What is determine
Determine Definition & Meaning - Merriam-Webster
de·ter·mine di-ˈtər-mən
dē-
transitive verb
1
a
: to fix conclusively or authoritatively
determine national policy
b
law : to decide by judicial sentence
determine a plea
c
: to settle or decide by choice of alternatives or possibilities
trying to determine the best time to go
d
: resolve
she determined to do better
2
a
: to fix the form, position, or character of beforehand : ordain
two points determine a straight line
the extent to which genetics determines one's personality
b
: to bring about as a result : regulate
demand determines the price
3
a
: to fix the boundaries of
b
: to limit in extent or scope
c
: to put or set an end to : terminate
determine an estate
4
: to find out or come to a decision about by investigation, reasoning, or calculation
determine the answer to the problem
determine a position at sea
5
biology : to bring about the determination (see determination sense 7) of
determine the fate of a cell
intransitive verb
1
: to come to a decision
had determined on becoming a doctor
2
: to come to an end or become void
Synonyms
- adjudge
- adjudicate
- arbitrate
- decide
- judge
- referee
- rule (on)
- settle
- umpire
See all Synonyms & Antonyms in Thesaurus
Example Sentences
The new policy will be determined by a special committee. The demand for a product determines its price. He believes that one's personality is determined mostly by genetics. An autopsy will be performed to determine the cause of death. They are unable to accurately determine the ship's position at this time. Scholars have determined that the book was written in the late 16th century. I am trying to determine what happened and when. They are determining if they should stay.
They determined to leave immediately. See More
Recent Examples on the Web An investigation is now underway to determine who was responsible for what was one of the deadliest attacks in the country in years. —Alexandra Meeks, CNN, 31 Jan. 2023 The argument that the tax revenue could be used to fund things like public education or infrastructure is not as pressing this legislative session, when lawmakers will determine how to spend a near $33 billion surplus.
—Dallas News, 30 Jan. 2023 But disputes remain over how to determine what level of cuts are fair and legal. —Kathleen Ronayne, Fortune, 29 Jan. 2023 Organic farming may reduce pollution and support soil health, but Curl said there isn’t enough evidence to determine if organic foods are healthier. —Stephanie Brown, Verywell Health, 27 Jan. 2023 Toxicology results are pending, which would determine whether the incidents involved fentanyl, a synthetic opioid that has led to widespread deaths among users across the country. —Michael Laris, Washington Post, 23 Jan. 2023 But to determine which are commercial and which aren’t is to think in relative terms.
—Los Angeles Times Staff, Los Angeles Times, 23 Jan. 2023 At the Good Housekeeping Institute, our Textiles Lab analysts test all kinds of fitness and workout gear to determine which options are worth the cash, including the best sports bras and the best leggings for every activity. —Amanda Constantine, Good Housekeeping, 18 Jan. 2023 Troopers encourage anyone with information about the case to call the Maryland Center for Missing and Unidentified Persons at 1-800-637-5437, as police continue to determine whether there are additional victims connected with the case. —Greg Wehner, Fox News, 15 Jan. 2023 See More
These example sentences are selected automatically from various online news sources to reflect current usage of the word 'determine.
' Views expressed in the examples do not represent the opinion of Merriam-Webster or its editors. Send us feedback.
Word History
Etymology
Middle English, from Anglo-French determiner, from Latin determinare, from de- + terminare to limit, from terminus boundary, limit — more at term entry 1
First Known Use
14th century, in the meaning defined at transitive sense 1a
Time Traveler
The first known use of determine was in the 14th century
See more words from the same century
Dictionary Entries Near
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“Determine.
” Merriam-Webster.com Dictionary, Merriam-Webster, https://www.merriam-webster.com/dictionary/determine. Accessed 15 Feb. 2023.
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Kids Definition
determine
verb
de·ter·mine di-ˈtər-mən
1
a
: to fix exactly or with authority
determine who will be president
b
: to have a strong influence on : govern
demand determines the price
2
: to find out or come to a decision
determine the answer to the problem
she determined to do better
3
: to be the cause of or reason for
a pupil's work determines his grade
Medical Definition
determine
transitive verb
de·ter·mine di-ˈtər-mən
1
a
: to obtain definite information about with regard to quantity, character, magnitude, or location
determine the ionic concentration
determine the creatinine in blood serum
b
: to discover the taxonomic position or the generic and specific names of
2
: to bring about the determination of
determine the fate of a cell
Legal Definition
determine
transitive verb
de·ter·mine
: to make a determination regarding
More from Merriam-Webster on
determineNglish: Translation of determine for Spanish Speakers
Britannica English: Translation of determine for Arabic Speakers
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[ dih-tur-min ]
/ dɪˈtɜr mɪn /
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See synonyms for: determine / determined / determines / determining on Thesaurus.com
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verb (used with object), de·ter·mined, de·ter·min·ing.
to conclude or ascertain, as after reasoning, observation, etc.
to settle or decide (a dispute, question, etc.) by an authoritative or conclusive decision.
to cause, affect, or control; fix or decide causally: Demand for a product usually determines supply.
to give direction or tendency to; impel.
Geometry. to fix the position of.
Logic. to limit (a notion) by adding differentiating characteristics.
Chiefly Law. to put an end to; terminate.
to lead or bring (a person) to a decision.
to decide upon.
verb (used without object), de·ter·mined, de·ter·min·ing.
to come to a decision or resolution; decide.
Chiefly Law. to come to an end.
OTHER WORDS FOR determine
1 verify.
2 resolve, adjust.
3 influence.
4 induce, lead, incline.
See synonyms for determine on Thesaurus.com
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Origin of determine
First recorded in 1350–1400; Middle English, from Old French determiner, from Latin dētermināre “to mark out and fix boundaries,” equivalent to dē- prefix indicating separation + termināre “to bound, limit”; see de-, terminate
OTHER WORDS FROM determine
in·ter·de·ter·mine, verb (used with object), in·ter·de·ter·mined, in·ter·de·ter·min·ing.qua·si-de·ter·mine, verb, qua·si-de·ter·mined, qua·si-de·ter·min·ing.re·de·ter·mine, verb, re·de·ter·mined, re·de·ter·min·ing.un·de·ter·min·ing, adjectiveWords nearby determine
determinant, determinate, determination, determinative, determinator, determine, determined, determiner, determinism, deterministic, deterred
Dictionary.com Unabridged Based on the Random House Unabridged Dictionary, © Random House, Inc. 2023
MORE ABOUT DETERMINE
What does
determine mean?Determine means to conclude, as after reasoning or observing, as in After considering all my options, I’ve determined which college I want to attend.
Generally, to determine something is to come to a conclusive decision from a place of authority on the subject.
Determine can also mean to cause or control, as in How much homework my teacher assigns will determine whether I can go to the game tonight.
Determine is also used to mean to give direction to, as a boss might determine what tasks their employees will do.
Example: I have determined that the cause of death was cardiac arrest.
Where does
determine come from?The first records of the term determine come from the 1300s. It ultimately comes from the Latin dētermināre, meaning “to mark out and fix boundaries.”
In legal terms, to determine something is to bring it to an end. The term is normally used at the end of a case or a lawsuit and implies the final conclusion of the conflict between parties. When the court determines something, it can rarely be disputed, except by going through the appeals process or opening a new case.
Did you know … ?
How is
determine used in real life?Determine is commonly used to talk about decisions being made.
i wanna believe the warriors draw straws in the locker room to determine who gets to drop the 50 piece that night
— Rob Perez (@WorldWideWob) October 30, 2018
Blood aint thicker than water and time dont determine loyalty, character does
— Nav (@beatsbynav) November 1, 2018
Age shouldn't really determine anything
— Nash Grier (@Nashgrier) August 11, 2015
Try using
determine!Which of the following is NOT a synonym for determine?
A. elect
B. ignore
C. fix
D. resolve
WHEN TO USE
What are other ways to say determine?
To determine is to conclude or ascertain something, as after reasoning or observation.
How is determine different from resolve and decide? Learn more on Thesaurus.com.
Words related to determine
complete, regulate, resolve, rule, ascertain, check, demonstrate, detect, establish, figure out, learn, see, tell, verify, work out, elect, fix, affect, control, decide
How to use determine in a sentence
The NHL will also now be analyzing clusters of positive test samples with whole genomic sequencing to determine specific coronavirus strains.
NHL adds game-day rapid testing to coronavirus protocols|Samantha Pell|February 12, 2021|Washington Post
The preps-to-pros movement was shut down in 2005, after the league determined that getting a Kobe Bryant or LeBron James a little earlier wasn’t worth sending scouts to high school gymnasiums.
An NBA experiment lets draft prospects skip college, stay home and get paid to play|Michael Lee|February 11, 2021|Washington Post
After determining the spoon’s maker and pattern, she typed that information into the Google “shopping” tab for a second search.
Replacing pieces of flatware or china can be a challenge. Here’s how to track them down.|Laura Daily|February 11, 2021|Washington Post
The new charges could carry a maximum sentence of nearly 30 years, more if it’s determined Keller’s actions resulted in any injuries.
Grand jury beefs up charges against Olympian Klete Keller related to Capitol riot|Rick Maese|February 11, 2021|Washington Post
Trying to determine which bid will maximize your campaign goals without blowing through your budget can be a tough balancing act.
Smart Bidding: Five ways machine learning improves PPC advertising|Gabrielle Sadeh|February 10, 2021|Search Engine Watch
That strategy has been used in some cases to help determine GMO policy.
Anti-Fluoriders Are The OG Anti-Vaxxers|Michael Schulson|July 27, 2016|DAILY BEAST
The fear of violence should not determine what one does or does not say.
Trolls and Martyrdom: Je Ne Suis Pas Charlie|Arthur Chu|January 9, 2015|DAILY BEAST
That makes it incredibly difficult to determine the effects of airstrikes, for example.
Pentagon Doesn’t Know How Many People It’s Killed in the ISIS War|Nancy A. Youssef|January 7, 2015|DAILY BEAST
Where the U.S. once depended on its own forces to determine who was military material, this time the Iraqis will decide.
Pentagon Insider on New Plan to Fight ISIS: ‘Of Course It’s Not Enough’|Nancy A. Youssef|January 6, 2015|DAILY BEAST
What does Bondi mean that clerks now should “determine how to proceed”?
The Back Alley, Low Blow-Ridden Fight to Stop Gay Marriage in Florida Is Finally Over|Jay Michaelson|January 5, 2015|DAILY BEAST
How well they have merited that Degree of Confidence is left to the impartial World to determine.
Remarks on a Pamphlet Lately published by the Rev. Mr. Maskelyne,|John Harrison
Its first appearance is not possible to determine and will probably remain unknown.
Antonio Stradivari|Horace William Petherick
Twenty baskets of it were obtained by the said miners to assay and investigate its nature, and determine what it might be.
The Philippine Islands, 1493-1898, Volume XX, 1621-1624|Various
It was with great disapprobation that he heard Napoleon accept Caulaincourt's advice, and determine to advance to Moscow.
Napoleon's Marshals|R. P. Dunn-Pattison
More generally the nature of the chattels conveyed determine largely the character of the description.
Putnam's Handy Law Book for the Layman|Albert Sidney Bolles
British Dictionary definitions for determine
determine
/ (dɪˈtɜːmɪn) /
verb
to settle or decide (an argument, question, etc) conclusively, as by referring to an authority
(tr) to ascertain or conclude, esp after observation or consideration
(tr) to shape or influence; give direction toexperience often determines ability
(tr) to fix in scope, extent, variety, etcthe river determined the edge of the property
to make or cause to make a decisionhe determined never to marry
(tr) logic to define or limit (a notion) by adding or requiring certain features or characteristics
(tr) geometry to fix or specify the position, form, or configuration oftwo points determine a line
mainly law to come or bring to an end, as an estate or interest in land
(tr) to decide (a legal action or dispute)
Word Origin for determine
C14: from Old French determiner, from Latin dētermināre to set boundaries to, from de- + termināre to limit; see terminate
Collins English Dictionary - Complete & Unabridged 2012 Digital Edition © William Collins Sons & Co.
Ltd. 1979, 1986 © HarperCollins Publishers 1998, 2000, 2003, 2005, 2006, 2007, 2009, 2012
Other Idioms and Phrases with determine
determine
see bound and determined.
The American Heritage® Idioms Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Harcourt Publishing Company. Published by Houghton Mifflin Harcourt Publishing Company.
What determines the efficacy and safety of local drugs for the treatment of hemorrhoidal disease
Conservative treatment of hemorrhoids includes the use of topical combined drugs (multicomponent ointments, creams or suppositories). In various combinations, they may contain anti-inflammatory, antimicrobial, sclerosing, anticoagulant agents, anesthetics, venotonics and reparants. The optimal composition of agents for the local treatment of hemorrhoids has not been precisely established and continues to be discussed. It remains not entirely clear whether the presence of anticoagulants, antibiotics or anesthetics in the composition has a significant effect on the therapeutic efficacy, whether they potentiate each other, whether they are necessary and, therefore, mandatory components of medical preparations [1].
This article covers the following topics:
- what underlies the therapeutic effects of combined drugs;
- what factors influence the strength and duration of local therapy;
- what combination of components in a local remedy, in the opinion of a pharmacologist, can be considered rational;
- Safety and tolerability of topical treatments.
Modern pharmacotherapy is targeted in nature (from the English "target" - target). This means that the effect of topical drugs is realized only after binding their active principle with specific structures - targets of action that are located in the effector cells of inflammation (lymphocytes, macrophages, neutrophils), microvasculature (endotheliocytes, myocytes), in the paravasal space, connective tissue , vascular bed (components of the coagulation system, complement system). If the active component of the local drug does not recognize and bind to its target of action, it cannot show its therapeutic potential, i.
e. in this case, one can count, at best, on a placebo effect.
The individual components of a targeted drug, as a rule, have one pronounced target of action, they "work" according to the principle: "one target - one primary pharmacological effect." The triad of effects characteristic of NSAIDs in the form of anti-inflammatory, analgesic and antipyretic actions is due to the participation of one target of action (cyclooxygenase enzyme) in various physiological responses. The wide range of pronounced pharmacological effects of corticosteroids, anti-inflammatory, immunosuppressive and anti-allergic effects is also based on the ability of the glucocorticoid molecule to find, recognize and form a complex with its target - corticosteroid receptors [2].
The use of combined drugs takes into account the simultaneous effect on several targets of action (multi-target drug, multi-target drug).
The principle of combination therapy, the combination of drugs, including those from different pharmacological groups (for example, a combination of an anesthetic and an anti-inflammatory agent), is a priority approach in the treatment of diseases caused by various pathogenetic mechanisms, such as CVD, acute and chronic hemorrhoids, their complications [ 3].
So, the therapeutic effect of a targeted drug for local therapy is determined by its pharmacological composition, the ability of individual components to find their molecular targets of action. Let us dwell on their more detailed characteristics.
Anti-inflammatory component. Suggests the use of glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs).
Glucocorticosteroids (GCS) are the most effective known anti-inflammatory drugs, they act on all phases of inflammation, various types of inflammatory response [4]. The effect of corticosteroids extends to the migration of leukocytes to the focus of inflammation, the reaction of the microvascular bed (decrease in tone, increase in permeability and exudation), the formation of pro-inflammatory mediators (metabolites of arachidonic acid (eicosanoids), histamine, kinins, chemotaxis factors), remodeling of connective tissue in the final stages of inflammation [ 5]. All of the listed sequential processes of inflammation of GCS have an inhibitory/suppressive effect, which determines their vasoconstrictor, anti-exudative effect.
At the same time, corticosteroids reduce the sensitivity of neutrophils and eosinophils to chemotactic factors, reduce cell infiltration of the inflammation focus.
What is the reason for such a wide range of anti-inflammatory activity of GCS ? The targets of their action, glucocorticoid receptors, are located in all types of cells (with the exception of stem cells). By binding to intracellular receptors, glucocorticosteroids increase the expression of genes responsible for consolidating the anti-inflammatory response (transactivation) [6]. The activity of genes involved in the production of pro-inflammatory proteins, on the contrary, is under the negative control of GCS, i.e., it is inhibited in their presence (transrepression). Given that corticosteroids regulate activity at the genomic level, their action does not develop immediately, on average, 2 hours after application, but has a long-term character (8-36 hours depending on the drug) [7].
Thus, a unique dual mechanism of inflammation suppression [8] (Fig.
1) belongs to the features of GCS.
Rice. 1. Two ways to suppress inflammation with the help of corticosteroids: the mechanisms of transactivation and transrepression (deciphering the designations in the text).
Mechanism of transactivation ( trans - activation ): stimulation of gene transcription and formation of anti-inflammatory proteins (lipocortin-1, inhibitor of nuclear factor kB (I-kB), neutral endopeptidase that destroys bradykinin and tachykinins, IL receptor antagonist -1). Mechanism of transrepression ( trans - repression ): hormone receptor complexes (in the form of a monomer) directly and through CBP molecules (cAMP-sensitive element-binding protein), interact with transcription factors (NF-kB, AP -1, etc.), which are activated under the influence of inflammatory mediators, oxidants and viruses. The result of this is the inhibition of transcription of "inflammatory" genes (trans-repression).
There is a decrease in the formation of proteins and peptides: inducible forms of COX-2, NOS, FL A2, pro-inflammatory cytokines (IL 1-6, TNF-alpha, GMCSF), chemokines (IL-8, eotaxin, RANTES, monocytic chemotactic protein, macrophage inflammatory protein 1-alpha), adhesion molecules (VCAM-1, ICAM-1).
As part of topical preparations, one of the GCS line is usually used: hydrocortisone, methylprednisolone, fluocortolone, betamethasone.
They differ in chemical structure, ability to be absorbed and reach the targets of action, resistance to metabolism. From a practical point of view, it is important to distinguish them by the strength of their anti-inflammatory action. According to the generally accepted European Miller-Monro classification, depending on the quantitative content in the preparation, fluocortolone and betamethasone belong to strong topical corticosteroids, the rest belong to the group of moderately strong or light topical steroids (Table 1).
Table 1.
Classification of topical steroids by potency [9, abbreviated]
Although this classification is based primarily on testing the relatively rapid vasoconstrictor activity of corticosteroid drugs, this test also takes into account corticosteroid absorption, affinity for receptors, and the rate of elimination of the steroid from the site of application.
What factors influence the strength and duration of action of topical corticosteroid therapy?
The main determinants that determine the activity of external corticosteroids include: 1) the chemical structure of the steroid: the strength of binding and the duration of the existence of the corticosteroid-receptor complex; 2) the concentration of the steroid in the preparation; 3) dosage form.
One of the decisive factors is the lipophilicity of the GCS molecule (Fig. 2). The higher the lipid solubility, the easier it is for GCS to penetrate the epithelial barriers of the mucous membrane or skin of the perianal region, the easier it is for GCS to enter the cell and find its targets - intracellular glucocorticoid receptors.
The higher the lipophilicity of GCS, the higher its affinity for biological tissues, and, consequently, the higher the local concentration of steroids [10, 11].
Rice. 2. Effect of the lipophilicity of the GCS molecule on the pharmacological properties of topical preparations containing GCS.
The strength of GCS binding to the receptor also directly correlates with the lipophilic properties of the corticosteroid molecule, since in the hydrophobic pocket of the receptor, it is easier for a non-polar GCS molecule to stay [12].
What are pharmacologists and chemists doing to enhance the lipophilic qualities of corticosteroids and affinity for receptors? Modernization of the GCS molecule, aimed at increasing the strength of the GCS, includes the introduction of a methyl radical (-CH 3 ), a halogen atom (chlorine or fluorine), addition of residues of organic acids (-acetate, -propionate, -butyrate, -pivalate, -furoate, etc.). Any of the listed upgrades increases the strength of the GCS.
Consider the result of transformations on the example of fluocortolone pivalate (Fig. 3). Unlike the original natural hormone corticosterone, which has low anti-inflammatory activity, fluocortolone pivalate is classified as a strong corticosteroid. It contains in its molecule, in comparison with the original corticosterone, a fluorine atom, a methyl radical in the 16-position, a pivalic acid residue (pivalate) in the 21-position.
Rice. Fig. 3. Structural changes in fluocortolone pivalate responsible for the increase in its anti-inflammatory activity compared to corticosterone: fluorine atom (1), methyl radical in C16 (2), pivalic (trimethylacetic) acid residue in C21 (3).
For comparison, let's look at the structural formula of prednisolone, a synthetic GCS of medium strength (Fig. 4). It differs from the precursor of hydrocortisone (cortisol) only by the presence of a double bond in the first aromatic ring, which leads to an increase in its affinity for GCS receptors, but does not sufficiently change the lipophilic properties of the molecule.
Rice. 4. Structural formula of prednisolone, a modification of the molecule in the form of a double bond (1), which distinguishes it from the original natural hormone.
The pharmacokinetic parameter commonly used to assess the duration of action of medicinal substances - the half-life from blood plasma (t ½ ), is of little use in relation to topical preparations. Thus, the plasma half-life of fluocortolone is about 100 minutes. Instead of this parameter for GCS, it is customary to use the biological half-life (biological half-life) - the time during which the drug substance loses half of its pharmacological activity.
Depending on the duration of action (Table 2), corticosteroids are divided into short-acting (8-12 hours), long-acting (12-36 hours) and ultra-long-acting (36-72 hours).
Table 2. Classification of GCS by duration of action [13]
Lipophilic glucocorticosteroid molecules tend to "retain" in the tissue compared to hydrophilic glucocorticosteroids with a moderate and mild effect [7].
In the instructions for the medical use of topical steroids for the treatment of hemorrhoids, you can find recommendations for 1-, 2- and 3-fold application of the drug during the day. On the first day of pharmacotherapy, in order to saturate the receptors and accelerate the onset of the development of the anti-inflammatory effect, a 2-fold dose is recommended. In the case of improvement in clinical symptoms, you can switch to a single dosing regimen of GCS.
Topical glucocorticoids: a balance between potency and safety.
The issue of increasing the safety of therapy is also the targeted chemical modification of the drug substance (“engineering the molecule”, engineering the molecule) [14]. An example confirming this thesis is the feature of the chemical structure of GCS fluocortolone pivalate.
Fluocortolone pivalate is a prodrug (Figure 5). Its activation occurs upon hydrolysis of the molecule with the release of active fluocortolone and pivalic (trimethylacetic) acid.
This reaction proceeds most intensively in the foci of inflammation, undamaged tissues are less metabolically active. It turns out that the pivalate residue "helps" to deliver the GCS to the site of action first, and then the fluocortolone molecule "gets rid" of pivalate. And all this happens most effectively in the zone of therapeutic action of GCS. Fluocortolone pivalate enters the systemic circulation mainly in the form of an inactive prodrug, which reduces the risk of a resorptive effect and increases the safety of therapy. After a single rectal application of 1 g of cream or administration of one suppository, the absorption of glucocorticosteroid was maximum 5% of the applied or administered amount of the drug.
Rice. 5. Chemical transformation of pharmacologically inactive (prodrug) fluocortolone pivalate into active GCS fluocortolone.
The most commonly prescribed NSAIDs are: indomethacin, ibuprofen, diclofenac, ketoprofen, bufexamak. Bufeksamak, according to the decision of the regulatory body (European Medical Agency) in 2010, was recommended for withdrawal from circulation due to allergic complications [15].
All NSAIDs have a limited spectrum of anti-inflammatory action and, unlike GCS, have not found application in dermatological practice. Their use in the treatment of hemorrhoids and its complications also does not have a high class of evidence in international clinical guidelines [16]. On the contrary, in the treatment of internal hemorrhoids, it is recommended to avoid taking NSAIDs, as they increase the risk of hemorrhagic complications.
Heparin. Among the indications for the appointment of local drugs with heparin can be found: external and internal hemorrhoids, thrombophlebitis of the hemorrhoidal veins of the anus, fistulas, eczema, itching in the anus, etc. [1].
A 2015 current review [17] analyzes available published data from a study of the efficacy and safety of topical anticoagulant therapy from January 1, 1990 to January 1, 2013.
The review authors identified a total of 43 studies, of which only one study focused on topical antithrombotic therapy for acute hemorrhoids [18].
This controlled study included 89 patients, 67 patients were treated with topical heparin paste, 22 patients in the control group were treated with a paste containing glycerol and magnesium sulfate. To 30 g of the original heparin ointment (200 IU sodium heparin/g ointment) was added 10 tablets containing the enzymes trypsin and chymotrypsin (in a ratio of 6:1, equivalent to 100,000 units of enzymatic activity). The resulting paste was applied 3 times a day to inflamed areas for 4 weeks. Treatment with heparin and enzymes has been found to improve healing and resolution of acute hemorrhoids, in 91% of patients noted a more pronounced weakening of the symptoms of the disease in comparison with traditional treatment. Side effects were observed in 9% of patients due to hypersensitivity to the paste, their treatment was discontinued. Based on the design of the study, it can be assumed that the use of heparin in combination with enzymes increases its bioavailability. At the same time, it should be noted a very high frequency of side effects and a long period of treatment (1 month).
Thus, it is not possible to evaluate the effectiveness of local anticoagulant therapy for hemorrhoids based on this study.
It is known to use a conductor (diethanolamine) as part of a topical preparation of heparin, which provides "active uniform transport of heparin molecules through the skin barrier" [19]. However, in the text of the article and the instructions for the medical use of the drug, there are no quantitative data on the parameters of the local and systemic pharmacokinetics of heparin.
The use of sodium heparin as part of local preparations conflicts with the pharmacokinetic properties of this compound [20]. The high electric charge of the heparin molecule, high molecular weight (average 14,000 daltons) - all this opposes the topical use of heparin. Therefore, heparin and its semisynthetic derivatives in the form of low molecular weight heparins (m.m. 2500-5000) are administered intravenously or s / c. The intramuscular route of administration is not indicated due to the high risk of hematoma formation.
Topical application of heparin as part of topical agents is difficult to interpret from the standpoint of rational pharmacology. The anticoagulant effect of heparin is based on the inactivation, in combination with antithrombin III, of blood coagulation factors (thrombin, activated factor X). Thus, the pharmacological properties of heparin directly depend on its ability to penetrate the hemorrhoids and bind the target of action of the blood plasma protein antithrombin III. There are no data on the pharmacokinetics of heparin when applied topically, and with them evidence that heparin molecules are able to reach the site of action at therapeutic concentrations. In violation of the integrity of the mucous membrane of the rectum, the skin in the anorectal region, the absorption of heparin increases, although it remains difficult to predict.
Sclerosing agents. Consider the example of lauromacrogol. According to the instructions for medical use, lauromacrogol has a sclerosing and local anesthetic effect [21].
Causes denaturation of proteins in endothelial cells, stimulates the formation of connective tissue inside the vessels within 7 days. Lauromacrogol is used as part of parenteral dosage forms, so the feasibility of using this component in local therapy requires further study.
Anesthetics. Anesthetics from the group of local anesthetics, as the name suggests, were developed and introduced into medical practice for the purpose of local anesthesia. Depending on the chemical nature, they are divided into anesthetics containing an ester bond and amide anesthetics. Essential anesthetics (procaine / novocaine, chlorprocaine, amethocaine) are rapidly metabolized, including by enzymes in blood plasma and cell cytoplasm. It is for them that an allergic reaction is more characteristic [22]. Amide anesthetics (lidocaine, bupivacaine, articaine, mepivacaine) are more resistant to hydrolysis, are metabolized mainly by the liver, and therefore have a longer period of action. An allergic reaction to lidocaine is much less common.
Targets of action of local anesthetics (LA) are sodium channels of nerve endings and nerve fibers. Due to the blockade of sodium entry, MA prevent the generation and conduction of nerve impulses, which underlies the analgesic effect of MA, their ability to suppress sensations of burning, itching. The onset of action of MA occurs quickly, within a few minutes, since it does not require the participation of the genome. The duration of the effect is about 1 hour, increasing to 1.5-2 hours if they are used in combination with a vasoconstrictor (most often with adrenaline).
Let us summarize the known data on the dependence of the pharmacological activity of local anesthetics on their structure [23].
Power of action. Lipid solubility is a major determinant of anesthetic power. The neuron membrane and the sheath of nerve fibers are a lipoprotein matrix consisting of 90% lipids and 10% proteins. As a result, chemicals with high lipophilicity more easily penetrate the membrane, so that fewer molecules are needed to block conduction, which leads to an increase in the strength of the MA effect.
Duration of anesthesia. The duration of anesthesia is mainly determined by the degree of protein binding to various local anesthetics. Much of the information on protein binding of local anesthetics has been obtained from studies that have studied the binding of MA to plasma proteins. Therefore, this indicator of the pharmacological activity of MA in the composition of antihemorrhoidal drugs is difficult to interpret, since they are poorly absorbed. Thus, lidocaine hydrochloride, unlike lidocaine, is absorbed more slowly, therefore, it acts longer (several hours) [24].
Apparently, the most significant when using MA as part of topical agents is the speed of onset of effect . The start of the conduction block is determined mainly by the pKa of the anesthetic, that is, the pH at which ionized and non-ionized forms of the compound are present in equal amounts. Since the uncharged form of the local anesthetic is primarily able to pass through the neural sheath and neural membrane, the onset of MA action will be directly related to the amount of drug that exists in the non-ionized form.
According to the speed of onset of the anesthetic effect, MAs are arranged in the following order:
lidocaine > bupivacaine > amethocaine > novocaine.
The combination of what components in a local remedy for the treatment of hemorrhoids can be considered rational?
One of the rational combinations of active substances in the composition of a topical preparation for the treatment of hemorrhoids is the combination of GCS and lidocaine hydrochloride. Let us examine the advantage of such a composition using the analgesic effect as an example.
The first effect of lidocaine hydrochloride is observed, which occurs a few minutes after the use of a rectal cream or suppository and lasts several hours. For the use of the corticosteroid component of the drug, the opposite temporal pattern is characteristic: a new portion of GCS will begin to act no earlier than after 2 hours, but the effect is maintained for an incomparably longer period (12-24 hours), since the effect of GCS develops gradually.
The use of a combination of corticosteroids and lidocaine hydrochloride has another pharmacodynamic advantage, since it acts on different parts of the nociceptive response. Lidocaine, as MA, prevents the occurrence and conduction of pain impulses in the CNS. GCS due to the anti-exudative effect and inhibition of the formation of nociceptive modulators (kinins, histamine, prostaglandins, tissue metabolites formed during inflammation) indirectly reduces the activity of nociceptive stimulation.
Safety and tolerability issues in combination topical treatment.
Fluocortolone, when applied topically, suppresses inflammatory and allergic reactions of the skin and relieves itching, burning and pain, reduces capillary dilatation, interstitial edema and tissue infiltration [25].
During the period of daily administration of 2 suppositories 3 times a day for 4 weeks, the content of fluocortolone in the blood plasma did not reach the level that has a systemic effect.
A 10-year post-registration clinical experience with a rectal cream and suppositories containing a combination of fluocortolone pivalate and lidocaine hydrochloride included a total of about 4.2 million patients and showed good tolerability of therapy. The topical combination preparation in the form of cream or suppositories was prescribed for the symptomatic treatment of rectal and perianal/anal inflammatory processes, including hemorrhoids, eczema in the anus, anal fissures and proctitis, as well as in pre- and postoperative treatment (i.e. hemorrhoidectomy). During this period, four reports of unwanted drug side effects were received, three of which related to cases of an allergic reaction with redness, vesicle formation, accompanied by itching. In a fourth case, a cream prescribed for rectal administration was also applied to the lower leg, resulting in contact dermatitis with superficial skin ulcers. All patients recovered.
Another example of the relationship between the chemical nature and the safety profile of therapy is the active component of combined local preparations - lidocaine hydrochloride.
Absorption and bioavailability of lidocaine after rectal administration of the cream and suppository is about 30 and 24%, respectively. The kinetics of absorption is characterized by its gradual penetration into the epithelium and underlying tissues. This significantly reduces the risk of systemic adverse effects of LA: hypotension, cardiac arrhythmias, central effects.
Each time a doctor prescribes a drug, the doctor balances the benefits and risks of drug treatment. How, using a known set of medicinal substances, to increase the effectiveness and safety of treatment? The presence of various dosage forms of local preparations in the form of gels, creams, ointments and suppositories allows you to choose the optimal remedy in each specific clinical case, depending on the form, nature of the course and stage of the disease [26]. A rational combination of active substances also improves the efficiency and tolerability of local therapy for hemorrhoids and its complications.
The authors declare no conflict of interest.
What defines our identity | PSYCHOLOGIES
Know thyself
This riddle in philosophy is called the problem of personal identity. It was first formulated explicitly by the English philosopher John Locke. In the 17th century, when Locke wrote his writings, it was believed that man is a "substance" - this is the word philosophers call that which can exist by itself. The question was only what kind of substance is it - material or non-material? Mortal body or immortal soul?
Locke thought the question was wrong. The matter of the body changes all the time - how can it be a guarantee of identity? No one has seen and will not see the soul - after all, it is, by definition, non-material and does not lend itself to scientific research. How do we know if our soul is the same or not?
To help the reader look at the problem differently, Locke made up a story.
Personality and character traits depend on the brain.His injuries and illnesses lead to the loss of personal qualities
Let us imagine that a certain prince wakes up one day and is surprised to find that he is in the body of a shoemaker. If the prince has retained all his memories and habits from his previous life in the palace, where he may well no longer be allowed in, we will consider him the same person, despite the change that has occurred.
Personal identity, from Locke's point of view, is the continuity of memory and character over time.
Since the 17th century, science has taken a huge step forward. Now we know that personality and character traits depend on the brain. His injuries and illnesses lead to the loss of personal qualities, and pills and drugs, affecting the functioning of the brain, affect our perception and behavior.
Does this mean that the problem of personal identity is solved? Another English philosopher, our contemporary Derek Parfit, does not think so. He came up with a different story.
Not a very distant future. Scientists have invented teleportation. The recipe is simple: at the starting point, a person enters a booth where the scanner records information about the position of each atom of his body. After scanning, the body is destroyed. Then this information is transmitted by radio to the receiving booth, where exactly the same body is assembled from improvised materials. The traveler feels only that he enters a cabin on Earth, loses consciousness for a second and comes to his senses already on Mars.
At first people are afraid to teleport. But there are enthusiasts who are ready to try. When they arrive at their destination, they report every time that the trip went great — it's much more convenient and cheaper than traditional spaceships. In society, the opinion is taking root that a person is just information.
Personal identity over time may not be so important - it is important that what we value and love continues to exist
But one day there is a failure.
When Derek Parfit presses the button in the teleporter booth, his body is properly scanned and the information is sent to Mars. However, after being scanned, Parfit's body is not destroyed, but remains on Earth. An earthling Parfit comes out of the cabin and learns about the trouble that happened to him.
No sooner does Parfit the earthling get used to the idea that he has a doppelganger than he receives new unpleasant news - his body was damaged during the scan. He is to die soon. Parfit the earthling is horrified. What does it matter to him that Parfit the Martian remains alive!
Still need to talk. They go on a video call, Parfit the Martian consoles Parfit the Earthman, promising that he will live his life the way they both planned in the past, that he will love their wife, raise children and write a book. At the end of the conversation, Parfit the Earthman is a little comforted, although he still cannot understand how he and this man on Mars, even if indistinguishable from him in nothing, can be the same person?
What is the moral of this story? The Parfit philosopher who wrote it suggests that identity over time may not be all that important—what matters is that what we value and love continues to exist.
