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si multe altele au la baza aceeasi traducere.

Sper ca am fost de folos

Dupa parerea ema, toate site-urile de tradus au aceeasi traducere.

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Eu de obicei traduc cu freakz. dar toate site-urile de tradus au la baza aceeasi baza de date... adica aceeasi traducere

Nici unu nu cred ca e exact
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Captopril background review
Introduction
Captopril is an oral drug, used for treating high blood pressure, heart failure, and for preventing kidney failure due to high blood pressure and diabetes. It has high water solubility and is readily absorbed after oral administration, 60–75% of the dose being absorbed and peak plasma concentrations are achieved within 1 h. (Clarke's Analysis of Drugs and Poisons 4th).
Captopril is an angiotensin I-converting enzyme inhibitor (Liebau G., Captopril in congestive heart failure, Klinische Wochenschrift, 1982: 60: 107–113).
That has been widely used for the treatment of hypertension. This drug acts orally and the dosage used ranges from 50 mg to 150 mg per day. With a single oral dose, its maximum hemodynamic effect is observed after 45–90 minutes. (Liebau G., Captopril in congestive heart failure, Klinische Wochenschrift, 1982: 60: 107–113).

Mechanism of Action of Captopril:

The mechanism of action this drug is not well-known. The main effect of hypertension appears after the suppression of angiotension_renin system. Also, there is no relation between angoitension_ renin system and the drug response. Renin is an enzyme that is produced by the renal system after producing this enzyme it will be in the blood stream after corporation with plasma globulin substrate that in the end result in the angiotensin I will be formed after awhile will be converted to angiotensin II by the effect of angiotensin-converting enzyme (ACE) to produce angiotensin II that is well known as effective vasoconstrictor agent as shown in figure (1)

Figure 1 Renin _angiotensin system
Angiotensin II will play a role in activating the secretion of aldosterone from the adrenal cortex, that in the final result will participate with sodium and fluid retention. Sodium will play role in increasing the contractility of cardiac muscles that make cardiac output increased, also water and salt retention will play a role as circulating volume will be increased and the perfusion of juxtaglomerular apparatus also increased.




Captopril is considered as a preventive factor that will block the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyl dipeptidase carboxy hydrolase.
ACE is related to bradykinin, the job of captopril act to interfere with the damaging of the vasodepressor peptide, bradykinin. Increased percentage of bradykinin or prostaglandin E2 is also having a connection with the effect of captopril.
The main role of captopril is to inhibit ACE that in the end will increase plasma angiotensin II in the same time plasma _renin action, the result is the loss if negative feedback on renin-producing in the circulation system that caused by reducing the level of angiotensin II, this reduction will make the level of aldosterone secretion will be decreased, in the end, the level serum potassium, sodium and fluid will increase.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood (Physicians GenRx, 1997 p 306)
Captopril has other pharmacological unknown effects on 72 kDa type IV collagenase, which targeted on Zinc ion binding.
Also, there are new recently discovered pharmacological actions of captopril for playing a role on an enzyme called (Ubiquitous metalloproteinase )that is involved in diverse functions such as remodelling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several non matrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also, cleaves KISS at a Gly. (Brower GL, Levick SP, Janicki JS: Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodelling in a rat model of heart failure. Am J Physiol Heart Circ Physiol. 2007 Jun; 292 (6): H3057-64. Epub 2007 Feb 16. ).

Also, captopril, has another unknown pharmacological action on Matrix metalloproteinase-9 that May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. (Reinhardt D, Sigusch HH, Hesse J, Tyagi SC, Korfer R, Figulla HR: Cardiac remodelling in end-stage heart failure: up-regulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart. 2002 Nov; 88 (5): 525-30)





Pharmacokinetics of captopril
Absorption:
After oral use of captopril, there will be rapid absorption happens with peak plasma level about one hour. This peak level affected by the presence of food in the GIT that will reduce the absorption to 40 percent that is why captopril should be taken one hour before food.
The minimal absorption rate is 75 percent this makes captopril with less absorption that leads to low permeability. More than 95 percent of this absorption drug will be eliminated in urine (50 unchanged drugs).
On the other hand 25 to 30 percent of captopril is bound to plasma proteins. And the half-life of this drug is less than 3 hours. The recovering of hypertension almost will occur after 60 to 90 minutes after oral use of captopril for elevated blood pressure patients.
For the drugs in general to have their therapeutic effects it will exert their receptors –drugs reactions.this binding depend on drugs concentrations near to these receptors and also this forms concentrations depends on physiochemical properties of these drugs. drugs must be dissolved in a site of absorption in GIT and then it will cross several membranes until it will arrive to receptors site, after drug distribute to several compartments model of body. small portion of these drugs will find conjugate to receptors.the transport as well as the distribution of the most drugs are influenced by passive diffusion, and this factor deepens on lipophilicity which depends on lipophilicity, since lipid barriers need to be crossed(Artursson, P. Application of Physicochemical Properties of Molecules to Predict Intestinal Permeability. AAPS Workshop on Permeability Definitions and Regulatory Standards, Arlington, VA, 17-19 Aug. 1998. ).
Drug-like captopril is I n addition to passive absorption of captopril from either the gastric or intestinal regions, there is the possibility of an active absorption process in the small intestine (Gastric and Intestinal Absorption of Captopril in acutely and chronically Treated Rats: Comparison with Salicylic Acid) (PETER J. WORLAND", OLAF H. DRUMMER, and BEVYN JARROTT April 4, 1984)
The most important factors that also effect passive diffusion is acid-base properties(which limits charge state of the molecule in PH of solution and also lipophilicity (which affect the distribution of the molecules between hydro-lipid membranes of the body) and solubility (that determines the concentrations of dosage forms of the molecules as it can be as a solution and also affect the rate of the molecules to dissolve from solid dosage forms) finally permeability of the membranes (which limits how molecules can rapidly cross membranes of the body).

Fick’s first law applied to a membrane shows that passive diffusion of a solute is the product of the diffusivity and the concentration gradient of the solute inside the membrane. (Flynn, G.L.; Yalkowsky, S.H.; Roseman, T.J. Mass Transport Phenomena and Models: Theoretical Concepts. J. Pharm. Sci., 1974, 63, 479-510)
These above challenges and factors, including ADME now is the main factors that affect production line in pharmaceutical industries, where these will decrease (attrition rate of drug developments) it has been accounted that approximately 30 percent of the molecules that arrived at development line rejected because of pharmacokinetics profile failure (ADME), more money is spent on compounds that fail than those that succeed (Taylor, P.J. Hydrophobic properties of drugs. In: Hansch, C.; Sammes, P.G.; Taylor, J.B. (Eds.) Comprehensive Medicinal Chemistry, Vol. 4, Pergamon: Oxford, 1990, p. 241-294., Halliday, R.G.; Drasco, A.L.; Lumley, C.E.; Walker, S.R. The Allocation of Resources for R&D in the World's Leading Pharmaceutical Companies. Res. Develop. Management, 1997, 27, 63-77.).
A large pharmaceutical company may screen 3 million molecules for biological activity each year. Some 30, 000 hits are made. Most of these molecules, however potent, do not have the right physical, metabolic, and safety properties. Large pharmaceutical companies can cope with about 30 molecules taken to develop each year (Physicochemical Profiling (Solubility, Permeability and Charge State) Alex Avdeef* pion INC, 5 Constitution Way, Woburn, MA 01801, USA).
Distribution:
Distributed into most body tissues except CNS; the drug is about 25% to 30% protein-bound Captopril (Pharmacist's Drug Handbook, P 536)
It clearly appears that it may distribute inside three compartment model. The end result of the volume of distribution is (2L/kg) that has led to the suggestion that captopril distributed in whole deep tissues.
Metabolism:
Captopril metabolized mainly in the liver is About 50% is metabolized in the liver. (Physician's 1992 Drug Handbook p170).
Excretion:
Excreted primarily in urine; small amounts are excreted in feces. Duration of effect is usually 2 to 6 hours, increasing with higher doses. Elimination half-life is less than 3 hours. Duration of action may be increased in patients with renal dysfunction (Springhouse Drug Reference p 322).
In down below table shows, all the ADME predicted factors of captopril
Property Value Probability
Human Intestinal Absorption + 0.97
Blood Brain Barrier + 0. 6467
Caco-2 permeable + 0. 8867
P-glycoprotein substrate Non-substrate 0. 6276
P-glycoprotein inhibitor I Non-inhibitor 0. 8448
P-glycoprotein inhibitor II Non-inhibitor 0. 7415
Renal organic cation transporter Non-inhibitor 0. 8073
CYP450 2C9 substrate Non-substrate 0. 7898
CYP450 2D6 substrate Substrate 0. 8918
CYP450 3A4 substrate Non-substrate 0. 6293
CYP450 1A2 substrate Non-inhibitor 0. 9045
CYP450 2C9 inhibitor Non-inhibitor 0. 9102
CYP450 2D6 inhibitor Non-inhibitor 0. 9537
CYP450 2C19 inhibitor Non-inhibitor 0. 9025
CYP450 3A4 inhibitor Non-inhibitor 0. 9049
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0. 8975
Ames test Non-AMES toxic 0. 8164
Carcinogenicity Non-carcinogens 0. 9434
Biodegradation Not ready biodegradable 0. 6577
Rat acute toxicity 1. 7403 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0. 9604
hERG inhibition (predictor II) Non-inhibitor 0. 9118

Table 1 predicated ADME for captopril from drugbank


Pharmacodynamic of captopril

Antihypertensive action Captopril inhibits ACE, preventing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Reduced formation of angiotensin II decreases peripheral arterial resistance, which results in decreased aldosterone secretion, thus reducing sodium and water retention and lowering blood pressure. (Spring House Drug Reference p322) which will lead to cardiac load reduced by acting to decrease systemic vascular resistance (afterload) as well as will decrease preload (pulmonary capillary pressure). These factors effacing by increasing cardiac output in patients with congestive heart failure (CHF).

Physiochemical properties of captopril:
Captopril is a White to off-white, crystalline powder in Crystals from ethyl acetate/hexane (Budavari, S. (Ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. , p. 289). And Slight acid-sulfhydryl odor and has a chemical structure as shown in figure 2.




Figure 2 chemical structure of captopril

Captopril has molecular Wight 217.285 and has chemical formula as C9H15NO3S


Also has chemical name as (2S) -1-[(2S) -2-Methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid.Captopril is free water soluble as well as in the ethanol logo for captopril is 0.34 (RANADIVE, SA-ET AL. (1992)).








Physicochemical property
Value
Water Solubility 4.52 mg/mL
logP 1.02
logP 0.73
logS -1.7
pKa (Strongest Acidic) 4.02
pKa (Strongest Basic) -1.2
Physiological Charge -1
Hydrogen Acceptor Count 3
Hydrogen Donor Count 2
Polar Surface Area 57.61 Å2
Rotatable Bond Count 3
Refractivity 54.63 m3•mol-1
Polarizability 21.72 Å3
Number of Rings 1
Bioavailability 1
Rule of Five Yes
Ghose Filter Yes
Veber's Rule Yes
MDDR-like Rule Yes














Table 2 captopril physiochemical values
Captopril significant interactions:
Captopril has many interactions with drugs and food, for drugs, have with Abacavir, Abiraterone, Acebutolol, Acetaminophen, Acetazolamide, Acetylsalicylic acid, and Aceclofenac.
With these above-motioned drugs, captopril may contribute either to increase serum concentrations of some of the mentioned drugs or by increase risk and severity of side effects of these drugs.
Captopril with food has significant interactions Captopril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia(Govoni & Hayes Drugs and Nursing Implications p288).
Food decreases absorption by 25 - 40%. The clinical significance is debatable.

Captopril current uses in the emergency department as sublingually (unlicensed use):
Captopril currently used in the emergency room to treat hypertension urgencies that will give effect in 10 to 15 minutes after given sublingually, but unacceptable by patients because of the bitter taste of captopril.
There are new studies and trials about captopril to use as sublingually, but not approved use until now and still need to design emergent and fast dissolve tablet of captopril to solve the problem of hypertensive emergent crises.

For example literature has been published in title (Sublingual vs. Oral Captopril in Hypertensive Crisis Adnan Kaya, MD∗,, Mustafa Adem Tatlisu, MD∗, Department of Cardiology, Dr. Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey 2015) has been concluded that sublingual captopril was found to decrease BP more efficiently in the first 30 min, but this difference equalized at 60 min.

Captopril recently used as an oral and sublingual form to treat hypertensive urgencies. The dosage range from 6.25 to 50 mg An initial effect is seen within approximately 5 to 15 minutes of administration, reaching a maximum reduction of BP within 30 minutes (Bender S, Filippone J, Heitz S, Bisognano J. A systematic approach to hypertensive urgencies and emergencies. Curr Hypertens Rev. 2005; 1:275-281. ).

Current researchers regard permeability enhancing methods for captopril:
As clearly known that captopril, has a low permeability that makes the drug to get low bioavailability and to be effective after 2 to 3 hours after oral absorption our current goal is to design the drug to make it more permeable and more bioavailable and have a fast onset of action to be available in an emergency to cure the problem of hypertensive crises urgencies.
There are many methods to do so, but the most effective and reliable method is to use permeability enhancer, There are a number of penetration enhancers known to influence the permeability of drugs across epithelial membranes [for a recent review see Walker, R.B. And Smith, E.W., Advanced Drug Delivery Reviews 1996, 18, 295-301).
Cyclodextrins and their derivatives have found extensive application as solubilizers and stabilizers due to their ability to form inclusion complexes with a wide variety of compounds [J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press) and (J. Szejtli & K-H Froemming, Cyclodextrins in Pharmacy, Kluwer Academic Press).
Cyclodextrins have been used to enhance intestinal absorption of drugs primarily through increasing the solubility. Recently, Cyclodextrins have been shown to have positive and negative effects on the transdermal penetration of drugs (see Lofton, T. Et al, International Journal of Pharmaceutics 1995, 115, 255-258), (Vollmer, U. Et al, International Journal of Pharmaceutics 1993, 99, 51-58), (Legendre, J.Y. Et al, European Journal of Pharmaceutical Sciences 1995, 3, 311-322) and (Vollmer, U. Et al, Journal of Pharmacy and Pharmacology 1994, 46, 19- 22).

Penetration enhancers may be used to promote the passage of the drug active substance across the mucosal membranes. Typical permeation enhancer’s fatty acids and their salts such as sodium caprate, beta cyclodextrin and its derivatives consider a preferable choice to do this job because it has multi-job at the same time as it will be discussed in the chapter of the inclusion complex of beta cyclodextrin

Summary:
As known now the most widely worldwide disease is hypertension, almost the elder patients have hypertension so to solve this. Captopril is one of the most effective drug used for this purpose and has potential effect to treat hypertensive crises, its better to be designed in a more acceptable way to solve the problem of permeability as well as bioavailability in the final result the drug will be more effective in accurate time that will help a lot of patients that they have hypertensive.
Hypothesis:
Captopril can be formulated in the way more effective that can be capsulated by permeability enhancer to overcome the problem of absorption to do so beta-cyclodextrin is the best choice to do this job, as inclusion complex.
Beta-cyclodextrin will solve the problem of bitter taste as well as the problem of bioavailability; all this will be discussed in details in the chapter of an inclusion complex.


Specific aims:
The first aim is to perform inclusion complex in an accurate molar ratio and to make all the chemical and physical analysis to prove the inclusion complex going well or not these analyses include The inclusion complex, the physical mixture and the processed β-CD will evaluate by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction, and Fourier-transform infrared spectroscopy (FT-IR) analyses.
The second aim is formulation part will formulate the inclusion complex of captopril to the suitable orodispersible tablet after performing formulation tests including friability and hardness.etc.
After that vitro analysis test, including dissolution tests and disintegration test. Etc.

Captopril background review
Introduction

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