Ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin e1 agent which exhibits uterotonic activity
SUBSTANCE: invention relates to chemical and pharmaceutical industry and specifically to an agent which is ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1 of formula (I), which exhibits uterotonic activity. This compound relates to the family of 11-deoxyprostaglandines and has a chemical structure similar to misoprostol.
EFFECT: agent, which is more chemically stable and is twice less toxic, surpasses misoprostol on uterotonic activity which, along with synthetic availability and absence of side effects, makes it exceptionally promising in practical use for replacing misoprostol in gynaecological binary preparations.
2 tbl, 3 ex
The invention relates to pharmaceutical industry and relates to funds that represent ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1formula (I), showing uterotonic activity and low toxicity.
Previously described synthesis , antiulcer and a number of other types of activity of compound (I) [2-4].
Currently in obstetric practice is extremely urgent problem of labor activation and termination of pregnancy in I and II trimesters of pregnancy complications in pregnancy or extragenital diseases. There are 2 ways to solve this problem: instrumental and medication. The first approach, especially in case of early termination of pregnancy, it is extremely dangerous possible far-reaching consequences (childlessness). Of great importance is the choice of the most rational medical methods for early termination of pregnancy for medical reasons and in the interests of the fetus, for the accelerated ripening of the cervix, labor activation and agostinelli.
One of the most promising drugs in this direction are the prostaglandins (PG). They are able to stimulate contractions of the myometrium and can lead to maturation and disclosure of cervical match is, and the use of prostaglandins during therapeutic abortion in the third trimester of pregnancy may induce uterine activity. Prostaglandins can also promote the release of oxytocin from the pituitary gland of the mother and to create a low threshold of excitability in relation to oxytocin .
As is known, for early termination of pregnancy and childbirth in women apply PG E-type prostaglandin E1, sulfa-derived prostaglandin E2 - sulprostone, 9-methylene isaster PGE2- metropost , and in recent years became widely used misoprostol [5, 8].
However, these prostaglandins are characterized by a number of disadvantages, namely: low chemical and metabolicheskoi stability, relatively high toxicity, the presence of negative side-hypertensive and dialoging action and high cost drugs based on them. It should be noted that, although the production of prostaglandins is a complex and multistage process, however, it is economically advantageous, since prostaglandins are effective in very low doses.
Globally important achievement of recent years in the field of gynecology was the creation of the combined drugs (antigistaminny steroid + prostaglandin) for early termination of pregnancy and childbirth. As Stero the ne components used highly modified steroid Mifepristone (Mifegyne, RU 486), prostaglandin component is an analogue of prostaglandin E1- Misoprostol (II) .
The combination of steroid (600 mg) with a low dose (0.2 mg Misoprostol not only increases abortifacient efficacy (from 84% to 96%), but also reduces side effects (diarrhea, vomiting).
The closest analogue to the properties of the claimed object - ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(11-desoximetasone) is a synthetic analogue of PGE1is misoprostol with uterotonic activity .
However, despite effectively, misoprostol has a number of side effects such as gastro-intestinal tract. In addition misoprostol relatively chemically unstable in the presence of the cyclic part of the misoprostol β-hydroxyketones groups capable of easy digitately with the formation of compounds cyclopentenone type, prone to subsequent reactions of isomerization and seals. In addition, the misoprostol is marked by a significant toxicity and high market value.
In view of the above shortcomings existing in gynecology and obstetrics GHGs, including misoprostol, remains an urgent search for new PG analogues with uterotonic action devoid of these shortcomings.
The problem to which direction is about the claimed technical solution, is to search among the derivatives of prostaglandins available compounds with high uterotonic activity and clinical acceptability (less toxic and devoid of unwanted side effects).
The problem is solved by means represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(I)showing uterotonic activity.
The compound (I) was obtained according to the scheme  by processing at a temperature of -60°C readily available cyclopentenone (III) prepared in situ cuprate reagent (IV) (molar ratio 1:1.5) in tetrahydrofuran. After acid hydrolysis of the reaction mass and the HRO-
maturational purification on a column with SiO2isolated compound (I) with the release of 76%.
In the study of biological activity of compound (I) as the reference drug used synthetic PG - Misoprostol. Acute toxicity of the compound (I) was determined on outbred mice weighing 18-20 g at single intraperitoneal route of administration. It is established that the compound (I) is low toxic substance (LD5075 mg/kg)and 2 times less toxic than misoprostol, LD5035 mg/kg
Uterotonic activity of compound (I) was studied in outbred rats according to the method of Magna is and . Conducted in vivo tests on pregnant female rats showed that the compound (I) has a high uterotonic activity and surpass those of misoprostol. The research results are summarized in table 1.
|The influence of the 11-desoximetasone and misoprostol on the contractile activity of the uterus in rats|
|Connection||Breeding, g/ml||The number of animals||The amplitude of uterine contractions %||The tone of the uterus, %|
|11 dioximes-prostol||2×10-6||15||of 98.2±2,9||15,9±1,3|
|P1- significantly in relation to spontaneous contractions|
|P2- significantly towards misoprostol|
Study of the influence of the 11-desoximetasone on the motility of the gastrointestinal tract hungry rats showed that the compound (I) does not increase evacuation capacity of the small intestine (table 2), i.e. does not show side dialoging dasve characteristic misoprostol .
|The influence of the 11-desoximetasone and misoprostol in evacuation capacity of the small intestine of rats (n=15)|
|Connection||Dose, mg/kg||The length of the small intestine, cm||Distance traveled label, cm||Evacuation capacity, %|
Thus, the proposed remedy represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1(11-desoxypipradrol) (I)related to certain 11-deoxyprostaglandin, and similar in chemical structure with misoprostol, but more stable and with less 2 times the toxicity, surpassing its uterotonic activity. In addition, synthetic accessibility, combined with the above makes it extremely promising for implementation in practice with the aim of replacing misoprostol in gynecology binary products.
The invention is illustrated by the following examples.
Example 1. Determination of acute toxicity.
Acute toxicity 11-desoximetasone of whom were on outbred mice weighing 18-20 g at single intraperitoneal route of administration. The compound (I) and misoprostol was dissolved in vegetable oil. Observation of the animals was carried out for 10 days. The clinical picture of poisoning animals with the introduction of the studied compounds was expressed in the lateral position of the body, slow breathing and convulsions.
Parameters of acute toxicity was evaluated according to the method of Litchfield and Wilcoxon signed . LD5011-Desoximetasone equal to 75 mg/kg LD50misoprostol - 35 mg/kg classification GOST 12.1.007.76, 11-desoxypipradrol belongs to the class of non-lethal substances and misoprostol belongs to the class of srednetonnazhnyh connections.
Example 2. The study of the uterotonic activity of compound (I).
Uterotonic activity of compound (I) was studied in outbred rats according to the method of Magnus . With this purpose an isolated segment of the uterus was placed in aerated by air a solution of ringer-Locke (composition of solution of NaCl (9 g/l; KCl - 200 mg/l; NaHCO3200 mg/l; CaCl2200 mg/l; glucose, 1 g/l) with temperature of 37°C and was attached to the recorder. The effect of compound (I) on uterine contractions was investigated in a dilution of 2×10-6g/ml. About uterotonic activity was judged by the percentage increase in the amplitude reduction relative to the original (inotropic effect) and by the percentage change in uterine tone (donotreply effect). Uterotonic activity was compared with that of misoprostol in the same breeding.
In a dilution of 2×10-6g/ml of compound (I) increased the amplitude of uterine contractions on to 98.2% (P1<0,01), whereas misoprostol - by 74.3% (P1<0,02) in relation to spontaneous contractions. This 11-desoxypipradrol and misoprostol slightly changed the tone of the uterus (table 1).
Thus, 11-desoxypipradrol has a more pronounced uterotonic properties (P2<0.01) compared with misoprostol.
Example 3. Study of the influence of the 11-desoximetasone on the motility of the gastrointestinal tract.
To study side dialoging effect of compound (I) investigated the effect on the motility (evacuation ability of the small intestine) of the gastrointestinal tract to the hungry rats . The compound (I) and misoprostol was administered 5 min prior to the introduction of coal labels (1 ml of 5%coal usesi in starch). About dialogando activity was judged based on distance traveled coal label 30 minutes from the pyloric part of the stomach through the intestines. Evacuation capacity of the small intestine expressed in percent as the ratio of the distance that the main part of the label, to the whole length of the intestine.
The rat 11-desoximetasone slowed peristalsis. After 30 minutes the distance traveled main part of the label, in the experimental animals of both groups was less than that of the control. 11-Deso seminoprotein significantly decreased evacuation ability of the small intestine compared with the control group. In the group of animals treated with misoprostol in the same dose, the evacuation capacity of the small intestine was lower than the control, and the results unreliable (table 2).
Thus, the tool that represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1has a more pronounced uterotonic activity than misoprostol and 2 times less toxic than he, and does not cause side dialoging actions.
1. Ivanova N.A., Shainurova A.M., Miftakhov MS Prostanoids. LXIX. Synthesis of ethyl ester of (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1. // Chem.-Pharm. Log. - 1998. No.. 6. - P.39-40.
2. Sapozhnikova T.A., Saudi FS, Karachurina LT, Makar NS, khisamutdinova HE, Ivanov N.A., Shainurova A.M., Miftakhov MS Pharmacological properties 11-desoximetasone. // Experimental. and clinically. pharmacology. - 2003. - So 66. No. 1. - P.34-36.
3. Ivanova N.A., Sapozhnikova T.A.; Saudi F.S.; Maschenko NJ; Makar NS; khisamutdinova RU; Gabdrakhmanova SF; Nazarov, V.S. Hepatoprotective activity 2-demethoxycurcumin-2-etoxycarbonyl-11-desoximetasone. // Experimental. and clinically. pharmacology. - 2007. - So 70. No. 4. - P.30-31.
4. Sapozhnikova T.A.; Saudi F.S.; Maschenko NJ; Gabdrakhmanova SF; Makar NS; khisamutdinova RU; Nazarov, V.S. Choleretic activity 2-demethoxycurcumin-2-ethoxycarbonyl the-11-desoximetasone on the model of hepatitis, caused by CCL. // Bulletin of experimental biology and medicine. - 2008. - 145 so. No. 2. - .183-184.
5. Abramenko CENTURIES Prostaglandins and antigestagen in obstetrics and gynecology. - Petrozavodsk: Intelteck. - 2003. - 208 S.
6. Mashkovsky PPM Medicines. - M.: New wave. - 2005. - 535 S.
7. Collins P.W., Stevan W.D. Synthesis of therapeutically useful prostaglandin and prostacyclin analogs. // Chem. Rev. - 1993. - V.93. - P.1533-1564.
8. Abramenko B.B., Abrahamian P.A., Abrahamian LR Induction birth and their regulation by prostaglandins. SPb.: ALBI-SPb. - 2005. - 288 S.
9. George VI a Practical guide to the physiology of farm animals. M: High school in 1976. - S-273.
10. Belyaev O.A., A. Fedin. Evaluation of the effects of microbial enzymes on the motility of the small intestine of rats // Exp. and the wedge. Pharm. - 1998. - T. No. 5. - P.24-26.
11. Belenky, M. elements of a quantitative evaluation of the pharmacological effect. L., Medgiz. - 1963. - 152 C.
The tool represents ethyl ester (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1formula (I)
showing uterotonic activity.
SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts which are able to inhibit the replication of HIV-virus, to pharmaceutical composition thereof and to the method of inhibition of HIV-virus replication. formula (A) where R1 is hydrogen; R2 is OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is (CH2)bCOOR9 where b takes up the integer values from 1 to 5; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.
EFFECT: claimed compounds inhibit the replication of HIV-virus.
4 cl, 6 dwg, 7 ex
SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts possessing anti hiv-activity, to the pharmaceutical composition thereof and to the method of HIV-integrase inhibition. formula (A) where R1 is selected from the group consisting of the hydrogen and halogen; R2 is selected from the group consisting of the hydrogen and OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is COOR9; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.
EFFECT: claimed compounds possess anti HIV-activity.
5 cl, 6 dwg, 13 ex
SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.
EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.
124 cl, 52 ex, 17 tbl, 2 dwg
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to photoinitiating agents of phenylglyoxylic acid order used in polymerizing compositions to be subjected for hardening. Invention describes a photoinitiating agent of the formula (I): wherein Y means (C3-C12)-alkylene, butenylene, butinylene or (C4-C12)-alkylene that are broken by groups -O- or -NR2- and not following in sequence; R1 means a reactive group of the following order: -OH, -SH, -HR3R4, -(CO)-OH, -(CO)-NH2, -SO3H, -C(R5)=CR6R7, oxiranyl, -O-(CO)-NH-R8-NCO and -O-(CO)-R-(CO)-X; R2 means hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R3 and R4 mean hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R, R and R mean hydrogen atom or methyl; R8 means linear or branched (C4-C12)-alkylene or phenylene; R9 means linear or branched (C1-C16)-alkylene, -CH=CH-, -CH=CH-CH2-, C6-cycloalkylene, phenylene or naphthylene; X, X1 and X2 mean -OH, Cl, -OCH3 or -OC2H5. Also, invention describes a method for synthesis of a photoinitiating agent, polymerizing composition and substrate covered by its. Proposed photoinitiating agent possesses the effective introducing capacity and absence of migration in thermal treatments.
EFFECT: improved and valuable properties of agent.
13 cl, 1 tbl, 16 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.
EFFECT: improved method of synthesis.
12 cl, 8 ex
FIELD: organic chemistry, perfumery.
SUBSTANCE: invention relates to an aromatizing composition containing at least compound of the formula (I): as an active component wherein values w, m, P, X, G, Q and n are given in claim 1 of the invention description, and one or more aromatizing component. Also, invention relates to a method for improving, enhancing or modifying odor, to a method for aromatizing surface, method for enhancing or prolonging the diffusion effect of component on surface and to novel compounds of the formula (I) with exception of compounds enumerated in claim 10 of the invention description and to invention relating to aromatizing article using compounds of the formula (I).
EFFECT: valuable cosmetic properties of compounds.
13 cl, 14 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and to a new method for preparing 4-substituted alkyl-3-oxobutanoates of the formula: wherein: R is C6H5CH2, 2-F-6-ClC6H3CH2, 2,6-Cl2C6H3CH2, 1-C10H7CH2, Ph2CH; Alk is Me; R is 1-AdCH2; Alk is i-Pr that are used precursors of antiviral agents of pyrimidine order. Method involves acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione with acyl chlorides in dichloromethane in the presence of triethylamine followed by alcoholysis of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione wherein acylation is carried out with acyl chlorides in the presence of trimethylsilyl chloride in the mole ratio 2,2-dimethyl-1,3-dioxane-4,6-dione : acyl chloride : trimethylsilyl chloride : triethylamine = (1-2):1:1.1:3.5, respectively, with formation of an intermediate product 5-[1-(trimethylsilyloxy)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione that is subjected for hydrolysis with formation of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and its following alcoholysis and formation of the end product. Method provides enhancing yield and purity of claimed compounds.
EFFECT: improved method for preparing.
2 cl, 8 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to new method for production of m- or p-substituted α-arylalkanecarboxylic acids of general formula I
from respective α-hydroxylated derivatives using inexpensive reagents and without converting of any reducible groups such as ester or ketone ones in side chains. In formula R is hydrogen, C1-C6-alkyl; R1 is hydrogen, linear or branched C1-C6-alkyl, phenyl, p-nitrophenyl, alkali or earth-alkali cation or cation of pharmaceutically acceptable ammonia salt: A is C1-C4-alkyl, aryl, optionally substituted with one or more alkyl, hydroxy, etc., aryloxy, arylcarbonyl; A is in m- or p-sites; P - linear or branched C1-C6-flkyl, phenyl, nitrophenyl. Claimed method includes the next steps: a) converting of compounds of formula II to compound of formula III either by reaction of II with compound of formula in presence of organic or inorganic base or by reaction of II with thiophene of formula and followed by reaction of obtained product with HNRaRb, wherein Ra andRb are as defined above; b) thermal rearrangement of III to form IIIb ; c) catalytic dehydration of IIIb to form IIIc ; and d) optional hydrolysis of IIIc to obtain target compound of formula I. Also are disclosed new compounds of formulae III and IIIb.
EFFECT: new α-arylalkanecarboxylic acids and intermediates thereof.
6 cl, 5 ex
SUBSTANCE: algae Gracilaria verrucoza are incubated in distilled water in order to transform unsaturated fatty acids under influence of present in alga enzymes into prostaglandins. Prostaglandins are transferred into distilled water. Extraction of prostaglandins from water solution by sorption with further eluting with water-organic solvents is carried out. Freshly collected alga is used, incubation is carried out during 1-3 hours with light illumination with intensity 100-300 mcE/m2s and temperature not higher than 4°C, before extraction of prostaglandins by sorption obtained water solution is acidified to pH 2.5-3.0, as sorbent non-polar modified silicagel with graft hydrocarbons with grain size to 100 mcm.
EFFECT: increase of product yield and process simplification.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to derivative of prostaglandin of the general formula (I): wherein X means halogen atom in α- or β-position; Y means ethynylene group; R1 means (C3-C10)-cycloalkyl group; R2 means hydrogen atom (H) or -CO2R; R3 means H, (C1-C4)-alkyl group; n = 1-3; p = 0, or to its pharmaceutically acceptable salt or hydrate. Compounds of the formula (I) possess the sleep-inducing effect.
EFFECT: valuable medicinal property of compound and pharmaceutical composition.
8 cl, 2 tbl, 2 sch, 5 ex
FIELD: organic chemistry, medicine, pharmacology, pharmacy.
SUBSTANCE: invention relates to novel compounds possessing properties of EP4 agonist and their using as EP4 agonist for preparing a pharmaceutical composition used in treatment of disorders associated with reducing the osseous mass. Invention provides the enhanced effectiveness of treatment.
EFFECT: valuable medicinal properties of pharmaceutical compositions.
13 cl, 125 tbl, 32 ex
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to a novel intermediate compound of the formula (VI)
and its salts wherein R3 means hydrogen atom (-H); R4 means -H, and means a simple or double bond, and its pharmaceutically acceptable salts.
EFFECT: improved preparing method.
4 cl, 12 ex
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to 1-ethanolamide PGF2α of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.
EFFECT: new effective compound for relaxation of mammalian intraocular pressure.
4 cl, 1 ex, 16 dwg, 16 tbl
< / BR>where R is a saturated or unsaturated, branched or unbranched or cyclic C1-7alkyl or phenyl, or benzyl group
< / BR>where R the rest prostaglandin formula:
< / BR>where one of the two groups at C-9 atom (R1or R2) a hydrogen atom, and the other hydroxyl (R2or R1or R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-11 of the atom (R3or R4) a hydrogen atom, and the other hydroxyl (R4or R3or R3and R4together form a keto or hydroxyisopropyl; provided that R3and R4do not form a keto or hydroxyisopropyl when R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-15 atom (R5or6) a hydrogen atom, and the other (R6or R5) hydroxyl or fluorine atom; the symbolrepresents a single or a CIS-double bond; or R is the residue of a prostaglandin of the formula:
represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or provided that if7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond; and where one of the two groups at C-15 atom (R9or R10) a hydrogen atom, and the other (R10or R9) hydroxyl;
or R the rest of the prostaglandin type I formula:
< / BR>where the group Q at C-5 of the atom the atom is iodine or bromine, the symbolrepresents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond;
or R residue of the unsaturated fatty acids of the formula:
< / BR>where a 0 6, f 1 6, 1 7, provided that the total carbon chain length from 18 to 22 carbon atoms;
or R residue hydroxy acid of the formula:
< / BR>where m 1 7 x 0 4, k 0 4, n is 0 to 3, provided that the total carbon chain length from 18 to 22 carbon atoms, and str is
SUBSTANCE: invention refers to medicine, particularly to obstetrics and clinical pharmacology, and can be used for augmentation of uterine contractions with oxytocin solution in full-term pregnancy. An oxytocin dose is pre-calculated from the relation DDR. = 1IU M·/80, where DDR. is a required dose of oxytocin in IU, M is a digital expression of weight of a parturient woman, kg. Oxytocin is dissolved in 300-500 ml of 0.9% sodium chloride. In the absence of labour activity, the preparation is introduced continuously, starting with 1 drop a minute and once-a-minute increasing introduction rate 1 to more drops to the first uterine contractions. The effective introduction rate is calculated, and the preparation is introduced during periods of uterine relaxation. The insufficient labour activity requires a single dose increased in 1.5 times. In overdosing, introduction of oxytocin solution is stopped with immediately venous infusion of 0.9% sodium chloride.
EFFECT: method provides accurate dosage of oxytocin solution and reduced by-effects of augmentation.