
IDENTIFICATION
A. Acacia occurs as yellowish-white, yellow or pale amber, sometimes with a pinkish tint, friable, opaque, spheroidal, oval or reniform pieces (tears) of a diameter from about 1 cm to 3 cm, frequently with a cracked surface, easily broken into irregular, whitish or slightly yellowish angular fragments with conchoidal fracture and a glassy and transparent appearance. In the centre of an unbroken tear there is sometimes a small cavity.
B. Reduce to a powder (355). The powder is white or yellowish-white. Examine under a microscope using glycerol R (50 per cent V/V). The powder presents angular, irregular, colourless, transparent fragments. Only traces of starch or vegetable tissues are visible. No stratified membrane is apparent.
C. Examine the chromatograms obtained in the test for glucose and fructose. The chromatogram obtained with the test solution shows three zones due to galactose, arabinose and rhamnose. No other important zones are visible, particularly in the upper part of the chromatogram.
D. Dissolve 1 g of the powdered drug (355) in 2 ml of water R by stirring frequently for 2 h. Add 2 ml of alcohol R. After shaking, a white, gelatinous mucilage is formed which becomes fluid on adding 10 ml of water R.
TESTS
Solution S
Dissolve 3.0 g of the powdered drug (355) in 25 ml of water R by stirring for 30 min. Allow to stand for 30 min and dilute to 30 ml with water R.
Insoluble matter
To 5.0 g of the powdered drug (355) add 100 ml of water R and 14 ml of dilute hydrochloric acid R, boil gently for 15 min, shaking frequently, and filter while hot through a tared sintered-glass filter. Wash with hot water R and dry at 100-105 °C. The residue weighs not more than 25 mg (0.5 per cent).
Glucose and fructose
Examine by thin-layer chromatography (2.2.27) , using a TLC silica gel plate R.
Test solution To 0.100 g of the powdered drug (355) in a thick-walled centrifuge tube add 2 ml of a 100 g/l solution of trifluoroacetic acid R, shake vigorously to dissolve the forming gel, stopper the tube and heat the mixture at 120 °C for 1 h. Centrifuge the hydrolysate, transfer the clear supernatant carefully into a 50 ml flask, add 10 ml of water R and evaporate the solution to dryness under reduced pressure. To the resulting clear film add 0.1 ml of water R and 0.9 ml of methanol R. Centrifuge to separate the amorphous precipitate. Dilute the supernatant, if necessary, to 1 ml with methanol R.
Reference solution Dissolve 10 mg of arabinose R, 10 mg of galactose R , 10 mg of glucose R , 10 mg of rhamnose R and 10 mg of xylose R in 1 ml of water R and dilute to 10 ml with methanol R.
Apply to the plate as bands 10 µl of each solution. Develop over a path of 10 cm using a mixture of 10 volumes of a 16 g/l solution of sodium dihydrogen phosphate R, 40 volumes of butanol R and 50 volumes of acetone R. Dry the plate in a current of warm air for a few minutes and develop again over a path of 15 cm using the same mobile phase. Dry the plate at 110 °C for 10 min, spray with anisaldehyde solution R and heat again at 110 °C for 10 min. The chromatogram obtained with the reference solution shows five clearly separated coloured zones due to galactose (greyish-green to green), glucose (grey), arabinose (yellowish-green) xylose (greenish-grey to yellowish-grey) and rhamnose (yellowish-green), in order of increasing R f value. The chromatogram obtained with the test solution shows no grey zone and no greyish-green zone between the zones corresponding to galactose and arabinose in the chromatogram obtained with the reference solution.
Starch, dextrin and agar
To 10 ml of solution S previously boiled and cooled add 0.1 ml of 0.05 M iodine . No blue or reddish-brown colour develops.
Sterculia gum
A. Place 0.2 g of the powdered drug (355) in a 10 ml ground-glass-stoppered cylinder graduated in 0.1 ml. Add 10 ml of alcohol (60 per cent V/V) R and shake. Any gel formed occupies not more than 1.5 ml.
B. To 1.0 g of the powdered drug (355) add 100 ml of water R and shake. Add 0.1 ml of methyl red solution R. Not more than 5.0 ml of 0.01 M sodium hydroxide is required to change the colour of the indicator.
Tannins
To 10 ml of solution S add 0.1 ml of ferric chloride solution R1. A gelatinous precipitate is formed, but neither the precipitate nor the liquid shows a dark blue colour.
Tragacantha
Examine the chromatograms obtained in the test for glucose and fructose. The chromatogram obtained with the test solution shows no greenish-grey to yellowish-grey zone corresponding to the zone of xylose in the chromatogram obtained with the reference solution.
Loss on drying (2.2.32)
Not more than 15.0 per cent, determined on 1.000 g of the powdered drug (355) by drying in an oven at 100-105 °C.
Total ash (2.4.16)
Not more than 4.0 per cent.
Microbial contamination
Total viable aerobic count (2.6.12) not more than 104 micro-organisms per gram, determined by plate count. It complies with the test for Escherichia coli (2.6.13) .
Ph Eur

hi

hi to all

new online books

n engl j med 351;25 www.nejm.org december 16, 2004
2665
to say. Hematologists, immunologists, and pathologists
will certainly enjoy it. It is their own personal
history, and they may even know some of the actors
in it. Historians of medicine and their graduate students,
if they are interested in the history of immunology,
will also read it, since they have doubtless
read and admired the authors’ other work. Such
readers should appreciate the link between epistemology
and the practical, the technical, and the clinical
— a connection that the historiography of immunology
has often tended to play down — as well
as the attractive idea of the platform. But subtle and
insightful as the book may be, it will not have many
general readers. Narrative history with a sociological
twist is usually more accessible than this. Of
course, it might attract some readers who are Benedictines
at heart and love the nightly lectio continua.
Pauline M.H. Mazumdar, Ph.D.
Institute for the History and Philosophy of Science
and Technology at the University of Toronto
Toronto, ON M5S 1K7, Canada
pmazumda@chass.utoronto.ca
alzheimer disease:
neuropsychology
and pharmacology
Edited by Gérard Emilien, Cécile Durlach, Kenneth L. Minaker,
Bengt Winblad, Serge Gauthier, and Jean-Marie Maloteaux.
288 pp. Basel, Switzerland, Birkhäuser Verlag, 2004. $129.
ISBN 3-7643-2426-0.
ess than 20 years ago, alzheimer’s disease
was described in epidemiologic studies as
"the silent epidemic." Some 10 years later, the first
risk factors and genetic mutations were reported,
and today the epidemic is no longer silent. Despite
its subtitle of Neuropsychology and Pharmacology, this
book has a broad scope, with excellent chapters on
the causes of Alzheimer’s disease and dementia.
Its 15 chapters are organized into three sections,
which deal with the biologic correlates of Alzheimer’s
disease, neuropsychology, and treatment.
The section on biologic correlates reviews the causes,
pharmacology, and molecular genetics of Alzheimer’s
disease, along with the various animal
models that have been used in studies of the disease.
The section on neuropsychology, the longest
in the book, is a good introduction to memory and
its assessment; the cognitive, behavioral, and psychological
impairment of Alzheimer’s disease; and
functional and behavioral assessment. The section
on treatment, which discusses in detail the various
pharmacologic options, includes a short chapter
on psychological support.
The book is generally up to date and well balanced,
and it is reasonably uniform in style. Although
the authors strike me as being a bit too
optimistic about the possibilities of treatment, I certainly
prefer their tack to the generally nihilistic attitude
that has clouded discussions of this important
disease in the past. The book is a tribute to the
tremendous effort that has been made in the past
decade in the search for the causes and treatment
of this enigmatic disease.
Albert Hofman, M.D., Ph.D.
Erasmus Medical Center
3015 GE Rotterdam, the Netherlands
a.hofman@erasmusmc.nl
the return of the white plague:
global poverty and the ‘new’
tuberculosis
Edited by Matthew Gandy and Alimuddin Zumla. 330 pp.,
illustrated. New York, Verso, 2003. $35. ISBN 1-85984-669-6.
ince the world health organization
declared tuberculosis a global emergency in
1993, its resurgence has become the source of several
recent publications. Gandy and Zumla have assembled
a prestigious and knowledgeable group of
authors for an updated account that appropriately
goes beyond the usual biomedical assessment of
the current global situation. As suggested by the title
and an introductory quotation provided by the
editors, René and Jean Dubos had already drawn
attention to the social and economic aspects of tuberculosis
51 years earlier in The White Plague: Tuberculosis,
Man and Society (Camden, N.J.: Rutgers University
Press, 1952).
There is special emphasis in the book on the social
and economic factors that have influenced the
persistence of tuberculosis in many parts of the
world. Unfortunately, as the editors acknowledge,
the limitations of the available data make it "difficult
to disentangle fully the relationship" and
interactions among socioeconomic status, racial
differences, sex, wars, the pandemic of human immunodeficiency
virus (HIV) infection, multidrugresistant
tuberculosis, and transmission of the disl
s
Downloaded from www.nejm.org on December 19, 2006 . Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
2666 n engl j med 351;25 www.nejm.org december 16, 2004
ease in prisons. The reviews of these topics are fairly
balanced and thorough, with appropriate citations
and references.
The broad overview of the book challenges the
prevailing notion that the global efforts to control
tuberculosis and the attribution of credit to directly
observed therapy have been the principal contributors
to the reduction of tuberculosis in New York
City and other places. In putting forth this challenge,
the authors may provoke controversy. Ultimately,
it becomes clear that both causal inference
about and potential solutions to the problem of tuberculosis
involve many factors. Some of the chapters
outline the unmet humanitarian needs of persons
with tuberculosis that involve race and ethnic
background, "gender-sensitive" approaches to care,
and immigration from countries where tuberculosis
is prevalent. Instead of blindly siding with the
good intentions that accompany much-needed reforms
in the health sector, authors Harries, Hargreaves,
and Zumla, who contribute a chapter on
tuberculosis and HIV infection in sub-Saharan Africa,
acknowledge the potentially drastic consequences
of the "rapid dismantling of disease control programmes."
Other formidable challenges posed by HIV and
multiple-drug resistance are adequately covered, as
are potential solutions that emphasize the need to
pay attention to neglected areas such as the primary
prevention of tuberculosis. Authors also emphasize
the importance of operational interdisciplinary research
and the need for new drugs and safe and effective
vaccines.
The call for the alleviation of poverty and the
promotion of ethical and human rights is refreshing,
and it is consistent with the control of tuberculosis
in high-burden countries as integral to economic
development. Both the editors and the
chapter authors appropriately identify the need to
go increasingly beyond humanitarian declarations
into action and implementation. Doing so is a crucial
component of a comprehensive and responsive
approach to the global crisis of tuberculosis. The
Return of the White Plague is a commendable treatise
of much interest to socially minded health care practitioners.
Kenneth G. Castro, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
kgc1@cdc.gov
Book Reviews Copyright © 2004 Massachusetts Medical Society.
Notices submitted for publication should contain a mailing
address and telephone number of a contact person or department.
We regret that we are unable to publish all notices received.
Notices also appear on the Journal’s Web site
(www.nejm.org/meetings). The listings can be viewed in
their entirety or searched by location, month, or key word.
call for nominations
The International Society for the Study of the Lumbar Spine is
accepting nominations for its "ISSLS Wiltse Lifetime Achievement
Award," which awards exceptional achievement in the spinal
field. The award is sponsored by the Styker Corporation and
will be awarded at the annual meeting of the International Society
for the Study of the Lumbar Spine, to be held in New York, May
10–14. Deadline for submission is Feb. 1.
Contact International Society for the Study of the Lumbar Spine,
Sunnybrook and Women’s Health Science Centre, Room MG 323,
2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; or call (416)
480-4833; or fax (416) 480-6055; or e-mail shirley.fitzgerald@
sw.ca.
4th annual southwest cardiology symposium
The symposium will be held in Phoenix, Ariz., Feb. 11–13. It is
jointly presented by the University of British Columbia and the
Cardiovascular Society of Arizona.
Contact Hazel Wilcox, The Cardiovascular Society of Arizona,
1331 N. 7th St., Suite 375, Phoenix, AZ 85006; or call (604) 875-
5787; or see http://www.cardiovascularsocietyofaz.org; or e-mail
hwilcox@vanhosp.bc.ca.
arora board review
The following courses will be offered: "Weekly Course in Internal
Medicine" (Livingston, N.J., Sundays, Feb. 13–June 5); "Unusual
Board Review in Internal Medicine" (East Rutherford, N.J.,
June 13–18); and "Crash Course in Internal Medicine" (East Rutherford,
N.J., Aug. 13 and 14).
Contact Dr. R.K. Arora, 389 E. Mount Pleasant Ave., Livingston,
NJ 07039; or call (973) 673-4410; or fax (973) 673-2850; or see http://
www.aroraboardreview.com; or e-mail boardreview@comcast.net.
3rd international symposium on targeted
anticancer therapies
The symposium will be held in Amsterdam, March 3–5. It is
jointly organized by the NDDO Research Foundation and the European
Society of Medical Oncology.
Contact Convenience Conference Management, P.O. Box 77,
3480 DB Harmelen, the Netherlands; or call (31) 348-567667; or fax
(31) 348-446057; or e-mail congress@nddo.org; or see http://www.
nddo.org.
cleveland clinic florida
The following meetings will be held in Naples, Fla., unless otherwise
indicated: "4th Annual Essentials in Colorectal Diseases:
A Course for the Practicing Physician" (Jan. 8 and 9); "16th Annual
International Colorectal Disease Symposium" (Fort Lauderdale,
Fla., Feb. 17–19); "4th Annual Surgery of the Foregut Symposium"
(Coral Gables, Fla., Feb. 21–23); and "ENT Disorders
for the Primary Care Practitioner" (March 19).
Contact Cleveland Clinic Florida, 6101 Pine Ridge Rd., Naples, FL
34119; or call (877) 675-7223, extension 4366 (national) or (239)
348-4366 (Florida); or fax (239) 348-4287; or e-mail cme@ccf.org;
or see http://www.clevelandclinicflorida.org.
notices
Downloaded from www.nejm.org on December 19, 2006 . Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Drug Self-Administration

Procedures for assessing self-administration of' i.v. cocaine have
been reported by Fischman and Schuster (1982) with experienced
cocaine users prepared with two indwelling Angiocath Teflon
catheters, one for drug infusion and one for blood withdrawal.
Subjects were instructed that each of two buttons would be
associated with the same solution (drug or saline) throughout the
study. On the first day, subjects were exposed to each solution and
for the next 8 days were required to press the response button 10
times in order to receive an injection. Once a single response was
made on a given button, the other one was deactivated. A total of
10 injections could be taken during a l-hour session with blood
drawn prior to and after each injection followed by completion of
the POMS and ARC1 questionnaires. After initial sampling on the
first day, subjects consistently chose cocaine over saline.
Subjective ratings of drug effect correlated with the self-injection
of cocaine. The most pronounced effects on subjective states, blood
pressure, heart rate, and cocaine levels occurred after this initial
injection.

CNS Stimulant Physical Dependence Potential a. Tolerance to Drug Effects

The assessment of tolerance to the effects of the CNS stimulants has
been directed mainly at two of their pharmacologic effects:
anorexia and mood elevation. Tolerance to the appetite-suppressant
effects has been demonstrated to occur in numerous studies. It
appears; however, that obesity has many complex components, at least
one of which, the 'craving" for food, may interact with the
evaluation of tolerance effects (Wooley and Wooley 1981).
The currently accepted criterion for the appetite suppressant effect
is that weight is lost and not recovered. The fact that the rate of
weight loss rapidly decreases over the course of treatment is taken
as evidence of tolerance. Stunkard (1979) has suggested that these
criteria are not valid for assessing tolerance, since a deceleration
in weight loss is common even in more drastic treatments of obesity
such as jejunoileal bypass surgery. Additionally, the metabolic
characteristics of the body change as a result of weight loss, and
these changes should be taken into account when assessing tolerance.
Food that has been ingested during a period of weight loss is more
efficiently metabolized than when the caloric balance is in steady
state (Keesey et al. 1976). A more appropriate determinant of
whether tolerance has developed or not may be the degree of weight
gain following cessation of drug treatment. Tolerance would be
shown by a return to normal weight despite continued administration
of the drug. Rebound hyperphagia and weight gain, upon withdrawal
of the drug, would constitute a withdrawal reaction.
Tolerance to the mood elevating effects of CNS stimulants has been
assessed and, in addition,
effects (Gunne 1977).
is distinct, from the appetite-suppressant
Tolerance to the euphoric effects of
amphetamine (as measured by a subjective questionnaire) was found to
develop rather quickly over 14 days of daily treatment (Rosenberg et
al. 1963). In addition, these authors demonstrated that there was
no cross-tolerance to LSD. To date, no studies have been conducted
to directly compare the degree of tolerance development to the
subjective effects of CNS stimulants.

Appetite

Procedures for assessing the effects of stimulants on appetite have
been developed for short-term, single dose experiments. Hoebel et
al. (1975) utilized a procedure that tests a drug's effectiveness in
reducing intake of a diet liquid meal product. Volunteers report to
the laboratory having refrained from eating for 2 hours prior to
lunchtime (12 noon). Using a double-blind cross-over design,
subjects were given either placebo or 25 mg of phenylpropanolamine
30 minutes before lunch. Lunch consisted of a canned chocolateflavored
drink which was dispensed via a long straw from a graduated
cylinder. The reservoir was hidden from the subject's view.
Subjects were instructed to drink as much as they wished.. Upon
completion of lunch they filled out questionnaires that related to
the taste of the lunch, the reason for stopping, the amount that
they consumed relative to the previous day, and the taste of the
lunch relative to the previous day.

Electroencephalographic (EEG) Activity and Sleep

The direct effects of CNS stimulants on EEG activity have been shown
to be alerting or activating as determined by the qualitative
techniques of visual inspection. The desynchronized pattern of EEG
activity, characterized by a slight decrease in amplitude and an
increase in predominant frequency, has been quantified by the use of
voltage integration procedures (Goldstein et al. 1963). Although
the use of power spectral analysis has not been employed extensively
to assess the EEG effects of this class of compounds, a report by
Gibbs and Maltby (1943) did describe a shift in the spectrum to
higher frequencies following benzedrine.

Candida albicans

Inositol is considered a growth factor in yeast cells and it plays an important role in Candida as
an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored
glycolipid on the cell surface of Candida which is involved in the pathogenicity of this opportunistic
fungus and which binds to and stimulates human macrophages. In addition, inositol plays an
essential role in the phosphatidylinositol signal transduction pathway, which controls many cell
cycle events. Here, high-affinity myo-inositol uptake in Candida albicans has been characterized,
with an apparent Km value of 240±15 mM, which appears to be active and energy-dependent
as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). Candida
myo-inositol transport was sodium-independent but proton-coupled with an apparent Km value of
11?0±1?1 nM for H+, equal pH 7?96±0?05, suggesting that the C. albicans myo-inositol–H+
transporter is fully activated at physiological pH. C. albicans inositol transport was not affected by
cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol
transport. Furthermore, myo-inositol transport showed high substrate specificity for inositol and
was not significantly affected by hexose or pentose sugars as competitors, despite their structural
similarity. Transport kinetics in the presence of eight different inositol isomers as competitors
revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of myo-inositol and the
transporter protein play a critical role for substrate recognition and binding. It is concluded that
C. albicans myo-inositol–H+ transport differs kinetically and pharmacologically from the human
sodium-dependent myo-inositol transport system and constitutes an attractive target for delivery of
cytotoxic inositol analogues in this pathogenic fungus.


The yeast Candida albicans is one of the most commonly
encountered human pathogens and is a normal component
of the human endogenous microflora. As an important
nosocomial and opportunistic fungus, C. albicans can cause
a wide variety of infections ranging from mucosal infections
in generally healthy persons to life-threatening
systemic infections in individuals with impaired immune
defence, cancer therapy, antibiotic treatment, diabetes or
burn victims. Furthermore, the development of drug
resistance and the limitations and severe side effects of
drug treatment pose an increasing problem with regard to
C. albicans infections (Vanden Bossche et al., 1998; Pfaller
et al., 1998; Cowen et al., 2002).
Inositol is considered a growth factor in yeast cells and
necessary for their optimum growth (Nikawa et al., 1982,
1991), despite the ability of some yeasts, including Saccharomyces
cerevisiae, to also synthesize myo-inositol de novo
at the expense of glycolysis. Inositol plays an important
role in Candida as an essential precursor for phospholipomannan,
a family of glycophosphatidylinositol (GPI)-
anchored glycolipids on the cell surface of Candida that
is involved in the pathogenicity of this fungus and which
binds to and stimulates human macrophages (Trinel et al.,
1999). Thus, phospholipomannan is considered a virulence
factor in Candida and has been shown to possess immunomodulatory
properties such as TNF-a induction (Jouault
et al., 1994). GPI-membrane anchors are of particular
significance in lower eukaryotes and parasitic protozoa
(McConville & Ferguson, 1993), and about 60 GPIanchored
membrane proteins were estimated in yeast from
the Saccharomyces cerevisiae genome project (Su¨tterlin et al.,
1997). Moreover, inhibition of GPI-anchor biosynthesis was
shown to be lethal in Saccharomyces cerevisiae (Leidich et al.,
1994). In addition to its role as an essential precursor for
GPI-membrane anchors, inositol plays a central role also
in the phosphatidylinositol signal transduction pathway,
which controls many cell cycle events in eukaryotic cells.
Hence, myo-inositol transport in C. albicans appears to
be an attractive drug target to interfere with important
Abbreviations: FCCP, carbonylcyanide-4-(trifluoromethoxy) phenylhydrazone;
GPI, glycophosphatidylinositol.

Advantage Processors

The Advantage Processors is A Merchant account is an account at a financial institution that allows you to accept credit cards. You may find that you can acquire a Merchant account directly from your local bank or you may decide to use any of a number of Merchant account Providers that can be found using your favorite search engine. Not all Merchant Accounts can connect to the Internet, and the ones that can may be limited to a particular Secure Payment Gateway, so be sure to determine how this account will connect to your site if you are a web Merchant. A Merchant account Provider will open an account at a financial institution (a bank they are partnered with) for you that can handle Internet transactions. Be aware that there are a lot of non-reputable Merchant account Providers out there, so make sure you check them out before you commit to one. Avoid all the hype and jargon, and don't pay more than a $100 processing fee to get the account. Providers can get you equipment and software to process credit cards, however you don't necessarily have to buy the equipment or software from them if you feel their prices aren't within your budget range. All Merchant accounts will have some kind of set up or application fee, which is usually at least $99. In cases where there is no fee, they are making up the difference with software or equipment sales, or otherwise marking up the transaction charges to cover this cost.The process a transaction goes through is actually quite complicated, however it only takes a few seconds. Here's an inside look at how credit card transactions are processed using an Internet credit card processing solution:
1. The customer elects to move to the check out with the items they placed into their shopping cart or selected from the order form on a Merchant's Website.

http://www.advantageprocessors.com/

2. The customer then selects "credit card" as their method of payment.
3. Their browser connects to the Website host's secure server, and brings up the secure payment form.
4. The customer enters in his or her credit card information on the secure payment form, and authorizes the transaction by clicking a "Complete Order" type button.
5. The transaction information flows to the Website host's secure server using SSL encryption.
6. The secure server connects to the Merchant's processing bank either via a Secure Payment Gateway (a third party who provides the connection to the processing bank via land line), or directly (some processors have their own proprietary Secure Payment Gateway and therefore do not require a third party to provide this service).
7. The processor polls the card network, such as Visa® or MasterCard®, directly, and the validity of the card, and availability of funds is confirmed.8. If the transaction's approved, an authorization code is returned to the processor, or to the Secure Payment Gateway from the processor.
9. The authorization is encrypted by the Payment Gateway or processor and transmitted in encrypted form to the Web server of the Merchant , which triggers fulfillment of the order.
10. The Merchant's Web server then sends the customer's browser a confirmation receipt.
11. The amount due is moved from the card holder's bank to the Merchant 's processing bank. The Merchant's processing bank will then move the money to the Merchant 's local bank within 2 to 3 business days.

s.c.s college of pharmacy

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