text:
|Publication number
|Publication type
|Application number
|Publication date
|Apr 9, 1985
|Filing date
|Aug 1, 1983
|Priority date
|Sep 18, 1980
|Fee status
|Also published as
|Publication number
|Richard Berthold
|Original Assignee
|Sandoz Ltd.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (4), Non-Patent Citations (15), Referenced by (4), Classifications (12), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation of application Ser. No. 302,900, filed Sept. 16, 1981, now abandoned.
The invention relates to new pharmaceutical compositions effective against coronary heart disease and hypertension, and to their production and use. The present invention provides a pharmaceutical composition containing as active agents
(A) a compound of formula I, ##STR1## wherein
R1 is hydrogen, (C1-6)alkyl, hydroxy(C2-6)alkyl, (C3-6)alkoxyalkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C7-9)phenylalkyl or (C9-12)phenylalkenyl, the phenyl ring being unsubstituted or independently mono-, di- or trisubstituted by halogen, hydroxy, (C1-4)alkyl or (C1-4)alkoxy,
R2 and R5, independently, are hydrogen, (C1-6)alkyl, (C7-10)phenylalkyl, (C3-7)cycloalkyl or (C4-8)cycloalkylalkyl,
R3 and R4, independently are CN, COOR7, COR8, S(O)n R9, or ##STR2## wherein n is 0, 1 or 2,
R7, R8 and R9 independently are (C1-6)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, hydroxy(C2-6)alkyl, (C3-6)alkoxyalkyl, hydroxy(C4-8)alkoxyalkyl, amino(C2-6)alkyl, (C1-4)alkylamino(C2-6)alkyl, di[(C1-4)alkyl]aminoalkyl, phenyl, (C7-10)phenylalkyl, a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and which may contain additionally 1, 2 or 3 ring nitrogen atoms, or (C1-4)alkyl substituted by a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and which may contain additionally 1, 2 or 3 ring nitrogen atoms,
A is (C1-6)alkylene,
R10 and R11 independently are (C1-6)alkyl, (C3-6)alkenyl or (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, hydroxy(C2-6)alkyl, (C3-6)alkoxyalkyl, hydroxy(C4-8)alkoxyalkyl, amino(C2-6)alkyl, (C1-4)alkylamino(C2-6)alkyl, di[C1-4)alkyl]aminoalkyl, phenyl, (C7-10)phenylalkyl, or
R10 and R11 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may contain a further heteromember selected from oxygen, sulphur and a group ═N--R12, wherein R12 is (C1-4)alkyl, and
R6 is hydrogen, halogen, (C1-4)alkyl, (C1-4)alkoxy, (C1-4)alkylthio, (C1-4)alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, (C1-4)alkylamino, di[(C1-4)alkyl]amino, (C1-5)alkanoylamino, (C2-5)carbalkoxy, aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, (C1-4)alkylsulfamyl or di[(C1-4)alkyl]sulfamyl, and
X is oxygen or sulphur,
in free base or in a pharmaceutically acceptable acid addition salt form and
(B) a β-adrenoceptor blocking agent and/or
(C) a vasodilating nitrate, hereinafter referred to as a composition of the invention.
The components (A), (B) and (C) of the composition are generally known. Particularly the compounds of formula I are known from e.g. European Patent Publication No. EP 150 (application No. 78100165.6), U.K. Patent Publication No. 20 41 358 (application No. 7943112) and U.K. Patent Publication No. 20 37 766 (application No. 7943113).
In any of the above radicals for active component (A) of formula I, alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 to 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in COOR7 is preferably not attached to the α-carbon atom and is preferably attached to the distant terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably has an ethylene or propylene moiety substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino respectively. The alkyl moiety of cycloalkylalkyl is conveniently methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine. Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in R1 or COOR7 is preferably not in the α,β position. Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is conveniently allyl or 2-methylallyl. Alkinyl is conveniently propinyl. Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl. When R1 is optionally substituted phenylalkyl, the phenyl group is preferably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same. When R7, R8 or R9 contain a heterocyclic ring this may be for example furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpholinyl or triazinyl.
When R10 and R11 together with the nitrogen atom to which they are bound, form a heterocyclic ring, this is preferably saturated and may be for example pyrrolidine, piperidine, piperazine, N-alkylpiperazine, morpholine, azepane, diazepane or N-alkyl-diazepane.
R2 is conveniently identical to R5.
R6 is conveniently halogen, alkyl or alkoxy, or hydrogen and is conveniently adjacent to the dihydropyridine moiety.
__________________________________________________________________________As components (A) the following compounds of formula I, wherein yindicates the positionof the dihydropyridine moiety, may be used.CompoundNo. R1 R2 R3 R4 R5 R6 X y__________________________________________________________________________1 H CH3 CN COOi-Bu CH3 H O 42 H CH3 COOC2 H5 SO2 CH3 CH3 H O 43 H CH3 CN COOC2 H5 CH3 H O 44 H CH3 CN COOC2 H5 CH3 H S 45 H CH3 CN COOCH2 CH(CH3)2 CH3 H S 46 H CH3 COOCH3 COC6 H5 CH3 H O 47 H CH3 ##STR3## COOC2 H5 CH3 H O 4 8 H CH3 ##STR4## COOC2 H5 CH3 H S 4 9 H CH3 COO(CH2)2 N(CH3)2 COO(CH2)2 N(CH3)2 CH3 H O 410 H CH3 COO(CH2)2 N(CH3)2 COO(CH2)2 N(CH3)2 CH3 H S 411 H CH3 COO(CH2)2 N(CH3)2 COOC2 H5 CH3 H O 412 H CH3 COO(CH2)2 N(CH3)2 COOC2 H5 CH3 H S 4 13 H CH3 ##STR5## COOC2 H5 CH3 H S 5 14 H CH3 ##STR6## COOC2 H5 CH3 H O 5 15 H CH3 ##STR7## COOCH3 CH3 H O 4 16 H Δ COOC2 H5 COOC2 H5 CH3 H O 417 H Δ COOCH3 COOCH3 CH3 H O 418 H Δ COOCH3 COOCH3 Δ H O 419 H Δ COOC2 H5 COOC2 H5 Δ H O 420 H CH3 COO(CH2)2C 6 H5 COOCH3 CH3 H O 421 H CH3 COOCH3 COOCH2 C6 H5 CH3 H O 422 H CH3 COOC2 H5 COOC2 H5 CH3 H O 423 H CH3 COOC2 H5 COOC2 H5 CH3 H S 424 H CH3 COOC(CH3)3 COOC(CH3)3 CH3 H S 425 H CH3 COOCH3 COOCH3 CH3 7-Cl O 426 H CH3 COOCH3 COOCH3 CH3 H S 427 H CH3 COOC2 H5 COOC2 H5 CH3 5-OCH3 S 428 H CH3 COOC2 H5 COOC2 H5 CH3 7-Cl S 429 H CH3 COOC2 H5 COOC2 H5 CH3 H S 530 H CH3 COOC2 H5 COOC2 H5 CH3 4-Cl S 531 H CH3 COC(CH3)3 COC(CH3)3 CH3 H S 432 H CH3 COCH3 COCH3 CH3 7-Cl O 433 H CH3 COCH3 COCH3 CH3 H S 434 H CH3 COC2 H5 COC2 H5 CH3 5-OCH3 S 435 H CH3 COC2 H5 COC2 H5 CH3 7-Cl S 436 H CH3 COC2 H5 COC2 H5 CH3 H S 537 H CH3 COC2 H5 COC2 H5 CH3 4-Cl S 538 H CH3 COCH3 COCH3 CH3 H O 439 H CH3 COCH3 COOC2 H5 CH3 H O 440 H CH3 COCH3 COOC2 H5 CH3 H S 441 H CH3 COOCH2 CH(CH3)2 COOCH3 CH3 H O 442 H CH3 COOCH3 COOCH3 CH3 H O 443 H CH3 COOC2 H5 COOC2 H5 CH3 H O 544 H CH3 COOCH2 CH(CH3)2 COOC2 H5 CH3 H S 445 H CH3 COOCH2 CH(CH3)2 COOC2 H5 CH3 H O 446 H CH3 COOC(CH3)3 COOC(CH3)3 CH3 H O 447 H CH3 COOCH2 CH(CH3)2 COOCH2 CH(CH3)2 CH3 H O 448 H CH3 COO(CH2)2 OC2 H5 COOC2 H5 CH3 H O 449 H CH3 COO(CH2)2 OC2 H5 COOC2 H5 CH3 H S 450 H CH3 COO(CH2)2 OC2 H5 COOC2 H5 CH3 H S 551 H CH3 COOCH(CH3)2 COOCH3 CH3 H O 452 H CH3 COO(CH2)2 OCH3 COOCH3 CH3 H O 453 H CH3 COO(CH2)2 OCH(CH3)2 COOCH3 CH3 H O 454 H CH3 COO(CH2)2 OC2 H5 COOCH3 CH3 H O 4 55 H CH3 ##STR8## COOCH3 CH3 H O 4 56 H CH3 COO(CH2)2 OCH3 COOCH(CH3)2 CH3 H O 457 H CH3 COOCH3 COOC2 H5 CH3 H O 458 CH3 CH3 COOC2 H5 COOC2 H5 CH3 H O 459 n-C3 H7 CH3 COOC2 H5 COOC2 H5 CH3 H O 4__________________________________________________________________________
Preferred compositions of the invention contain a component (A) of formula I in which R1 is hydrogen or (C1-6)alkyl or R2 and R5 independently are (C1-6)alkyl or the dihydropyridine ring is in position 4 of the benzoxa- or -thia diazolyl moiety or X is oxygen or R6 is hydrogen or R3 and R4 independently are COOR7, COR8 or ##STR9## in which R7, R8, R10, R11 and A are as defined above. However, R7 is preferably (C1-6)alkyl, (C3-6)alkoxyalkyl, (C3-7)cycloalkyl or (C7-10)phenylalkyl, R8 is preferably (C1-6)alkyl and preferably one of R10 and R11 is (C1-6)alkyl and the other (C7-10)phenylalkyl and A is preferably (C1-2)alkylene.
Particularly preferred components (A) are such of formula Ia, ##STR10## wherein
R1a is hydrogen or (C1-6)alkyl,
R2a and R5a independently are (C1-6)alkyl
R3a and R4a independently are COOR7a, COR8a or ##STR11## in which R7a is (C1-6)alkyl, (C3-6)alkoxyalkyl, (C3-7)cycloalkyl or (C7-10)phenylalkyl,
R8a is (C1-6)alkyl, one of R10a and R11a is (C1-6)alkyl, the other is (C7-10)phenylalkyl and Aa is (C1-2)alkylene.
In the components (A) of formula Ia, preferably one of R3a and R4a is COOR7a and the other is COR8a, ##STR12## or COOR7a, in which R7a, R8a, Aa, R10a and R11a are as defined above.
If both R3a and R4a independently are COOR7a, preferably one of R3a and R4a is (C2-7)alkoxycarbonyl and the other is (C4-7)alkoxyalkoxycarbonyl, (C4-8)cycloalkoxycarbonyl, (C8-11)phenylalkoxycarbonyl or (C2-7)alkoxycarbonyl. If one of R3a and R4a is (C2-7)alkoxycarbonyl, and the other is (C5-7)alkoxyalkoxycarbonyl or (C4-7)alkoxycarbonyl, preferably at most one of the terminal alkoxy groups having at least 4 carbon atoms is branched. Preferred as active components (A) are the compounds having the compound Nos. 7, 21, 22, 39, 41, 45, 48, 51-57 and 59. Especially preferred are the compound Nos. 21, 22, 51, 54 and 55, particularly 22.
A suitable β-adrenoceptor blocking agent (B) is e.g. a compound having an ##STR13## side chain attached through the 1-oxygen thereof directly to an aryl moiety, or a ##STR14## side chain attached through the 1-carbon atom thereof directly to an aryl moiety.
The aryl moiety may be, for example, of up to 10 carbon atoms, e.g. phenyl or naphthyl, e.g. 4-indolyl or 1-naphthyl, and may contain one or two heteroatoms, e.g. nitrogen as in indolyl or nitrogen and sulphur as in thiazolyl. The aryl moiety may also have one or two ring substituents, e.g. acetyl, allyl, allyloxy, aminocarbonylmethyl, cyano, methyl, chloro, methoxy, methoxyethyl, amido, hydroxy, nitro, propinyloxy, (C1-4)alkanoylamino, methylsulfamoyl, morpholino, methylthio, oxo and tetrahydrofurylmethyloxy substituents.
The aryl moiety may also have an alkyl chain between two adjacent carbon atoms, thereby forming a saturated ring. For example, the aryl moiety nucleus may be tetralone or tetraline.
The amino group of the ##STR15## side chain conveniently has a branched chain alkyl substituent of 3 to 7 carbon atoms, e.g. isopropyl or tert-butyl.
Examples of suitable known β-blocking agents are Acebutolol, Alprenolol, Atenolol, Bufetolol, Bunitrolol, Bunolol, Bupranolol, Labetalol, Metoprolol, Nadoxolol, Oxprenolol, Pargolol, Procinolol, Propranolol, Talinolol, Timolol, Tiprenolol, Tolamolol, Toliprolol, Trimepranol.
Preferred as active agents (B) are compounds interfering little with myocardial contractile function and having little effect on heart rate, e.g. compounds possessing some degree of intrinsic sympathomimetic activity.
Especially interesting compounds are:
4-(2-hydroxy-3-isopropylaminopropoxy)indole (Pindolol) and
4-(2-benzoyloxy-3-tert-butylaminopropoxy)-2-methylindole (LT).
Preferred as active components (C) are known (C1-6)aliphatic alcohol esters of nitric acid. Especially preferred are (C3-6)aliphatic polyol esters of nitric acid, such as glyceryl trinitrate and mannitol hexanitrate, particularly erythrityl tetranitrate and pentaerythritol tetranitrate, especially isosorbide dinitrate.
Active agents (A) and (B) may be in the free base form or in salt, e.g. in acid addition salt form. The new composition may be prepared by a process comprising formulating component (A), with component (B) and/or component (C), in a state of purity sufficient for pharmaceutical acceptability. Conventional pharmaceutical excipients including carriers and diluents, may also be formulated therewith.
Preferred is a composition containing components (A) and (B).
The composition of the invention possesses pharmacological activity in animals and are therefore useful as pharmaceuticals, e.g. for therapy. In particular, the composition of the invention is useful as a calcium-antagonist, as indicated in standard tests, e.g. as follows:
An inhibition of the calcium-induced contraction of isolated dog coronary arteries suspended in a depolarizing solution is observed at a concentration of about 10-10 M to about 10-8 M of active agent (A) (method of Godfraind and Kaba, Brit. J. Pharm. 36 [1969] 549-560).
The composition containing components (A) and (B) is additionally useful as a β-adrenoceptor blocking agent as indicated in the following standard test.
In the isolated, spontaneously-beating guinea pig atrium (method of K. Saameli, Helv. Physiol. Acta [1967] CR 219-CR 221) inhibition of the positive inotropic effect of adrenaline is observed at a bath concentration of about 10-9 to about 10-6 M of active agent (B). The composition containing components (A) and (C) in addition to its calcium-antagonistic effect is useful as an arterial and venous smooth muscle relaxing agent as indicated in the hemodynamic standard test with the open chest cat in the form of a reduction of preload and afterload.
The composition containing component (A) and component (B) and/or component (C) exhibits antihypertensive activity, as indicated by a blood pressure lowering activity in standard tests.
For example, the composition exhibits a blood pressure lowering effect in the Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol. and Med. 57, 104 (1944)] as well as in tests carried out in a similar way in spontaneously hypertensive rats on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the composition.
The composition of the invention is therefore useful in the treatment of coronary heart disease, e.g. Angina pectoris, and hypertension.
For the above-mentioned uses the dosage will, of course, vary depending on the compounds employed, the mode of administration and the therapy desired. However, in general, satisfactory results are obtained when active agent (A), e.g. compound No. 22, is administered at a daily dosage of from about 0.01 mg to about 10 mg, particularly of about 0.1 to about 10 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day, or in sustained release form. For the larger mammal, the total daily dosage is in the range of from about 5 mg to about 200 mg, particularly from about 5 to about 100 mg, and dosage forms suitable for oral administration comprise from about 1.25 mg to about 100 mg, particularly from about 1.25 to about 50 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent. An indicated preferred weight ratio of active agent (A) to active agent (B), calculated on the free base moiety thereof, is from about 100:1 to about 1:10, particularly from about 100:1 to about 1:1, preferably from about 50:1 to about 5:1. Thus for compound No. 22 and LT a preferred range is from about 100:1 to about 1:1, especially about 50:1. For compound No. 22 and Pindolol a preferred range is from about 10:1 to about 1:10, particularly from about 10:1 to 1:1, especially about 7:1.
An indicated preferred weight ratio of component (A) to component (C), calculated on the free base of component (A), is from about 1:3 to about 10:1, particularly about 10:3. For compound No. 22 and isosorbide dinitrate the preferred range is from about 1:3 to about 10:3, particularly from about 1:3 to about 10:1, especially about 10:3. An indicated preferred weight ratio of component (A) to component (B) to component (C), calculated on the free bases of components (A) and (B), is from about 2:20 to about 0.2:24 to about 2:10.
For compound No. 22, Pindolol and isosorbide dinitrate, the preferred weight ratio is from about 2:20 to about 1:1.5 to about 2:6, particularly about 7:1.5:6.
For compound No. 22, LT and isosorbide dinitrate, the preferred weight ratio is about 70:2:60.
Conveniently components (A) and (B) and/or (C) are administered in the form of a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable acid addition salt form, and a β-adrenoceptor blocking agent in free base form or in pharmaceutically acceptable salt, e.g. acid addition salt form, and/or (C1-6)aliphatic alcohol ester of nitric acid, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution, such as an injectable solution, or a tablet.
It has now been found that the composition of the invention surprisingly does not lead to the unfavourable effects that can be expected on the basis of the components (A), (B) and (C) when taken alone. For compositions containing components (A) and (B), surprisingly no clinical observations can be made which indicate that the combination of a β-adrenergic blocking agent and a calcium-antagonist generally may be highly dangerous.
It is known that β-adrenergic blocking agents as well as standard calcium antagonists such as Verapamil and Nifedipine have some degree of cardiodepressant effect. It was therefore to be expected that their use in combination would be dangerous since an interaction in any heart that does not have much functional reserve might precipitate congestive heart failure. This condition of insufficient functional reserve is difficult to exclude completely and is common in patients with severe coronary heart disease.
It has therefore generally been stated that patients should not be simultaneously treated with a calcium antagonist and an adrenergic β-blocking agent. For the combination of Nifedipine and an adrenergic β-blocking agent very conflicting opinions have been expressed. Thus cardiovascular accidents have been reported in cases of concomittant administration of Verapamil and a β-blocking agent (Witchitz, S. et al., Nouv. Presse Med. 4 [1975] 337) and of Nifedipine and Atenolol (G. Motte et al., Nouv. Presse Med. 9 [1980] 379). Great caution in such simultaneous administration has generally been recommended (K. E. Wirth, Med. Welt 29 [1978] 413).
However, to our surprise it has now been found that the dosage of active agent (A) necessary to produce a significant cardiodepressant effect is several orders of magnitude higher than the dosage effective in producing a potent calcium antagonistic effect.
This observation was arrived at as follows:
First the potency of calcium antagonism was determined on coronary arteries in vitro:
Mongrel dogs of either sex weighing between 15 and 30 kg were anaesthetized by rapid i.v. injection of pentobarbitone (50 mg/kg) and killed by i.v. injection of 100 ml of air. The heart was removed and placed in a modified Krebs-Henseleit solution (mM): NaCl 118, KCl 4.7, MgSo4 1.2, CaCl2 2.5, KH2 PO4 1.2, NaHCO3 25, glucose 11, at 37� C., gassed with 95% O2 -5% CO2. Branches of the ventral interventricular artery (about 500 to 1000 μm outer diameter) were dissected and cut into helical strips, approximately 1 to 3 mm wide and 10 mm long.
The strips were suspended in 10 ml organ baths containing Krebs-Henseleit solution at 37� C. gassed continuously with 5% CO2 in oxygen. Changes in the tension of the strips were recorded isometrically with electromechanical transducers (Statham model UC 3) and a potentiometric recorder. At the beginning of the experiments the strips were stretched to an initial tension of 500 mg and then allowed to equilibrate for 120 to 180 minutes in the bathing medium. Thereafter the Krebs-Henseleit solution was replaced by a solution containing 100 mM KCl in equimolar replacement for NaCl. Cumulative response curves for CaCl2 were established, using the method described by Van Rossum, J. M., Arch. Intern. Pharmacodyn. 143 (1963) 299. The duration of exposure to a particular concentration depended on the time to reach equilibrium (the maximum response reached with that particular concentration). Thus there was no fixed interval at which the concentration of the agonist were increased. Component (A) or Verapamil was added 30 min. before the first administration of CaCl2. The effects were expressed as percentage of the preceding response to nM CaCl2. In all experiments at least one strip was used as control.
The pA2 values obtained were 10.5 for compound No. 22 and 7.8 for Verapamil.
Then the effects on contractility of paced guinea pig left arteria in vitro was measured:
Guinea pigs of either sex weighing 250 to 400 g were killed by a blow on their heads and the left atrium was rapidly dissected from the heart and suspended in a modified oxygenated Tyrode solution at 30� C. The preload was adjusted to 1 g, rectangular impulses of 10 msec. at a rate of 1 Hz were used for pacing through a platinum cathode attached to the lower end of the tissue. The tension developed was measured isometrically with a Statham UC 3 transducer.
Compound No. 22 or Verapamil was added to the bath in increasing amounts.
The highest dose of compound No. 22, 0.444 μM, reduced the contractile force to 56% of its baseline value. With Verapamil a comparable reduction was obtained at about 1.4 μM. These results should be compared with the results obtained on coronary arteries. In the case of compound No. 22 there is an about 10,000 fold difference between the concentration mentioned and the pA2 of Ca-antagonism whereas for Verapamil this difference is only about 100 fold. This shows that compound No. 22 is about 100 times less cardiodepressant than Verapamil for a similar degree of calcium antagonism. Due to this, selectively component (A) can be combined with agents that have negative influences on myocardial contractility, e.g. beta-blockers. Secondly, it has been found that a combination of active agent (A) with an active agent (B) has unexpected non-additive properties for these undesirable side-effects.
This observation was arrived at in the anaesthetized open chest cat as follows:
The microsphere method as described in 1967 by Rudolph, A. M. and Heymann, M. S. in Circ. Res. 21 (1967) 163 and modified by R. P. Hof, F. Wyler and G. Stalder, Basic Res. Cardial. 75, 747-756 (1980) was used. Cardiac output was calculated from the flow signal of an electromagnetic flow meter. Since the calibration factors indicated by the producer of the flow probes did not apply to cat aortic blood flow, these probes were calibrated at the end of each experiment with a microsphere injection, using the reference flow method of Buckberg, G. D. et al., J. of Applied Physiology 31 (1971), 598-604. This consists in sampling blood at a known flow rate into a syringe, which can be regarded as "an external organ".
This sampling is done during the time of microsphere circulation. The number of microspheres in the syringe is then determined and cardiac output can be calculated as follows:
CO=Qs �(Ni /Ns)
where CO is cardiac output, Qs is flow to the syringe, Ni is the number of spheres injected and Ns is the number of spheres in the syringe.
Cats of 2 to 4 kg of body weight were anaesthetized with chloralose urethane (43 and 430 mg/kg) and ventilated with a Loosco M.K.II infant ventilator with positive end-expiratory pressure. Catheters were inserted into the femoral artery and vein. The thorax was opened through the left fourth intercostal space, the aorta was freed of its adventitia and an electromagnetic flow probe was placed around it. The electromagnetic flow signal and its first derivative, acceleration of the blood in the aorta, mean aortic flow, phasic and mean aortic blood pressure, heart rate and mean right atrial pressure were recorded on a Beckmann R612 8 channel recorder. For flow measurements a Narco RT500 flowmeter was used. Differentiation was performed by a HSE 401 differentiator. The flow signal, which is a measurement of the velocity of blood in the aortic root was electronically integrated to obtain mean aortic flow. At the same time this signal was fed into the differentiator mentioned. The output of the differentiator, acceleration of blood in the aorta, is an indicator of myocardial function and was used instead of dp/dt (R. R. Rushmer, Circulation 29 [1964] 268, G. C. Van den Bos et al., Cardiovascular Research 7 [1973] 834), applied to cats by R. P. Hof and A. Hof, Journal of Pharmacological Methods, accepted for publication in 1981. At the end of the experiments the cats were dissected and the organs or samples of tissue placed in counting vials. The samples were counted in a Packard Mod. 9012 gamma counter with a 1024 channel pulse height analyser. Component (A), e.g. compound No. 22 was dissolved in polyethyleneglycol 400 1 ml plus ethanol 1 ml per milligram of active substance and administered intravenously at a dose of 43 μg/kg i.v. Coronary blood flow was markedly increased. The experiment was then repeated, with LT being infused intravenously at the dose of 50 μg/kg. After a stabilisation time of 60 minutes, compound No. 22 was then administered exactly as described above to obtain results strikingly similar to those without pretreatment. Thus, the magnitude of change and time course of all relevant general hemodynamic parameters indicative of myocardial contractility, such as acceleration of blood and cardiac output, were comparable in cats not pretreated and in cats pretreated with the β-adrenoceptor blocking agent, which means that the combination of components (A) and (B) is a non-additive one, since β-blockers are known to diminish coronary blood flow. The same was observed with regard to heart rate. The adequacy of betablockage was checked by comparing the effects of a test dose of isoproterenol 0.05 μg/kg before, to the effects of 0.1 μg/kg after the betablockade. All isoproterenol effects were completely or almost completely suppressed by the dose of LT used.
Additionally there can be established that a diminuation of the coronary blood flow, caused by a component (B), is compensated by a component (A) and an increase of the preload caused by component (A) is compensated by component (C). The simultaneous administration of an active agent (A) and an active agent (B) and/or (C) is therefore unexpectedly safe.
The combination of the invention can be used, surprisingly, without untoward cardiodepressant effect, e.g. in cases of hypertension and especially in cases of coronary disease that do not respond satisfactorily when either active agent (A) or active agent (B) or active agent (C) is administered alone.
It is to be appreciated that the beneficial effects of the combination may also be obtained when active agents (A) and (B) and/or (C) are administered separately, in analogous manner to that indicated above, e.g. in the form of pharmaceutical compositions. Thus a therapeutically effective amount of active agent (A) and of active agent (B) and/or (C) may be administered to a subject in need of such treatment.
If desired the active agents may be ordered in a pack to facilitate administration of a particular dosage regimen, e.g. in a particular order in a blister pack. A suitable composition may consist of a pack containing separately active agents (A) and (B) and/or (C) until required for concomitant administration, conveniently together with instructions for the concomitant administration of a predetermined amount of active agent (A) and a predetermined amount of active agent (B) and/or (C).
The following compositions may be formulated using standard encapsulating or tabletting techniques and are useful for oral administration 2 to 3 times a day for the treatment of coronary heart disease or hypertension.
______________________________________ CapsuleIngredient (mg)______________________________________Compound No. 22 (in free base form) 25.0Pindolol (in free base form) 5.0Lactose 158.0Polyvinyl pyrrolidone 7.5Magnesium Stearate 3.0Silica (colloidal) 1.5Total 200.0______________________________________
______________________________________ CapsuleIngredient (mg)______________________________________Compound No. 22 35.0Isosorbide dinitrate 30.0Pindolol 7.5Lactose 58.0Mannitol 150.0Corn Starch 15.0Silica (colloidal) 1.5Magnesium stearate 3.0Total 300.0______________________________________
______________________________________ CapsuleIngredient (mg)______________________________________Compound No. 22 35.0Isosorbide dinitrate 30.0Lactose 65.5Mannitol 150.0Corn Starch 15.0Silica (colloidal) 1.5Magnesium stearate 3.0Total 300.0______________________________________
______________________________________ TabletIngredient (mg)______________________________________Compound No. 22 (in free base form) 25.0Pindolol (in free base form) 5.0Polyvinylpyrrolidone 15.0Lactose 185.2Corn Starch 30.0Talcum 6.0Silica (colloidal) 0.8Magnesium stearate 3.0Total 270.0______________________________________
______________________________________ TabletIngredient (mg)______________________________________Compound No. 22 35.0Isosorbide dinitrate 30.0Pindolol 7.5Lactose 53.5Mannitol 150.0Corn Starch 15.0Polyvinylpyrrolidone K 30 6.0Magnesium stearate 3.0Total 300.0______________________________________
______________________________________ TabletIngredient (mg)______________________________________Compound No. 22 35.0Isosorbide dinitrate 30.0Lactose 61.0Mannitol 150.0Corn Starch 15.0Polyvinylpyrrolidone K 30 6.0Magnesium stearate 3.0Total 300.0______________________________________
Compound No. 22 in the formulations of Examples 1-6 may be replaced by compound No. 41 to obtain formulations for similar uses.
Compound No. 22 in the formulations of Examples 1-6 may be replaced by compound No. 51 to obtain formulations for similar uses.
Pindolol in the formulations of Examples 1, 2, 4 and 5 may be replaced by an amount of 1 mg of LT to obtain formulations for similar use.
|Cited Patent
|Filing date
|Publication date
|Oct 6, 1969
|Aug 27, 1974
|H Russek
|Treatment of angina pectoris with a long-acting vasodilating agent and a beta adrenergic receptor blocking agent
|May 1, 1974
|Oct 7, 1975
|1-(O-METHOXY-PHENOXY)-3-ISOPROPYL-AMINO-PROPANE-2-OL HCl and nitroglycerine coronary insufficiency composition
|Jan 26, 1976
|Sep 6, 1977
|Imperial Chemical Industries Limited
|6-Aryl-pyrrolo[1,2-a]Imidazole derivatives which possess anti-hypertensive activity
|Apr 12, 1977
|Mar 13, 1979
|Deutsche Gold Und Silber- Scheideanstalt Vormals Roessler
|Basic substituted xanthine derivatives
|Aoki, K., et al., Am. Heart J., 96(2), 218 226 (1978).
|Aoki, K., et al., Am. Heart J., 96(2), 218-226 (1978).
|Chemical Abstracts, 92:94,404j (1980) [Neumann, Eur. Pat. Appl. No. 0,150, 1/10/79].
|Chemical Abstracts, 92:94,404j (1980) Neumann, Eur. Pat. Appl. No. 0,150, 1/10/79 .
|Chemical Abstracts, 93:239,419a (1980) [Neumann, Ger. Offen. No. 2,949,464, 6/26/80].
|Chemical Abstracts, 93:239,419a (1980) Neumann, Ger. Offen. No. 2,949,464, 6/26/80 .
|Chemical Abstracts, 93:239,420u (1980) [Neumann, Ger. Offen. No. 2,949,491, 6/26/80].
|Chemical Abstracts, 93:239,420u (1980) Neumann, Ger. Offen. No. 2,949,491, 6/26/80 .
|Hiwatari, M., et al., Arzneim. Forsch./Drug. Res. 29(I), No. 2, 256 260 (1979).
|Hiwatari, M., et al., Arzneim.-Forsch./Drug. Res. 29(I), No. 2, 256-260 (1979).
|Kaufmann, R., et al., Advances in Blocker Therapy (Proc. from the 1st Inter. Bayer Blocker Symp. held in May, 1980) Exc. Med., pp. 111 119.
|Kaufmann, R., et al., Advances in β-Blocker Therapy (Proc. from the 1st Inter. Bayer β-Blocker Symp. held in May, 1980) Exc. Med., pp. 111-119.
|Mott , G., et al., La Nouvelle Presse Medicale, vol. 9, No. 6, pp. 379 and 380 (1980).
|Motte, G., et al., La Nouvelle Presse Medicale, vol. 9, No. 6, pp. 379 and 380 (1980).
|Wade, A. (Editor), The Extra Pharmacopoeia, 27th Ed., The Pharmaceutical Press, London, 1977, p. 1663.
|Citing Patent
|Filing date
|Publication date
|Mar 18, 1987
|Mar 21, 1989
|Schering Aktiengesellschaft
|Nifedipine combination preparation
|Sep 12, 1986
|May 22, 1990
|Aktiebolaget Hassle
|Controlled release beads having glass or silicon dioxide core
|Sep 29, 1988
|Jul 17, 1990
|Aktiebolaget Hassle
|Pharmaceutical preparation and a process for its preparation
|Feb 14, 1989
|Sep 18, 1990
|Aktiebolaget Hassle
|Pharmaceutical preparation
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Jan 22, 1985
Owner name: SANDOZ LTD., (A/K/A SANDOZ AG), 4002 BASLE, SWITZE
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text:
Chickamauga and Chattanooga National Military Park will host several commemorative activities for the 150th anniversary of the Battle of Chickamauga.
Numerous programs will take place on Chickamauga Battlefield throughout the weekend of Sept. 14 and 15, with the featured activity being a historic "walk through time." Visitors to this program will be propelled through various living history stations where they will learn about the occurrences in North Georgia between 1860 and 1864.
Due to limited space, tickets are required for this program. All tickets are free and are available at http://www.nps.gov/chch/planyourvisit/civil-war-timeline-and-special-programs.htm. In order to enable visitors the opportunity to be transported back in time, several road closures will be required throughout the park over the weekend. Since this is a walking tour, visitors may wish to bring portable chairs/stools for this program. There will be no seating along the timeline. However, it should be noted that chairs/stools will need to be carried from location to location. Additional visitors are expected this weekend and assistance to designated parking areas will be provided. Access to the timeline program will be via shuttle bus from the Chickamauga Battlefield Visitor Center
Additional programs will occur throughout the weekend. At the Visitor Center, activities include artillery demonstrations and music by the 8th Georgia Regimental Band. On Sunday, Sept. 15, at 2 p.m., a special musical performance by the combined local high school bands of Heritage High, Lakeview-Fort Oglethorpe High, and Ringgold High will take place at the park administrative building. For kids visiting the park over the weekend, there will be several interactive, hands-on activities located at an education tent managed by the park's Teacher-Ranger-Teachers.
At Snodgrass Hill, visitors will experience the battle from the perspective of Union soldiers portraying members of the 21st Ohio Infantry and Confederate soldiers portraying members of the 7th South Carolina Infantry. Visitors will be provided transportation to these special programs via a shuttle bus. Parking for these programs will be at the Recreation Field, off of Glenn-Kelly Road.
At the Wilder Brigade Monument, visitors are encouraged to experience the battle action as living historians portraying Wilder's Brigade of mounted infantry demonstrate the intensity of fighting with the Spencer Repeating Rifle. These programs will be conducted at 9 a.m., 11 a.m., 1 p.m., and 3 p.m.
Visitors will also have the opportunity to learn about the ultimate moment of the battle – the Confederate breakthrough – by participating in walking tours of Confederate Lieutenant General James Longstreet's battle-deciding assault on the Union's line. Tours will take place both days at 9:30 a.m., 12:30 p.m., and 2:30 p.m. Parking for this program will be located at the intersection of Glenn-Kelly and Dyer Roads.
Throughout the weekend, Eastern National Bookstore will be hosting various authors inside the Chickamauga Battlefield Visitor Center. These authors will meet visitors and conduct book signings.
All programs will be conducted rain or shine. Most parking will take place in fields throughout the park. In the event of inclement weather, mired vehicles may need to be towed at the owner's expense.
For additional information concerning 150th anniversary programs at Chickamauga and Chattanooga National Military Park, please visit http://www.nps.gov/chch/planyourvisit/150th-anniversary-of-the-campaign-for-chattanooga.htm
June 24, 2016
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A 50-year-old man died in a house fire in Red Bank early Friday morning after the homeowner said he was awakened by popping sounds. Red Bank Police Chief Tim Christol said the case is being considered an arson/suicide. He said, " At approximately 12:30 a.m., the Red Bank Fire and Police Departments responded to a residential fire at 604 Bitsy Lane where they discovered a body ... (click for more)
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In the days following the horrifying massacre of 50 people at an Orlando nightclub, several of the crazies in the media have dashed about trying to prove how easy it is to obtain an assault weapon. Some guy in Philadelphia claims he bought one in seven minutes when, in fact, we would all have been better served if he had written how long it took him to get a psychiatric exam and ... (click for more)

subset: commoncrawl


text:
Explore the rich world of Transformers Prime! Loaded with character animation models, concept art, interviews with the creators and more, Transformers: The Art of Prime provides and unprecendented look behind the scenes of bringing the TF movie universe to the small screen. Jim Sorenson (Transformers The Ark, Transformers AllSpark Almanac) brings this deep, vivid world into focus!
"Justice League": Exploring How Superman Returns (Again)
Film, Comic Books


text:
Walker signs bill affecting Medicaid timing
Gov. Scott Walker has signed a bill affecting the timing of Medicaid coverage for some Wisconsin residents.
Walker signed the bill Thursday, two days after the state Legislature passed it.
The bill relates to a three-month coverage delay Walker requested, and the Legislature approved, last month. That pushed back from January until April when 77,000 people just above the federal poverty line will lose Medicaid coverage. It also pushed back by three months when 83,000 childless adults will begin receiving Medicaid.
Under the bill, anyone who qualifies for the BadgerCare Medicaid program could receive it through March 31 if they apply before Feb. 1. After that, if the applicant is above the federal poverty limit, they will be directed to seek federally subsidized private coverage through the online exchange instead.
Brewers 5, Nationals 3: Brewers power past Scherzer, Nationals
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Chef Jason Tofte to open second restaurant in downtown Waukesha
Sheriff Clarke calls on city to hire 400 new police officers
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text:
Freedom Ride 09/19/09
Published: Monday, September 21, 2009 at 2:45 p.m.
Last Modified: Monday, September 21, 2009 at 2:45 p.m.
This is just a few of the 92 motorcycles that signed up for the Freedom Ride on Saturday that left Mike Bruno's Harley Davidson Shop going to the Vetrans Memorial Park.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.
Comments are currently unavailable on this article


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I'm making client-server app and we've chosen Netty as a connection management framework. We use SSL TCP connections. As of now, the client is also being made on Java. But in future the project should support mobile devices: Android and iOS. The question is: how painful is to implement C++ or Objective C client connecting to Java server on Netty?
You could use CocoaAsyncSocket, I have used it as a client with server that implemented in Netty using a protocol I have defined that will send and receive data as JSON and it's as good as Netty.
It really depends on what protocol you are using. If you define a protocol where you are sending serialised java objects as binary like this then you will trouble writing a client in a non JVM language. If you use a text based protocol (see here) or a HTTP based web-service then it will be easy.


text:
shovel ready jobs (Obama)<quoted text>
I agree that some of those streets should have been cleared to a degree. But take Capital Ave for instance, that road is like a one lane road any other time during the year. When cars are parked on both side you can BARELY squeeze two cars through. How is a huge plow pushing 3 feet of snow suppose to do any sort of decent job.....
Blizzard a lesson for Bridgeport
There are 45 comments on the Connecticut Post story from Feb 19, 2013, titled Blizzard a lesson for Bridgeport. In it, Connecticut Post reports that:
Five of the men charged with shepherding the city through the heart of this month's blizzard and digging neighborhoods out from beneath 30 inches of snowfall pledged Tuesday night to do better.
Join the discussion below, or Read more at Connecticut Post.
#21 Feb 20, 2013
Since: Aug 10
Location hidden
#22 Feb 20, 2013
#21 is very true.
Since: Mar 11
Location hidden
#23 Feb 20, 2013
Good point, the question is whether they tried in a timely manner. Plow, no way. Bucket loader, it would be slow and tedious, but you have to simply go at it. Do you realize the entire city could have burned (I'm being 100% serious) and no emergency vehicle would have even gotten near where a fire was spreading.
They need a call list and a stack of money to bring in contractors when this happens. I do not believe they have that.
#24 Feb 20, 2013
I know you are not going to care what the rest of the country is saying about you schmucks who showed up to rip your mayor for something nobody had any control over... But here goes!!!
Whenever something happens to you poor bastards "out east"; that really messes up your precious-over-crowded cities, you start crying and bitching about how "unfair" or how you were personally treated with no regard. You know what? Nobody gives a shit about you or your worthless insignificant little lives !!!! Grow the hell up! Start taking responsibility for yourselves!!!! How in the hell can you blame your city leaders for something like this? Are you "fricken" brain dead? It is not about you! to the people who were on national TV complaining, Go $&#$! yourselves!
#25 Feb 20, 2013
Wow, thanks for sharing!
#26 Feb 20, 2013
My apartment house has a parking lot, but I do not have a car. You people who complain should sell your cars and take public transportation like I do. You will be helping the environment too. Stop complaining you losers
Since: Mar 11
Location hidden
#27 Feb 21, 2013
First off, I don't live in Bridgeport. Second, Bridgeport took an entire week to free up its streets, while most surrounding towns didn't. So there is a problem there. Can you comprehend that logic? Try.
#28 Feb 21, 2013
funny you guys said capitol ave. when i rented it was on capitol ave. there are cars parked on both sides forever, lots of multi family houses. but they did not clear any roads. i was shoveling at 10;30 pm i did not see or hear any plows going up and down main st when it was managable. if we got 20 inches between the hours of 10:30 and 7:30 am when i came back out, that could of been taken care of. however they did not plow at all during the storm and that is why we had this problem
if my job was to drive and plow during the storm i would have to do it.
#29 Feb 21, 2013
I was shoveling around that time also and didn't see a plow either. But I was still able to get out Saturday night if I wanted to. If cars are on both sides of the road that means you're losing roughly 10 to 12 feet of space to push the snow. Even with let's say, two feet of snow (20 inches is roughly two feet)where is all that snow going? you already push a foot and a half into the cars on the side, which means it's pretty much covering the car, which means it's so high that the snow can't get over it, which means it lands right back into the road...
Since: Mar 11
Location hidden
#30 Feb 21, 2013
I agree. If you sign up for a job that occasionally has a horrible side to it, thats what you signed up for. If you're a cop, you get shot at. If you're a surgeon, you have to watch people die. Etc. etc. If you're a plow driver, you might have to work all night.
#31 Feb 21, 2013
LOL, not to be a jerk but if the city was burning down, wouldn't it be hot enough for the snow to melt.... Just thought I'd be a wise a**.... Where is this stack of money coming from??? I know the residents don't want their taxes going up again.... The better question is, is what are they doing with the money in the first place??? I guess the people of Bpt think the money is being well spent seeing they keep voting in the same political party every time....
#32 Feb 21, 2013
well i guess we beat this subject to death.
what's next?
ahh, the squester!!!! on march 1st.
Since: Mar 11
Location hidden
#33 Feb 21, 2013
Think of it though- if a house fire started, it would have been left to burn. It could have literally started spreading roof to roof.
Your second question is spot on- bridgeport taxes are twice as high as surrounding towns, towns which removed the snow twice as fast. So looking at how the money is allocated is the key. I personally don't view raising taxes as a viable option. But then again, I'm not a democrat.
As for the average blue-state voter: those people would return democrats to office even if they put everyone in concentration camps. It's inexplicable from a logical standpoint. I've stopped even stressing about it because it's a lost cause.
Since: Aug 10
Location hidden
#34 Feb 21, 2013
Not yet, BPT.
Since: Mar 11
Location hidden
#35 Feb 21, 2013
That will be the republicans fault- no matter what.
#36 Feb 21, 2013
it's outta hand with the blame game. if this goes through , GOOD, we gotta cut back sooner or later. i'm beginning to think that these "crisis" that we go through are just a diversion to deflect from the lack of work that ANY of these politicians are doing.
#37 Feb 21, 2013
My apartment complex has a handicap ramp, but I don't have a wheelchair.
Since: Mar 11
Location hidden
#38 Feb 22, 2013
I doubt the cuts will be in any way sensible, though.
#39 Feb 22, 2013
storm coming this weekend.....
now it will be OVERKILL for these 4 inches........plows , sanders , salters, sparks shooting all over from the plows hitting the pavement..........should be amusing.
#41 Feb 22, 2013
But would it have made a difference if the plow was out at 10:30? My husband was shoveling at that time and when I got up a 5:00 the next morning, you couldn't even tell. The snow in the driveway and the walks was as high as the snow on the lawn. And we had already shoveled 3 times prior to the 10:30pm shoveling.
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text: Police: Argument over $20 turned violent on Seattle Street SHELBY- One man is in the hospital with a gunshot wound over a dispute for $20. On Sunday around 2 a.m. Shelby Police Department responded to 397 Seattle St., Shelby, in response to a shooting. When they arrived, they found Nelson Millard, 25, who lived at the apartment complex located on Seattle Street, suffering from a gunshot wound. He was transported to Carolinas HealthCare System- Cleveland. As officers investigated the scene, they discovered Millard had gotten into an altercation with a man identified as Rashawn Demetrius Dukes... Updated at 5:35 PM


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3 Comments
Realtime comments disabled
sheriefnahel 1807 days ago
Nice pic and great body
SilverLiningOK 1841 days ago
aka lying down game/facedowns/playing dead/extreme lying down - found on wiki. new to me as well !
Myoosli 1841 days ago
There's a loop somewhere, and here am I.....left out of it! :-P (No idea what the planking thing is about lol)


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WZ - Maintenance
I-66E from MM 60.0 to MM 61.0
On I-66 in the County of Fairfax from mile marker 60 to mile marker 61, motorists can expect potential delays in this area from 06/26/16 at 8:15 PM until 06/27/16 at 5:00 AM due to maintenance activities. The east right shoulder is a mobile closure. The west right shoulder is a mobile closure.


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Caixin OnlineFinance & EconomicsTop Stories Finance Regulator to Take Hard Look at Firms Waiting to List
Regulator to Take Hard Look at Firms Waiting to List
CSRC tells the 882 hopefuls to reexamine their financials for last year and vows to send teams to randomly chosen companies
(Beijing) – The securities regulator has ordered an unusually tough review of last year's financials for all IPO candidates in an effort to weed out unqualified applicants and enhance the others' information disclosure.
Reports from the 21st Century Business Herald say the review would be based on a policy the China Securities Regulatory Commission (CSRC) announced in December. It requires all companies waiting for the regulator's approval to go public to examine their financials for 2012 and submit the results before the end of March.
- CIC Announces Appointment of Shanghai Vice Mayor as General Manager
- Maiden Flight
- China's Bullet Train Export Hopes Hit a Wall
- Forex Woes Force Qihoo to Extend Privatization Deadline
- Shanghai Cracks Down on Illegal Capital Flight
- Unseen Opportunities Created by 'Brexit'
- Points to Ponder when Building China's Future Megalopolis
- Closer Look: Putin's Latest State Visit Highlights Mutual Interests with China
- Shenzhen Bourse Queries Vanke's Hostile Suitors
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Riddick star Vin Diesel has posted a mind-boggling video that shows him lip-synching to Katy Perry's Dark Horse and dancing to Beyonce's Drunk In Love.
The 46-year-old (yes, that's right: 46-years!) actor today shared this 7-minute Dadaistic piece of beauty with his 63 million Facebook fans.
This dance performance is more awkward than that time when your favourite drunk relative decided to bust a move at the last family shenanigans.
Diesel sings, places his head creepily close to the camera before dancing his way through Juicy J's rap.
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Latest update June 30th, 2016 12:59 PM
Defeat Grove by 7 wickets in final
Muslim Youth Organisation (MYO), are the Bakewell sponsored Muslim Youth Organisation Inter-Jamaat round-robin 15-over softball cricket champions, following a comfortable 7 wicket win over Grove in the final played on Sunday last at the MYO ground, Woolford Avenue, Thomas Lands.
Man-of-the-Final, Richard Latiff turned in a sterling all-round display to lead MYO to a sweet victory. Latiff first grabbed 3 wickets with 2 each for team mates Shaheed Gittens and Bilal Haslim, as Grove, who batted first were limited to 146-9 off their allotted overs.
For Grove, Shafeek Ishmael slammed 62, spiced with 8 sixes and a solitary boundary, Ameer Khan chipped in with 26 (3×6).
MYO in reply knocked off the required runs for victory, losing a mere 3 wickets. Latiff fell one short of 50, clearing the boundary 4 times and hit a similar amount of fours. Shaheed Gittens backed up with 32 (2×6 & 3×4).
In the semi-finals which were contested also on Sunday, Grove got past Farm 'B' while MYO took care of Farm 'A' who placed 3rd overall. Vivian Bissoon of Farm 'A' copped both the batsman scoring the most runs and bowler claiming the most wickets awards. Shazim Mohammed of Triumph Jamaat was rewarded for scoring the highest individual score of 88 against Diamond New Scheme.
The bowler with the best figures was Naeem Khalil of Cornelia Ida, who took 5-8 against Lusignan.
Meanwhile, another competition organised by the MYO and sponsored by the Trophy Stall (10 overs tapeball) is expected to commence shortly.
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Jun 30, 2016Displaying the tenacity of champions, Christianburg / Wismar rebounded from a dismal first half performance to escape with a 2-0 win over a determined New Silver City Secoindary to advance to the...
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In Guyana during the Burnham era, there was a song called, "Follow De Leadaah." It was a kind of glorification of... more
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By Sir Ronald Sanders The 12 English-speaking independent countries of the Caribbean Community (CARICOM) have at the... more
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Proview creditor calls for bankruptcy as iPad trademark suit drags onAs the legal battle between Proview and Apple over the iPad trademark in China continues, one creditor has become unwilling to wait for a settlement and has applied to have the ailing monitor maker declared bankrupt.
The Associated Press reports that Fubon Insurance, which is owed $8.68 million by Proview, is seeking to have the company liquidated. A Chinese official, who identified himself only by his surname, in Shenzhen said an announcement about the bankruptcy will come soon.
"It's a sensitive case in a sensitive period of time, so we won't comment or release information while we will have an announcement in the near future," he said.
Ma Dongxiao, a lawyer for Proview, assured that any financial problems the company is experiencing would not affect the ongoing trademark case. Apple is currently appealing a lower court decision that ruled in favor of Proview.
According to reports out of mainland China, Proview had requested that Fubon wait until it had resolved its complaint against Apple, but Fubon rejected the request. A lawyer for the insurance company reportedly said that her client was not convinced that any compensation payments from Apple would be enough for Proview to pay back its debts, which are said to be barely covered by its current assets.
Recent profiles of Proview have characterized it as being on its death bed. The company, which is at risk of being delisted from the Hong Kong Stock Exchange, formerly made computer monitors, but its main business now comes from LED street lights. Owner Yang Long-san has said that a win against Apple would help him rebuild the company and "overtake" its competitors.
"No thoroughfare" sign at a former Proview plant. | Credit: Caixin
Proview has been vocal about its interest in negotiating a settlement with Apple, but, as of last week, the two companies had yet to initiate formal negotiations. Apple continues to insist that it is the rightful owner of the Chinese iPad trademark through a deal that took place in 2009.
Apple has threatened Proview with a defamation countersuit over allegations that the company has made false or misleading public statements about the trademark suit. Proview has responded by accusing Apple of fraud and unfair competition because the iPad maker used an intermediary to negotiate the deal for the trademark.
On Topic: lawsuits
- Apple's FaceTime subject of renewed VoIP patent infringement lawsuit
- Judge tosses lawsuit over 'Error 53' triggered by Touch ID repairs
- Apple customers to receive $400M iBooks settlement payments on Tuesday
- Apple's Messages target of new Uniloc patent suit
- DOJ urges Supreme Court to return Apple vs. Samsung patent case to lower court


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EarphoneSolutions offers $30 coupon for iLoungers
EarphoneSolutions has issued a new $30 coupon code (IPODLOUNGEFREE30) to be used on any purchase of $99 or more. This is an exclusive offer for iLounge readers and can be used to save on all highend earphones for the iPod. EarphoneSolutions is an authorized Etymotic and Shure dealer. The coupon cannot be combined with any other offer.
Related Stories
- Target offering $50 discount on iPhone 4, 4S
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- Sam's Club stores offering iPhone 4 for $147 this week? (Updated)
- Apple TV available through Dec. 16 for $80
I used that site and the shipping is great. I got the ER-6i
Posted by ipodman715 on November 12, 2004 at 5:12 PM (CST)
er-6i's rock!
Posted by todd2fst4u on November 12, 2004 at 9:43 PM (CST)
wow, that is great.. but can anyone tell me where to enter the coupon code?
Posted by Gentleman_finn on November 13, 2004 at 3:27 AM (CST)
You enter it on the same page where you enter the credit card #. It's at the bottom under
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If you have a coupon that can be redeemed from EarphoneSolutions.com, please enter the offer code in the box below."
Posted by ipodman715 on November 14, 2004 at 11:26 AM (CST)
I tried the code for the Etymotic 6i, it refused to accept it, probably because they already have $30 of the list price?
Posted by theigster on November 23, 2004 at 9:05 PM (CST)
Can u use the coupon with a pricematch? Like if I price matched something and entered the coupon would I get an even bigger discount?
Posted by Havo on February 2, 2005 at 1:02 PM (CST)
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Coco Rocha and Alexa Chung lead the fashion pack at the star-studded pop-up store launch for designer Christian Siriano's debut fragrance, Silhouette
A who's who of the modelling world needed no incentive to come out in droves for the launch of designer Christian Siriano's debut fragrance at his pop-up store in New York's Meatpacking District on Wednesday night.
With in-demand Canadian beauty Coco Rocha the stunning face of his Silhouette perfume, the 25-year-old was front and centre, happily posing up a storm in front of the giant ad campaign featuring her gorgeous self clad in one of Siriano's extravagant creations.
But she was far from the only fashionista lending her support to the latest venture from the celebrity-adored designer, who shot to fame after winning the fourth season of Project Runway, with the likes of British It girl Alexa Chung also making a stylish arrival.
Dressed to impress! Model Coco Rocha went for all-out glamour as she attended the launch of designer Christian Siriano's fragrance pop-up store in New York's Meatpacking District on Wednesday night, of which she is the stunning face of his debut fragrance Silhouette
The 30-year-old displayed her signature quirky yet oh-so-cool style in a white shift dress that was given an ethereal quality covered in what appeared to be ostrich feathers.
Her chunky black patent leather ankle boots and small clutch which was a miniature suitcase were the perfect contrast to the otherwise delicate look.
Her glossy chestnut locks were styled in soft waves, with a wispy fringe framing her stunning face, which was beautifully made up with a golden base, soft pink on her cheeks and lips and a swipe
of mascara.
Coco, meanwhile, went for all-out glam in a fitted knee-length black and white patterned frock featuring three-quarter sleeves.
Picture-perfect: The statuesque Canadian beauty displayed her enviably toned physique in a fitted black and white patterned knee-length frock featuring three-quarter sleeves, paired with black pumps, her dark red locks slicked back into a chignon, her make-up featuring dramatic smoky eyes and plum lips
Ethereal: British It girl Alexa Chung was a vision in a white shift dress covered with what appeared to be ostrich feathers, paired with contrasting chunky black patent leather ankle boots and a small black suitcase clutch
A pair of classic black pumps and small black stud earrings brought the look together, while her long dark red tresses were slicked down and pulled back into a chignon with a heavy off-centre parting.
Her make-up was flawlessly applied, with dark smoky eyes and deep plum lips for added drama.
The man of the hour managed not to be overshadowed by his famous pals, standing out from the crowd in black and silver patterned pants, a black T-shirt and electric blue blazer which was pushed up at the sleeves.
A pair of black and gold dress shoes completed his ensemble, while he wore his dark brown mane
in a sleek style with a sideswept fringe and donned his signature black-framed rectangular glasses.
The man of the hour! Christian Siriano cosied up to his A-list guest for a photo opportunity, standing out from the fashion pack in black and silver patterned pants, a black top and electric blue blazer, which was pushed up at the sleeves, teamed with black and gold dress shoes
His muse: The 28-year-old, who rose to fame after winning the fourth season of Project Runway, posed up a storm with 25-year-old Coco in front of the stunning ad campaign for his debut fragrance
One-of-a-kind: Actress Mena Suvari opted for a rather unusual black V-neck belted wrap dress featuring a black brocade train at the back that finished at mid-calf and a short modesty flap in the same fabric at the front
Actress Mena Suvari also made an appearance at the launch party, showing off her own quirky style in an unusual black creation.
The V-neck, sleeveless wrap number featured a belted waist but had the rather unusual added adornment of a black brocade train hanging off the back that came down to mid-calf and a short modesty flap at the front in the same material.
Orange Is The New Black star Jackie Cruz was a vision in her deep gold textured crocodile-skin high-waisted skirt featuring a slit up one leg and a matching blazer, which she shrugged on in a cape-like manner over her shoulders.
Dressed to thrill! Orange Is The New Black star Jackie Cruz was a vision in her deep gold crocodile-skin high-waisted skirt featuring a slit up one leg, a matching blazer and a black and white patterned crop top
'50s chic: Actress Marisa Tomei covered up in an ankle-length black and white patterned floaty skirt, a black top and dark green half-sleeve leather jacket, paired with black pointy pumps
Friends in high places: The talented young designer has fast become a hit in the celebrity world with his gorgeous, flattering and feminine designs synonymous with high-end luxury
A black and white patterned crop top and a pair of black patterned heels featuring a gold T-bar completed her striking look.
Following the pop-up store's star-studded opening night, it will be open to the public for a limited time only from September 4 to 21.
Fans of the talented 28-year-old designer can snap up products including the Silhouette fragrance, bath products and candles while being entertained by a video and art installation.
Effortlessly chic: Atlanta de Cadenet - the daughter of British photographer Amanda de Cadenet and Duran Duran bassist John Taylor - opted for classic black in a flirty short dress black suede Mary Jane's
Outstanding: Former Dexter actress Nicole LaLiberte paired a sleek cream maxi-skirt with a white blouse that was tied at the waist and a shiny blush sequinned jacket that was draped over her shoulders
A standout: Model Anna Schilling was unmissable in a colourful striped shirt and matching linen pants
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The photo of the Bird of Paradise was taken at a friends place. I used a Canon 600D with a 55-250mm lens. Northern rivers area of NSW Australia.
crane lily bird of paradise
Congratulations on being featured in this week's all about flowers. hugs Hilaryxxx
Thank you so much for your lovely comment Hilary. xx
CONGRATULATIONS! Your beautiful image is featured in All Glorious Lilies on January 8, 2014. Superb work! FAVE:>).
You can see your announcement and view all the features HERE.-
That is so lovely to be featured in All Glorious Lilies, thank you!
These flowers are truly amazing…..excellent photo!
Thank you very much for your lovely comments.
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