<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ellipsis and explain in detail? [/INST] The ellipsis ... (, also known informally as dot dot dot) is a series of dots that indicates an intentional omission of a word, sentence, or whole section from a text without altering its original meaning. The plural is ellipses. The term originates from the Ancient Greek: ἔλλειψις, élleipsis meaning leave out.Opinions differ as to how to render ellipses in printed material. According to The Chicago Manual of Style, it should consist of three periods, each separated from its neighbor by a non-breaking space: . . .. According to the AP Stylebook, the periods should be rendered with no space between them: .... A third option is to use the Unicode character U+2026 … HORIZONTAL ELLIPSIS.

Background
The ellipsis is also called a suspension point, points of ellipsis, periods of ellipsis, or (colloquially) "dot-dot-dot". Depending on their context and placement in a sentence, ellipses can indicate an unfinished thought, a leading statement, a slight pause, an echoing voice, or a nervous or awkward silence. Aposiopesis is the use of an ellipsis to trail off into silence—for example: "But I thought he was..." When placed at the end of a sentence, an ellipsis may be used to suggest melancholy or longing.The most common forms of an ellipsis include a row of three periods or full points ... or a precomposed triple-dot glyph, the horizontal ellipsis …. Style guides often have their own rules governing the use of ellipses. For example, The Chicago Manual of Style (Chicago style) recommends that an ellipsis be formed by typing three periods, each with a space on both sides  . . . , while the Associated Press Stylebook (AP style) puts the dots together, but retains a space before and after the group, thus:  ... . Whether an ellipsis at the end of a sentence needs a fourth dot to finish the sentence is a matter of debate; Chicago advises it, as does the Publication Manual of the American Psychological Association (APA style), while some other style guides do not; the Merriam-Webster Dictionary and related works treat this style as optional, saying that it "may" be used.When text is omitted following a sentence, a normal full stop (period) terminates the sentence, and then a separate three-dot ellipsis is commonly used to indicate one or more subsequent omitted sentences before continuing a longer quotation. Business Insider magazine suggests this style and it is also used in many academic journals. The Associated Press Stylebook favors this approach.

In writing
In her book on the ellipsis, Ellipsis in English Literature: Signs of Omission (Cambridge University Press, 2015), Anne Toner suggests that the first use of the punctuation in the English language dates to a 1588 translation of Terences Andria, by Maurice Kyffin. In this case, however, the ellipsis consists not of dots but of short dashes. "Subpuncting" of medieval manuscripts also denotes omitted meaning and may be related.Occasionally, it would be used in pulp fiction and other works of early 20th-century fiction to denote expletives that would otherwise have been censored.An ellipsis may also imply an unstated alternative indicated by context. For example, "I never drink wine ..." implies that the speaker does drink something else—such as vodka.
In reported speech, the ellipsis can be used to represent an intentional silence.
In poetry, an ellipsis is used as a thought-pause or line break at the caesura or this is used to highlight sarcasm or make the reader think about the last points in the poem.
In news reporting, often put inside square brackets, it is used to indicate that a quotation has been condensed for space, brevity or relevance, as in "The President said that [...] he would not be satisfied", where the exact quotation was "The President said that, for as long as this situation continued, he would not be satisfied".
Herb Caen, Pulitzer-prize-winning columnist for the San Francisco Chronicle, became famous for his "three-dot journalism".

In different languages
In English
American English
The Chicago Manual of Style suggests the use of an ellipsis for any omitted word, phrase, line, or paragraph from within but not at the end of a quoted passage. There are two commonly used methods of using ellipses: one uses three dots for any omission, while the second one makes a distinction between omissions within a sentence (using three dots: . . .) and omissions between sentences (using a period and a space followed by three dots: . ...). The Chicago Style Q&A recommends that writers avoid using the precomposed … (U+2026) character in manuscripts and to place three periods plus two nonbreaking spaces (. . .) instead, leaving the editor, publisher, or typographer to replace them later.The Modern Language Association (MLA) used to indicate that an ellipsis must include spaces before and after each dot in all uses. If an ellipsis is meant to represent an omission, square brackets must surround the ellipsis to make it clear that there was no pause in the original quote: [ . . . ]. Currently, the MLA has removed the requirement of brackets in its style handbooks. However, some maintain that the use of brackets is still correct because it clears confusion.The MLA now indicates that a three-dot, spaced ellipsis  . . .  should be used for removing material from within one sentence within a quote. When crossing sentences (when the omitted text contains a period, so that omitting the end of a sentence counts), a four-dot, spaced (except for before the first dot) ellipsis . . . .  should be used. When ellipsis points are used in the original text, ellipsis points that are not in the original text should be distinguished by enclosing them in square brackets (e.g. text [...] text).According to the Associated Press, the ellipsis should be used to condense quotations. It is less commonly used to indicate a pause in speech or an unfinished thought or to separate items in material such as show business gossip. The stylebook indicates that if the shortened sentence before the mark can stand as a sentence, it should do so, with an ellipsis placed after the period or other ending punctuation. When material is omitted at the end of a paragraph and also immediately following it, an ellipsis goes both at the end of that paragraph and at the beginning of the next, according to this style.According to Robert Bringhursts Elements of Typographic Style, the details of typesetting ellipses depend on the character and size of the font being set and the typographers preference. Bringhurst writes that a full space between each dot is "another Victorian eccentricity. In most contexts, the Chicago ellipsis is much too wide"—he recommends using flush dots (with a normal word space before and after), or thin-spaced dots (up to one-fifth of an em), or the prefabricated ellipsis character U+2026 … HORIZONTAL ELLIPSIS (…, …). Bringhurst suggests that normally an ellipsis should be spaced fore-and-aft to separate it from the text, but when it combines with other punctuation, the leading space disappears and the other punctuation follows. This is the usual practice in typesetting. He provides the following examples:

In legal writing in the United States, Rule 5.3 in the Bluebook citation guide governs the use of ellipses and requires a space before the first dot and between the two subsequent dots. If an ellipsis ends the sentence, then there are three dots, each separated by a space, followed by the final punctuation (e.g. Hah . . . ?). In some legal writing, an ellipsis is written as three asterisks, *** or * * *, to make it obvious that text has been omitted or to signal that the omitted text extends beyond the end of the paragraph.

British English
The Oxford Style Guide recommends setting the ellipsis as a single character … or as a series of three (narrow) spaced dots surrounded by spaces, thus:  . . . . If there is an ellipsis at the end of an incomplete sentence, the final full stop is omitted. However, it is retained if the following ellipsis represents an omission between two complete sentences.

Contrary to The Oxford Style Guide, the University of Oxford Style Guide demands an ellipsis not to be surrounded by spaces, except when it stands for a pause; then, a space has to be set after the ellipsis (but not before). An ellipsis is never preceded or followed by a full stop.

In Polish
When applied in Polish syntax, the ellipsis is called wielokropek, literally multidot. The word wielokropek distinguishes the ellipsis of Polish syntax from that of mathematical notation, in which it is known as an elipsa. When an ellipsis replaces a fragment omitted from a quotation, the ellipsis is enclosed in parentheses or square brackets. An unbracketed ellipsis indicates an interruption or pause in speech. The syntactic rules for ellipses are standardized by the 1983 Polska Norma document PN-83/P-55366, Zasady składania tekstów w języku polskim (Rules for Setting Texts in Polish).

In Russian
The combination "ellipsis+period" is replaced by the ellipsis. The combinations "ellipsis+exclamation mark" and "ellipsis+question mark" are written in this way: !.. ?..

In Japanese
The most common character corresponding to an ellipsis is called 3-ten rīdā ("3-dot leaders", …). 2-ten rīdā exists as a character, but it is used less commonly. In writing, the ellipsis consists usually of six dots (two 3-ten rīdā characters, ……). Three dots (one 3-ten rīdā character) may be used where space is limited, such as in a header. However, variations in the number of dots exist. In horizontally written text the dots are commonly vertically centered within the text height (between the baseline and the ascent line), as in the standard Japanese Windows fonts; in vertically written text the dots are always centered horizontally. As the Japanese word for dot is pronounced "ten", the dots are colloquially called "ten-ten-ten" (てんてんてん, akin to the English "dot dot dot").In text in Japanese media, such as in manga or video games, ellipses are much more frequent than in English, and are often changed to another punctuation sign in translation. The ellipsis by itself represents speechlessness, or a "pregnant pause". Depending on the context, this could be anything from an admission of guilt to an expression of being dumbfounded at another persons words or actions. As a device, the ten-ten-ten is intended to focus the reader on a character while allowing the character to not speak any dialogue. This conveys to the reader a focus of the narrative "camera" on the silent subject, implying an expectation of some motion or action. It is not unheard of to see inanimate objects "speaking" the ellipsis.

In Chinese
In Chinese, the ellipsis is six dots (in two groups of three dots, occupying the same horizontal or vertical space as two characters) (i.e. ……).

In Spanish
In Spanish, the ellipsis is commonly used as a substitute of et cetera at the end of unfinished lists. So it means "and so forth" or "and other things".
Other use is the suspension of a part of a text, or a paragraph, or a phrase or a part of a word because it is obvious, or unnecessary, or implied. For instance, sometimes the ellipsis is used to avoid the complete use of expletives.
When the ellipsis is placed alone into a parenthesis (...) or—less often—between brackets [...], which is what happens usually within a text transcription, it means the original text had more contents on the same position but are not useful to our target in the transcription. When the suppressed text is at the beginning or at the end of a text, the ellipsis does not need to be placed in a parenthesis.
The number of dots is three and only three.

In French
In French, the ellipsis is commonly used at the end of lists to represent et cetera. In French typography, the ellipsis is written immediately after the preceding word, but has a space after it, for example: comme ça... pas comme ceci. If, exceptionally, it begins a sentence, there is a space before and after, for example: Lui ? ... vaut rien, je crois... . However, any omitted word, phrase or line at the end of a quoted passage would be indicated as follows: [...] (space before and after the square brackets but not inside), for example: ... à Paris, Nice, Nantes, Toulouse [...].

In German
In German, the ellipsis in general is surrounded by spaces, if it stands for one or more omitted words. On the other side there is no space between a letter or (part of) a word and an ellipsis, if it stands for one or more omitted letters, that should stick to the written letter or letters.
Example for both cases, using German style: The first el...is stands for omitted letters, the second ... for an omitted word.
If the ellipsis is at the end of a sentence, the final full stop is omitted.Example: I think that ...

In Italian
The Accademia della Crusca suggests the use of an ellipsis ("puntini di sospensione") to indicate a pause longer than a period and, when placed between brackets, the omission of letters, words or phrases. "Tra le cose più preziose possedute da Andrea Sperelli era una coperta di seta fina, d’un colore azzurro disfatto, intorno a cui giravano i dodici segni dello Zodiaco in ricamo, con le denominazioni […] a caratteri gotici." (Gabriele D’Annunzio, Il piacere)

Usage in computer system menus
In computer menu functions or buttons, an ellipsis means that upon selection more options (sometimes in the form of a dialog box) will be displayed, where the user can or must make a choice. If the ellipsis is absent, the function is immediately executed upon selection.
For example, the menu item "Save" indicates that the file will be overwritten without further input, whereas "Save as..." indicates that a dialog follows where the user can, for example, select another location, file name, or format.
Ellipses are also used as a separate button (particularly considering the limited screen area of mobile apps) to represent partially or completely hidden options. This usage may alternatively be described as a "More button" (see also hamburger button signifying completely hidden options).
In mobile, web, and general application design, the vertical ellipsis, ⋮, is sometimes used as an interface element, where it is sometimes called a kebab icon. The element typically indicates that a navigation menu can be accessed when the element is activated, and is a smaller version of the hamburger icon (≡) which is a stylized rendering of a menu.

In mathematical notation
An ellipsis is also often used in mathematics to mean "and so forth". In a list, between commas, or following a comma, a normal ellipsis is used, as in:

        1
        ,
        2
        ,
        3
        ,
        …
        ,
        100

    {\displaystyle 1,2,3,\ldots ,100}
  or to mean an infinite list, as:

        1
        ,
        2
        ,
        3
        ,
        …

    {\displaystyle 1,2,3,\ldots }
  To indicate the omission of values in a repeated operation, an ellipsis raised to the center of the line is used between two operation symbols or following the last operation symbol, as in:

        1
        +
        2
        +
        3
        +
        ⋯
        +
        100

    {\displaystyle 1+2+3+\cdots +100}
  Sometimes, e.g. in Russian mathematical texts, normal, non-raised, ellipses are used even in repeated summations.The latter formula means the sum of all natural numbers from 1 to 100. However, it is not a formally defined mathematical symbol. Repeated summations or products may similarly be denoted using capital sigma and capital pi notation, respectively:

        1
        +
        2
        +
        3
        +
        ⋯
        +
        100

        =

          ∑

            n
            =
            1

            100

        n
        =
        100
        ?

    {\displaystyle 1+2+3+\cdots +100\ =\sum _{n=1}^{100}n=100?}
   (see termial)

        1
        ×
        2
        ×
        3
        ×
        ⋯
        ×
        100

        =

          ∏

            n
            =
            1

            100

        n
        =
        100
        !

    {\displaystyle 1\times 2\times 3\times \cdots \times 100\ =\prod _{n=1}^{100}n=100!}
   (see factorial)Normally dots should be used only where the pattern to be followed is clear, the exception being to show the indefinite continuation of an irrational number such as:

        π
        =
        3.14159265
        …

    {\displaystyle \pi =3.14159265\ldots }
  Sometimes, it is useful to display a formula compactly, for example:

        1
        +
        4
        +
        9
        +
        ⋯
        +

          n

            2

        +
        ⋯
        +
        400

    {\displaystyle 1+4+9+\cdots +n^{2}+\cdots +400}
  Another example is the set of positive zeros of the cosine function:

          {

                π
                2

            ,

                  3
                  π

                2

            ,

                  5
                  π

                2

            ,
            …

          }

    {\displaystyle \left\{{\frac {\pi }{2}},{\frac {3\pi }{2}},{\frac {5\pi }{2}},\ldots \right\}}
  There are many related uses of the ellipsis in set notation.
The diagonal and vertical forms of the ellipsis are particularly useful for showing missing terms in matrices, such as the size-n identity matrix:

          I

            n

        =

            [

                  1

                  0

                  ⋯

                  0

                  0

                  1

                  ⋯

                  0

                  ⋮

                  ⋮

                  ⋱

                  ⋮

                  0

                  0

                  ⋯

                  1

            ]

    {\displaystyle I_{n}={\begin{bmatrix}1&0&\cdots &0\\0&1&\cdots &0\\\vdots &\vdots &\ddots &\vdots \\0&0&\cdots &1\end{bmatrix}}}

Computer science
Programming languages
A two- or three-dot ellipsis is used as an operator in some programming languages. One of its most common uses is in defining ranges or sequences, for instance 1..10 means all the numbers from 1 through 10. This is used in many languages, including Pascal, Modula, Oberon, Ada, Haskell, Perl, Ruby, Rust, Swift, Kotlin, Bash shell and F#. It is also used to indicate variadic functions in the C, C++ and Java languages. See Ellipsis (programming operator).

HTML and CSS
The CSS text-overflow property can be set to ellipsis, which cuts off text with an ellipsis when it overflows the content area.

On Internet chat rooms and in text messaging
The ellipsis is a non-verbal cue that is often used in computer-mediated interactions, in particular in synchronous genres, such as chat. The reason behind its popularity is the fact that it allows people to indicate in writing several functions:

The sign of ellipsis can function as a floor holding device, and signal that more is to come, for instance when people break up longer turns in chat.
Dot-dot-dot can be used systematically to enact linguistic politeness, for instance indicating topic change or hesitation.
Suspension dots can be turn construction units to signal silence, for example when indicating disagreement, disapproval or confusion.Although an ellipsis is technically complete with three periods (...), its rise in popularity as a "trailing-off" or "silence" indicator, particularly in mid-20th-century comic strip and comic book prose writing, has led to expanded uses online. Today, extended ellipses anywhere from two to dozens of periods have become common constructions in Internet chat rooms and text messages </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sofosbuvir and explain in detail? [/INST] Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are generally more common in interferon-containing regimens.: 7  Sofosbuvir may reactivate hepatitis B in those who have been previously infected. In combination with ledipasvir, daclatasvir or simeprevir, it is not recommended with amiodarone due to the risk of an abnormally slow heartbeat. Sofosbuvir is in the nucleotide analog family of medications and works by blocking the hepatitis C NS5B protein.Sofosbuvir was discovered in 2007 and approved for medical use in the United States in 2013. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Initial HCV treatment
In 2016, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir used in combination with other drugs is part of all first-line treatments for HCV genotypes 1, 2, 3, 4, 5, and 6, and is also part of some second-line treatments. Sofosbuvir in combination with velpatasvir is recommended for all genotypes with a cure rate greater than 90%, and close to 100% in most cases. The duration of treatment is typically 12 weeks.Sofosbuvir is also used with other medications and longer treatment durations, depending on specific circumstances, genotype and cost-effectiveness–based perspective. For example, for the treatment of genotypes 1, 4, 5, and 6 hepatitis C infections, sofosbuvir can be used in combination with the viral NS5A inhibitor ledipasvir. In genotype 2 and 3 HCV infections, sofosbuvir can be used in combination with daclatasvir. For the treatment of cases with cirrhosis or liver transplant patients, weight-based ribavirin is sometimes added. Peginterferon with or without sofosbuvir is not recommended in an initial HCV treatment.Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduction in therapy duration. Sofosbuvir allows most people to be treated successfully without the use of peginterferon, an injectable drug with severe side effects that is a key component of older drug combinations for the treatment of hepatitis C virus.

Prior failed treatment
For people who have experienced treatment failure with some form of combination therapy for hepatitis C infection, one of the next possible steps would be retreatment with sofosbuvir and either ledipasvir or daclatasvir, with or without weight-based ribavirin. The genotype and particular combination therapy a person was on when the initial treatment failed are also taken into consideration when deciding which combination to use next. The duration of retreatment can range from 12 weeks to 24 weeks depending on several factors, including which medications are used for the retreatment, whether the person has liver cirrhosis or not, and whether the liver damage is classified as compensated cirrhosis or decompensated cirrhosis.

Pregnancy and breastfeeding
No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. However, ribavirin, a medication that is often given together with sofosbuvir to treat hepatitis C, is assigned a Pregnancy Category X (contraindicated in pregnancy) by the FDA. Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus. It is recommended that sofosbuvir/ribarivin combinations be avoided in pregnant females and their male sexual partners in order to reduce harmful fetal defects caused by ribavirin. Females who could potentially become pregnant should undergo a pregnancy test 2 months prior to starting the sofosbuvir/ribavirin/peginterferon combination treatment, monthly throughout the duration of the treatment, and six months post-treatment to reduce the risk of fetal harm in case of accidental pregnancy.It is unknown whether sofosbuvir and ribavirin pass into breastmilk; therefore, it is recommended that the mother does not breastfeed during treatment with sofosbuvir alone or in combination with ribavirin.

Contraindications
There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with ribavirin or peginterferon alfa/ribavirin, or others, the contraindications applicable to these agents are applied.

Side effects
Sofosbuvir used alone and in combination with other drugs such as ribavirin with or without a peginterferon has a good safety profile. Common side effects are fatigue, headache, nausea, rash, irritability, dizziness, back pain, and anemia. Most side effects are more common in interferon-containing regimens as compared to interferon-free regimens. For example, fatigue and headache are nearly reduced by half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.: 7 Sofosbuvir may reactivate hepatitis B in those who have been previously infected. The European Medicines Agency (EMA) has recommended screening all people for hepatitis B before starting sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.

Interactions
Sofosbuvir (in combination with ledipasvir, daclatasvir or simeprevir) should not be used with amiodarone due to the risk of abnormally slow heartbeats.Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and St. Johns wort, could reduce the absorption of sofosbuvir.In addition, coadministration of sofosbuvir with anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine), antimycobacterials (rifampin, rifabutin, rifapentine), and the HIV protease inhibitor tipranavir and ritonavir is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended.The interaction between sofosbuvir and a number of other drugs, such as ciclosporin, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil, were evaluated in clinical trials and no dose adjustment is needed for any of these drugs.

Pharmacology
Mechanism of action
Sofosbuvir inhibits the hepatitis C NS5B protein. Sofosbuvir appears to have a high barrier to the development of resistance.Sofosbuvir is a prodrug of the Protide type, whereby the active phosphorylated nucleotide is granted cell permeability and oral bioavailability. It is metabolized to the active antiviral agent GS-461203 (2-deoxy-2-α-fluoro-β-C-methyluridine-5-triphosphate). GS-461203 serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis. Although sofosbuvir has a 3 hydroxyl group to act as a nucleophile for an incoming NTP, a similar nucleotide analogue, 2-deoxy-2-α-fluoro-β-C-methylcytidine, is proposed to act as a chain terminator because the 2 methyl group of the nucleotide analogue causes a steric clash with an incoming NTP. Sofosbuvir would act in a similar way.

Pharmacokinetics
Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose. Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive nucleoside.Plasma protein binding of sofosbuvir is 61–65%, while GS-331077 has minimal binding.Sofosbuvir is activated in the liver to the triphosphate GS-461203 by hydrolysis of the carboxylate ester by either of the enzymes cathepsin A or carboxylesterase 1, followed by cleaving of the phosphoramidate by the enzyme histidine triad nucleotide-binding protein 1 (HINT1), and subsequent repeated phosphorylation. Dephosphorylation creates the inactive metabolite GS-331077. The half life of sofosbuvir is 0.4 hours, and the half life of GS-331077 is 27 hours.Following a single 400 mg oral dose of sofosbuvir, 80% is excreted in urine, 14% in feces, and 2.5% in expired air recovery. However, of the urine recovery 78% was the metabolite (GS-331077) and 3.5% was sofosbuvir.

Chemistry
Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arose in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the ProTide approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.

History
Sofosbuvir was discovered in 2007 by Michael Sofia, a scientist at Pharmasset, and the drug was first tested in people in 2010. In 2011, Gilead Sciences bought Pharmasset for about $11 billion. Gilead submitted the New Drug Application for sofosbuvir in combination with ribavirin in April 2013, and in October 2013 it received the FDAs Breakthrough Therapy Designation. In December 2013, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive people with HCV genotypes 1 and 4. Two months before, the FDA had approved another drug, simeprevir, as a hepatitis C treatment.In 2014, the fixed dose combination drug sofosbuvir/ledipasvir, the latter a viral NS5A inhibitor, was approved; it had also been granted breakthrough status.Prior to the availability of sofosbuvir, hepatitis C treatments involved 6 to 12 months of treatment with an interferon-based regimen. This regimen provided cure rates of 70% or less and was associated with severe side effects, including anemia, depression, severe rash, nausea, diarrhea, and fatigue. As sofosbuvir clinical development progressed, physicians began to "warehouse" people in anticipation of its availability. Sofosbuvirs U.S. launch was the fastest of any new drug in history.

Society and culture
Sofosbuvir is on the World Health Organizations List of Essential Medicines.

Economics
Following its approval by the FDA in 2013, the price of sofosbuvir as quoted in various media sources in 2014 ranged from $84,000 to $168,000 depending on course of treatment in the U.S. and £35,000 in the United Kingdom for a 12-week regimine, causing considerable controversy. Sofosbuvir was more affordable in Japan and South Korea at approximately $300 and $5900 respectively for a 12-week treatment, with each government covering 99% and 70% of the cost respectively. In 2014, Gilead announced it would work with generic manufacturers in 91 developing countries to produce and sell sofosbuvir, and that it would sell a name brand version of the product in India for approximately $300 per course of treatment; it had signed agreements with generic manufacturers by September 2015.

United States
Since its launch, the price of sofosbuvir declined as more competitors entered the direct-acting antiviral (DAA) market. In 2020, the price for a course of sofosbuvir was $64,693 in the United States. In 2014, the list price of a 12-week combination treatment with a sofosbuvir-based regimen ranged from US$84,000 to $94,000. In April 2014, U.S. House Democrats Henry Waxman, Frank Pallone Jr., and Diana DeGette wrote Gilead Sciences Inc. questioning the $84,000 price for sofosbuvir. They specifically asked Gilead CEO John Martin to "explain how the drug was priced, what discounts are being made available to low-income patients and government health programs, and the potential impact to public health by insurers blocking or delaying access to the medicine because of its cost." Sofosbuvir is cited as an example of how specialty drugs present both benefits and challenges.
Sofosbuvir also is an excellent example of both the benefit and the challenge of specialty medications. On one hand, this agent offers up to a 95% response rate as part of an interferon-free treatment regimen for hepatitis C. Generally speaking, it is more effective and better tolerated than alternative treatments. Unfortunately, the current per pill cost—$1,000—results in an $84,000 treatment course, creating barriers to therapy for many. Patients, providers, and payors alike have expressed outrage, and the debate has even drawn the attention of the US Congress. Despite these concerns, sofosbuvir rapidly has become a top seller in the United States...
In February 2015, Gilead announced that due in part to negotiated discounts with pharmacy benefit managers and legally mandated discounts to government payers, the average discount-to-list price in 2014 was 22%. The company estimated that the average discount in 2015 would be 46%. According to the California Technology Assessment Forum, a panel of academic pharmacoeconomic experts, representatives of managed care organizations, and advocates for people with hepatitis, a 46% discount would bring the average price of treatment to about $40,000, at which price sofosbuvir-based treatment regimens represent a "high value" for people and healthcare systems.Because of sofosbuvirs high price in the United States, by 2017, some states—such as Louisiana—were withholding the medicine from Medicaid patients with hepatitis until their livers were severely damaged. This puts "patients at increased risk of medical complications" and contributes to the "transmission of the hepatitis C virus". In an article published in May 2016 in Health Affairs, the authors proposed the invocation of the federal "government patent use" law which would enable the government to procure "important patent-protected" drugs at lower prices while compensating "the patent-holding companies reasonable royalties ... for research and development." By July 2017, Louisianas health secretary Rebekah Gee, who described Louisiana as Americas "public-health-crisis cradle", was investigating the use of the "government patent use" as a strategy.

Japan and South Korea
Unlike other comparable Western developed countries, sofosbuvir is far more affordable in Japan and South Korea at approximately $300 and $2165 cost to patients respectively for a 12-week treatment, as each government covers 99% and 70% of the original cost respectively.

Germany
In Germany, negotiations between Gilead and health insurers led to a price of €41,000 for 12 weeks of treatment. This is the same price previously negotiated with the national healthcare system in France, except that additional discounts and rebates apply in France depending on the volume of sales and the number of treatment failures.

Switzerland
In Switzerland, the price is fixed by the government every three years. The price in 2016 was CHF 16,102.50 for 24 pills of 400 mg.

United Kingdom
In 2020, the originator price per course of sofosbuvir was £35,443. In 2013, the price in the United Kingdom was expected to be £35,000 for a 12-weeks course. NHS England established 22 Operational Delivery Networks to roll out delivery, which was approved by the National Institute for Health and Care Excellence in 2015, and proposes to fund 10,000 courses of treatment in 2016–17. Each was given a "run rate" of how many people they were allowed to treat, and this was the NHSs single biggest new treatment investment in 2016.

Croatia
As of 2015, sofosbuvir is included on the list of essential medications in Croatia and its cost is fully covered by the Croatian Health Insurance Fund. As a result of negotiations with the manufacturer, only therapies with successful outcome would be paid by the Fund with the rest being covered by the manufacturer.

India
In July 2014, Gilead Sciences filed a patent for sofosbuvir in India. If the office of the controller general of patents had granted it, Gilead would have obtained exclusive rights to produce and sell sofosbuvir in the country. However, in January 2015, the Indian Patent Office rejected Gileads application. Gileads lawyers moved the Delhi High Court against this decision. That decision was overturned on appeal in February 2015. In the meantime, it granted Indian companies voluntary licenses (VLs), which allowed them to make and sell in a selected few countries at a discounted price. This agreement also granted 7% of the royalties to Gilead. However, the list of countries open to Indian firms under this agreement excluded 73 million people with hepatitis C.

Developing world
In 2014, Gilead announced it would seek generic licensing agreements with manufacturers to produce sofosbuvir in 91 developing countries, which contained 54% of the worlds HCV-infected population. Gilead also said it would sell a name brand version of the product in India for $300 per course of treatment, approximately double a third party estimate of the minimum achievable cost of manufacture. It had signed licenses with generic manufacturers by September 2015. The leader of one Indian activist group called this move inadequate, but nine companies launched products, which "unleashed a fierce marketing war", according to Indias The Economic Times.In Egypt, which had the worlds highest incidence of hepatitis C, Gilead offered sofosbuvir at the discounted price of $900 to the Egyptian government. The government in turn made it free to patients. Later, Gilead licensed a generic version to be available in Egypt.The Access to Medicine Index ranked Gilead first among the worlds 20 largest pharmaceutical countries in the Pricing, Manufacturing and Distribution category in both 2013 and 2014, citing Gileads "leading performance in equitable pricing." In contrast, Jennifer Cohn of Doctors Without Borders and the organization Doctors of the World criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of people in developing countries.In Algeria, as of 2011 about 70,000 people were infected with hepatitis C. As of August 2015, Gilead had licensed its partners in India to sell sofosbuvir in Algeria. It had been criticized for not making the drug available in middle-income countries including Algeria prior to that.

Controversies
The price has generated considerable controversy. In 2017, the range of costs per treatment varied from about $84,000 to about $50.

Patent challenges
In February 2015, it was reported that Doctors of the World had submitted an objection to Gileads patent at the European Patent Office, claiming that the structure of sofosbuvir is based on already known molecules. In particular, Doctors of the World argued that the Protide technology powering sofosbuvir was previously invented by the Chris McGuigan team at Cardiff University in the UK, and that the Gilead drug is not therefore inventive. The group filed challenges in other developing countries as well. These challenges were unsuccessful and the court recognized the innovative step in pro-drug design and application to the specific example of sofosbuvir.

Medical tourism
Due to the high cost of sofosbuvir in the U.S., as of 2016 increasing numbers of Americans with hepatitis C were traveling to India to purchase the drug. Similarly, increasing numbers of Chinese were also traveling to India to purchase sofosbuvir, which had not yet been approved for sale in China by the countrys State Food and Drug Administration (SFDA).

Research
Combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir, ledipasvir or velpatasvir, have shown sustained virological response rates of up to 100% in people infected with HCV. Most studies indicate that the efficacy rate is between 94% and 97%; much higher than previous treatment options. That treatments could be conducted at very low costs was demonstrated by Hill and coworkers who presented data on 1,160 patients who used generic versions of solfosbuvir, ledipasvir, plus daclatasvir from suppliers in India, Egypt, China and other countries and reported over 90% success at costs of about $50 per therapy.Sofosbuvir has also been tested against other viruses such as the Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

See also
AT-527—a similar drug developed for the treatment of SARS-CoV-2
Tenofovir alafenamide—a nucleotide reverse-transcriptase inhibitor that uses similar phosphoramidate prodrug technology
Remdesivir—a nucleotide analogue RNA polymerase inhibitor originally intended to treat hepatitis C that uses similar phosphoramidate prodrug technology and displays very similar PK.

References
Further reading
Dean L (2017) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Capreomycin and explain in detail? [/INST] Capreomycin is an antibiotic which is given in combination with other antibiotics for the treatment of tuberculosis. Specifically it is a second line treatment used for active drug resistant tuberculosis. It is given by injection into a vein or muscle.Common side effects include kidney problems, hearing problems, poor balance, and pain at the site of injection. Other side effects include paralysis resulting in the inability to breathe. It is not recommended with streptomycin or other medications that may damage the auditory vestibular nerve. It is not recommended during pregnancy as it may cause kidney or hearing problems in the baby. Capreomycin is commonly grouped with the aminoglycoside family of medications.  How it works is unclear.Capreomycin was discovered from Streptomyces capreolus in 1960 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Nirmatrelvir/ritonavir and explain in detail? [/INST] Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged oral medication used as a treatment for COVID-19. It contains the antiviral medications nirmatrelvir and ritonavir.In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. It is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19. It was approved in the United Kingdom later that month, and in the European Union and Canada in January 2022.

Medical uses
The co-packaged medication is indicated for the treatment of mild to moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated adults is about 88% (95% CI, 75–94%).As of May 2022, the effectiveness among vaccinated people and the effectiveness against long COVID were unknown.  The drug does not prevent infection in people who live with an infected person.In the European Union, the co-packaged medication is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19.

Contraindications
The co-packaged medication is not authorized for the pre-exposure prophylaxis or post-exposure prophylaxis of COVID-19 nor for treatment in those requiring hospitalization due to severe or critical COVID-19, nor for use for longer than 5 consecutive days.
The drug is contraindicated in those with hypersensitivity to the two main components, and in those with severely reduced kidney or liver function.

During pregnancy
The co-packaged medication is not recommended during pregnancy and in women who can become pregnant and who are not using contraception. Breastfeeding should be interrupted during treatment. These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, spontaneous abortions (miscarriage), or adverse outcomes. There are also no human data on the presence of nirmatrelvir in human milk, its effects on milk production or the infant. In pregnant rabbits, a reduction in fetal body weight was observed with systemic exposure ten times higher than the authorized human dose of the co-packaged medication. A temporary reduction in body weight was observed in the offspring of nursing rats.

Interactions and side effects
Co-administration with certain drugs may have serious effects and may sometimes be fatal. The drug is contraindicated when co-administered with certain drugs, such as drugs dependent on CYP3A for removal, for which a raised concentration results in serious reactions, or those with potent CYP3A inducers, for which reduced blood concentration of the two main components may result in loss of effect against the virus and possible resistance, among others. Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring. Many of these drugs are widely prescribed to people at high risk from COVID-19. With the extension of the emergency authorization in August 2022, the FDA updated a checklist to help evaluate potential drug interactions and other patient factors before prescribing Paxlovid, including more than 120 drugs which are either contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included: dysgeusia (4.8–6%), diarrhea (3–3.9%), vomiting (1.3%), hypertension (1%), and myalgia (1%).There is no specific antidote for overdose with the co-packaged medication. Treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status.

Rebound
An additional analysis of the original EPIC-HR clinical trial data (Delta variant) showed that about 2% of both the treatment and placebo groups experienced a symptomatic rebound after the 5 day treatment, meaning they felt ill again and tested positive again (antigen test and PCR test) after testing negative. This is important, because people with rebound cannot go back to work or school. The exact cause is unknown. It may be due to virus reservoirs in tissues that are not reached by the medication, or reinfection. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there has been no evidence of benefit.In a 2022 US case report of 10 people with rebound while the Omicron variant has been circulating, viral load during relapse was comparable to levels during initial infection and high enough to cause secondary transmission. Also, sequencing of SARS CoV2 in three patients showed that rebound was a relapse with the same strain as it was not due to a mutation during treatment nor an infection with a different viral strain. As of September 2022, it is unknown how common rebound is among people after Paxlovid treatment, but study author David Ho thinks it is not uncommon. Besides him, President Joe Biden, First Lady Jill Biden, Anthony Fauci and Peter Hotez are known to have experienced rebound. As of September 2022, Pfizer is studying the phenomenon in a new trial it calls EPIC-SR (standard risk) while the omicron variant is circulating.As of July 2022, no Paxlovid drug resistant SARS CoV2 has been observed in clinical context. The engineering of a nirmaltrevir-resistant chimera of Vesicular Stomatitis Virus under laboratory conditions was published without formal peer review in July 2022.

Manufacturing
Pfizer selected its largest oral tablet factory in Freiburg as the launch facility for the manufacturing of the co-packaged medication. Nirmatrelvir, the novel portion of the co-packaged medication, was first developed in the United States and was initially manufactured in small amounts in Groton, Connecticut, to support clinical trials, but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale. Pfizer selected another factory in Ascoli Piceno, Italy, to assist the Freiburg factory with packaging tablets into blister packs.

History
The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir are from EPIC-HR, a randomized, double-blind, placebo-controlled clinical trial studying nirmatrelvir/ritonavir for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Participants were adults 18 years of age and older with a prespecified risk factor for progression to severe disease or were 60 years and older regardless of prespecified chronic medical conditions. All participants had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID-19 or died due to any cause during 28 days of follow-up. Nirmatrelvir/ritonavir significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among participants treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. In this analysis, 1,039 participants had received nirmatrelvir/ritonavir, and 1,046 participants had received placebo and among these participants, 0.8% who received nirmatrelvir/ritonavir were hospitalized or died during 28 days of follow-up compared to 6% of the participants who received placebo.In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir, and on 14 December, Pfizer announced that the Phase II/III study of nirmatrelvir combined with ritonavir showed a reduced risk of hospitalization or death. In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19. On 31 December, the United Kingdoms Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults with mild to moderate infection and at high risk of their illness worsening.The efficacy of the co-packaged medication against hospitalization or death in high-risk adults when administered within five days of symptom onset is about 88% (95% CI, 75–94%).In 2022, the PANORAMIC trial started testing the effectiveness of nirmatrelvir/ritonavir for treating COVID-19 infections.Pfizer also conducted a Phase II/III study in standard-risk patients called EPIC-SR, which began in December 2021. This study did not find a statistically significant reduction in the risk of hospitalization or death (treatment: 5/576; placebo: 10/569), nor did it achieve its primary goal of sustained alleviation of symptoms. However, it did find a 62% decrease in COVID-19–related medical visits (p=0.023), which was consistent with the 67% reduction from the EPIC-HR (high-risk patients) study. Pfizer discontinued enrollment in the study because of the low rate of hospitalization and death in this population.

Society and culture
Legal status
On 16 November 2021, Pfizer submitted an application to the US Food and Drug Administration (FDA) for emergency use authorization for the co-packaged medication. The authorization was granted on 22 December 2021, for adults and children ages 12 and older who are infected with Covid and at risk. The European Medicines Agency (EMA) issued guidance about the use of the co-packaged medication for the treatment of COVID-19 in the EU on 16 December 2021. The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021. South Korea approved the use of the co-packaged medication on 27 December 2021.The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of the co-packaged medication in December 2021. Health Canada approved the use of the co-packaged medication in January 2022. The Singapore Health Sciences Authority approved the use of the co-packaged medication for treating adults in February 2022. In February 2022, China approved the medication for the treatment of adults who have mild to moderate COVID-19 and are at a high risk of progressing to a severe condition.

Economics
In December 2021, the German government ordered 1 million doses of, but by August 2022, only around 43,000 had been delivered by wholesalers to pharmacies. In Germany, paxlovid is by prescription through physicians only and German physicians have been reluctant to prescribe it. Hence health minister Karl Lauterbach decided that general practitioners can stock 5 Paxlovid courses in their practice and dispense it directly to patients, that a prescription would be remunerated with 15 euros and that every nursing home should appoint a vaccination officer as well as a Paxlovid officer. As of August 2022 the treatment guidelines, which German family doctors follow, have not been updated since February 2022 and recommend Paxlovid only in unvaccinated risk patients, i.e. in only a few people.As of April 2022, the United States ordered a total of 20 million Paxlovid courses </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Lanreotide and explain in detail? [/INST] Lanreotide, sold under the brand name Somatuline among others, is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide.
Lanreotide (as lanreotide acetate) is manufactured by Ipsen </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Theophylline and explain in detail? [/INST] Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine, and is readily found in nature, being present in tea (Camellia sinensis) and cocoa (Theobroma cacao). A small amount of theophylline is one of the products of caffeine metabolic processing in the liver.Acebrophylline, an airway mucoregulator and anti-inflammatory agent is a combination product of ambroxol and theophylline 7 acetic acid.

Medical uses
The main actions of theophylline involve:

relaxing bronchial smooth muscle
increasing heart muscle contractility and efficiency (positive inotrope)
increasing heart rate (positive chronotropic)
increasing blood pressure
increasing renal blood flow
anti-inflammatory effects
central nervous system stimulatory effect mainly on the medullary respiratory center.The main therapeutic uses of theophylline are aimed at:

chronic obstructive pulmonary disease (COPD)
asthma
infant apnea
Blocks the action of adenosine; an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.
Treatment of post-dural puncture headache.

Uses under investigation
A clinical study reported in 2008 that theophylline was helpful in improving the sense of smell in study subjects with anosmia.In 2004, a small clinical study compared theophylline to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents.

Adverse effects
The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow therapeutic window (<20 mcg/mL). Its use must be monitored by direct measurement of serum theophylline levels to avoid toxicity.  It can also cause nausea, diarrhea, increase in heart rate, abnormal heart rhythms, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness). Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency. Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called dose dumping, but this does not occur with most formulations of theophylline.  Theophylline toxicity can be treated with beta blockers.  In addition to seizures, tachyarrhythmias are a major concern. Theophylline should not be used in combination with the SSRI fluvoxamine.

Spectroscopy
UV-visible spectroscopy
Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1).

Proton nuclear magnetic resonance spectroscopy (1H-NMR)
The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions.

Carbon nuclear magnetic resonance spectroscopy (13C-NMR)
The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone.

Natural occurrences
Theophylline is naturally found in cocoa beans.  Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L, which is significantly less than a therapeutic dose.
Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts cola (plant).

Pharmacology
Pharmacodynamics
Like other methylated xanthine derivatives, theophylline is both a

competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity
nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effectsTheophylline has been shown to inhibit TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD and asthma via cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein collagen.It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics who are active smokers (a condition resulting in oxidative stress) via a distinctly separate mechanism. Theophylline in vitro can restore the reduced HDAC (histone deacetylase) activity that is induced by oxidative stress (i.e., in smokers), returning steroid responsiveness toward normal. Furthermore, theophylline has been shown to directly activate HDAC2.  (Corticosteroids switch off the inflammatory response by blocking the expression of inflammatory mediators through deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity.  It has recently been shown that the oxidative stress associated with cigarette smoke can inhibit the activity of HDAC2, thereby blocking the anti-inflammatory effects of corticosteroids.)

Pharmacokinetics
Absorption
When theophylline is administered intravenously, bioavailability is 100%.

Distribution
Theophylline is distributed in the extracellular fluid, in the placenta, in the mothers milk and in the central nervous system. The volume of distribution is 0.5 L/kg. The protein binding is 40%. The volume of distribution may increase in neonates and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese.

Metabolism
Theophylline is metabolized extensively in the liver (up to 70%). It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and Michaelis-Menten pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pseudoephedrine and explain in detail? [/INST] Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.It was first characterized in 1889, by the German chemists Ladenburg and Oelschlägel, who used a sample that had been isolated from Ephedra vulgaris by the Merck pharmaceutical corporation of Darmstadt, Germany.  The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in a fixed-dose combination with one or more additional active ingredients such as antihistamines, guaifenesin, dextromethorphan, paracetamol (acetaminophen) or an NSAID (such as aspirin or ibuprofen).

Medical uses
Pseudoephedrine is a stimulant, but it is well known for shrinking swollen nasal mucous membranes, so it is often used as a decongestant. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. The same vasoconstriction action can also result in hypertension, which is a noted side effect of pseudoephedrine.
Pseudoephedrine can be used either as oral or as topical decongestant. Due to its stimulating qualities, however, the oral preparation is more likely to cause adverse effects, including urinary retention. According to one study, pseudoephedrine may show effectiveness as an antitussive drug (suppression of cough).Pseudoephedrine is indicated for the treatment of nasal congestion, sinus congestion and Eustachian tube congestion. Pseudoephedrine is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.Pseudoephedrine is also used as a first-line prophylactic for recurrent priapism.  Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Treatment for urinary incontinence is an off-label use ("unlabeled use") for these medications.

Adverse effects
Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include central nervous system stimulation, insomnia, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include tachycardia or palpitations. Rarely, pseudoephedrine therapy may be associated with mydriasis (dilated pupils), hallucinations, arrhythmias, hypertension, seizures and ischemic colitis; as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption. Pseudoephedrine, particularly when combined with other drugs including narcotics, may also play a role in the precipitation of episodes of paranoid psychosis. It has also been reported that pseudoephedrine, among other sympathomimetic agents, may be associated with the occurrence of stroke.

Precautions and contraindications
Pseudoephedrine is contraindicated in patients with diabetes mellitus, cardiovascular disease, severe or uncontrolled hypertension, severe coronary artery disease, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma, or by pregnant women. The safety and effectiveness of nasal decongestant use in children is unclear.

Interactions
Concomitant or recent (previous fourteen days) monoamine oxidase inhibitor use can lead to hypertensive reactions, including hypertensive crises.The antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids may be reduced by sympathomimetics. Beta-adrenergic antagonists may also interact with sympathomimetics. Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Antacids increase the rate of pseudoephedrine absorption, while kaolin decreases it.

Mechanism of action
Pseudoephedrine is a sympathomimetic amine. Its principal mechanism of action relies on its direct action on the adrenergic receptor system.  The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively. α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. Activation of β2-adrenergic receptors produces relaxation of smooth muscle of the bronchi,  causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.

Other uses
There have been reports of off-label uses of pseudoephedrine for its stimulant properties. Long-distance truck drivers and athletes, for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.A study has also found that pseudoephedrine can reduce milk production in breastfeeding women.

Manufacture of amphetamines
Its membership in the amphetamine class has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, many pharmaceutical firms have reformulated, or are in the process of reformulating medications to use alternative, but less effective, decongestants, such as phenylephrine.
In the United States, federal laws control the sale of pseudoephedrine-containing products. Many retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification. These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

Sports
Pseudoephedrine was on the International Olympic Committees (IOC) banned substances list until 2004, when the World Anti-Doping Agency (WADA) list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it went back onto the "banned" list on January 1, 2010.Pseudoephedrine is excreted through urine, and concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals. Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (µg/ml) with mean ± standard deviation 149 ± 72 µg/ml. Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 µg/ml set by WADA for about half of all users. Furthermore, hydration status does not affect urinary concentration of pseudoephedrine.Canadian rower Silken Laumann was stripped of her 1995 Pan American Games team gold medal after testing positive for pseudoephedrine.In February 2000, Elena Berezhnaya and Anton Sikharulidze won gold at the 2000 European Figure Skating Championships but were stripped of their medals after Berezhnaya tested positive. This resulted in a three-month disqualification from the date of the test, and the medal being stripped. She stated that she had taken cold medication approved by a doctor but had failed to inform the ISU as required. The pair missed the World Championships that year as a result of the disqualification.
Romanian gymnast Andreea Răducan was stripped of her gold medal at the 2000 Summer Olympic Games after testing positive. She took two pills given to her by the team coach for a cold. Although she was stripped of the overall gold medal, she kept her other medals, and, unlike in most other doping cases, was not banned from competing again; only the team doctor was banned for a number of years. Ion Ţiriac, the president of the Romanian Olympic Committee, resigned over the scandal.In the 2010 Winter Olympic Games, the IOC issued a reprimand against the Slovak ice hockey player Lubomir Visnovsky for usage of pseudoephedrine.In the 2014 Winter Olympic Games Team Sweden and Washington Capitals ice hockey player Nicklas Bäckström was prevented from playing in the final for usage of pseudoephedrine. Bäckström claimed he was using it as allergy medication. In March 2014, the IOC Disciplinary Commission decided that Bäckström would be awarded the silver medal. In January 2015 Bäckström, the IOC, WADA and the IIHF agreed to a settlement in which he accepted a reprimand but was cleared of attempting to enhance his performance.

Detection of use
Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but chromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50–300 µg/l range in persons taking the drug therapeutically, 500–3000 µg/l in people with substance use disorder involving pseudoephedrine, or poisoned patients and 10–70 mg/l in cases of acute fatal overdose.

Chemistry
Pseudoephedrine is a diastereomer of ephedrine and is readily reduced into methamphetamine or oxidized into methcathinone.

Nomenclatures
The dextrorotary (+)- or d- enantiomer is (1S,2S)-pseudoephedrine, whereas the levorotating (−)- or l- form is (1R,2R)-pseudoephedrine.
In the outdated D/L system (+)-pseudoephedrine is also referred to as L-pseudoephedrine and (−)-pseudoephedrine as D-pseudoephedrine (in the Fisher projection then the phenyl ring is drawn at bottom).Often the D/L system (with small caps) and the d/l system (with lower-case) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly named D-pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly L-ephedrine.
The IUPAC names of the two enantiomers are (1S,2S)- respectively (1R,2R)-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are psi-ephedrine and threo-ephedrine.
Pseudoephedrine is the International Nonproprietary Name of the (+)-form, when used as pharmaceutical substance.

Society and culture
Brand names
The following is a list of consumer medicines that either contain pseudoephedrine or have switched to a less-regulated alternative such as phenylephrine.

Actifed (made by GlaxoSmithKline) — contains 60 mg pseudoephedrine and 2.5 mg triprolidine in certain countries.
Advil Cold & Sinus (made by Pfizer Canada Inc.) — contains 30 mg pseudoephedrine hydrochloride and 200 mg Ibuprofen.
Aleve-D Sinus & Cold (made by Bayer Healthcare) — contains 120 mg pseudoephedrine hydrochloride (also 220 mg naproxen).
Allegra-D (made by Sanofi Aventis) — contains 120 mg of pseudoephedrine hydrochloride (also 60 mg of fexofenadine).
Allerclear-D (made by Kirkland Signature) — contains 240 mg of pseudoephedrine sulfate (also 10 mg of loratadine).
Benadryl Plus (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 60 mg pseudoephedrine hydrochloride (also 8 mg acrivastine)
Cirrus (made by UCB) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg cetirizine).
Claritin-D (made by Bayer Healthcare) — contains 120 mg of pseudoephedrine sulfate (also 5 mg of loratadine).
Claritin-D 24 Hour (made by Bayer Healthcare) — contains 240 mg of pseudoephedrine sulfate (also 10 mg of loratadine).
Codral (made by Asia-Pacific subsidiary of Johnson & Johnson) — Codral Original contains pseudoephedrine, Codral New Formula substitutes phenylephrine for pseudoephedrine.
Congestal (made by SIGMA Pharmaceutical Industries) — contains 60 mg pseudoephedrine hydrochloride  (also 650 mg paracetamol and 4 mg chlorpheniramine).
Contac (made by GlaxoSmithKline) — previously contained pseudoephedrine, now contains phenylephrine. As at Nov 2014 UK version still contains 30 mg pseudoephedrine hydrochloride per tablet.
Demazin (made by Bayer Healthcare) — contains pseudoephedrine sulfate and chlorpheniramine maleate
Eltor (made by Sanofi Aventis) — contains pseudoephedrine hydrochloride.
Mucinex D (made by Reckitt Benckiser) — contains 60 mg pseudoephedrine hydrochloride (also 1200 mg guaifenesin).
Nexafed (made by Acura Pharmaceuticals) — contains 30 mg pseudoephedrine per tablet, formulated with Impede Meth-Deterrent technology.
Nurofen Cold & Flu (made by Reckitt Benckiser) — contains 30 mg pseudoephedrine hydrochloride (also 200 mg ibuprofen).
Respidina – contains 120 mg of pseudoephedrine in the form of extended release tablets.
Rhinex Flash (made by Pharma Product Manufacturing, Cambodia) — contains pseudoephedrine combined with paracetamol and triprolidine.
Rhinos SR (made by Dexa Medica) — contains 120 mg of pseudoephedrine hydrochloride (also 5 mg loratadine).
Rino-Ebastel (made by Almirall) – contains 120 mg of pseudoephedrine hydrochloride (also 10 mg ebastine).
Sinufed (made by Trima) — contains 60 mg pseudoephedrine hydrochloride.
Sinutab (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 500 mg paracetamol and 30 mg pseudoephedrine hydrochloride.
Sudafed Decongestant (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 60 mg of pseudoephedrine hydrochloride.
Theraflu (made by Novartis) — previously contained pseudoephedrine, now contains phenylephrine.
Unifed (made by United Pharmaceutical Manufacturer, Jordan) — contains pseudoephedrine hydrochloride (also triprolidine and guaifenesin).
Zyrtec-D 12 Hour (made by McNeil Consumer Healthcare, a Johnson & Johnson company) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg of cetirizine).
Zephrex-D (made by Westport Pharmaceuticals) – a special meth-resistant form of pseudoephedrine that becomes gooey when heated

Legal status
Australia
Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. As of 2006, all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.
Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP. This system aims to prevent individuals from purchasing small quantities of pseudoephedrine from many different pharmacies.
As a result, many pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, a phenylephrine product that has not been proven effective in clinical trials.

Canada
Health Canada has investigated the risks and benefits of pseudoephedrine and ephedrine/Ephedra. Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may have strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephrine with other stimulants like caffeine. They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine.Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present.

Colombia
The Colombian government prohibited the trade of pseudoephedrine in 2010.

Japan
Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan.

Mexico
On 23 November 2007, the use and trade of pseudoephedrine in Mexico was made illegal as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine.

Netherlands
Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects.

New Zealand
In New Zealand, pseudoephedrine is currently classified as a Class B Part II controlled drug in the Misuse of Drugs Act 1975, making it illegal to supply or possess except on prescription.Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine. New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined for methamphetamine production. On 9 October 2009, Prime Minister John Key announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug. The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011.

Turkey
In Turkey, medications containing pseudoephedrine are available with prescription only.

United Kingdom
In the UK, pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007, the MHRA reacted to concerns over diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over the counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April 2008. No form of ID is required.

United States
Federal
The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice.
Attempts to control the sale of the drug date back to 1986, when federal officials at the Drug Enforcement Administration (DEA) first drafted legislation, later proposed by Senator Bob Dole, that would have placed a number of chemicals used in the manufacture of illicit drugs under the Controlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward, and were successful in exempting from the regulations all chemicals that had been turned into a legal final product, such as Sudafed.Prior to the passage of the Combat Methamphetamine Epidemic Act of 2005, sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the western United States. When purity dropped, so did the number of people in rehab and people admitted to emergency rooms with methamphetamine in their systems. This reduction in purity was usually short lived, however, as methamphetamine producers eventually found a way around the new regulations.Congress passed the Combat Methamphetamine Epidemic Act of 2005 ("CMEA") as an amendment to the renewal of the USA Patriot Act. Signed into law by president George W. Bush on March 6, 2006, the act amended 21 U.S.C. § 830, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by April 8, 2006, and the second to be completed by September 30, 2006. The first phase dealt primarily with implementing the new buying restrictions based on amount, while the second phase encompassed the requirements of storage, employee training, and record keeping. Though the law was mainly directed at pseudoephedrine products it also applies to all over-the-counter products containing ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers,
and salts of optical isomers.
Pseudoephedrine was defined as a "scheduled listed chemical product" under 21 U.S.C. § 802(45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:

Required a retrievable record of all purchases, identifying the name and address of each party, to be kept for two years
Required verification of proof of identity of all purchasers
Required protection and disclosure methods in the collection of personal information
Required reports to the Attorney General of any suspicious payments or disappearances of the regulated products
Required training of employees with regard to the requirements of the CMEA. Retailers must self-certify as to training and compliance.
The non-liquid dose form of regulated products may only be sold in unit dose blister packs
Regulated products must be stored behind the counter or in a locked cabinet in such a way as to restrict public access
Sales limits (per customer):
Daily sales limit—must not exceed 3.6 grams of pseudoephedrine base without regard to the number of transactions
30-day (not monthly) sales limit—must not exceed 7.5 grams of pseudoephedrine base if sold by mail order or "mobile retail vendor"
30-day purchase limit—must not exceed 9 grams of pseudoephedrine base. (A misdemeanor possession offense under 21 U.S.C. § 844a for the person who buys it.)In regards to the identification that may be used by an individual buying pseudoephedrine products the following constitute acceptable forms of identification:

US passport
Alien registration or permanent resident card
Unexpired foreign passport with temporary I-551 stamp
Unexpired Employment Authorization Document
Drivers License or Government issued identification card (including Canadian drivers license)
School ID with picture
Voters Registration card
US Military Card
Native American tribal documentsThe requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser:
Presents a government issued photographic identification; and
Signs the written logbook with their name, address, and time and date of the sale

State
Most states also have laws regulating pseudoephedrine.The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii (as of May 1, 2009) Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009), Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter". Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers.
The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However as of January 1, 2022 these restrictions have been repealed  The state of Oregon reduced the number of methamphetamine lab seizures from 467 in 2004 (the final full year before implementation of the prescription only law) to a new low of 12 in 2009. The decrease in meth lab incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titled Pseudoephedrine Prescription Laws in Oregon and Mississippi. The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices". Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, including Washington, Union, New Haven, Cape Girardeau and Ozark. Certain pharmacies in Terre Haute, Indiana do so as well.Another approach to controlling the drug on the state level mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Thirty-two states now require the National Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. Prior to implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004, but were reduced to 955 in 2005, and 589 in 2009. Kentuckys program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased. Oklahoma initially experienced success with their tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. In 2008, however, seizures began rising again, and have continued to rise in 2009.  Nonetheless, when Oklahoma adopted NPLEx, their lab seizures also dropped significantly.
NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale </s>