Persius/hicric huggingface dataset:
Darunavir indications and usage

# Indications and Usage

### Adult Patients
PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.
This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naive and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

### Pediatric Patients
PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and older.
The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects(24-week analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one trial in patients 3 to less than 6 years of age) . The indication for treatment-naive pediatric patients or antiretroviral treatment-experienced patients with no darunavir resistance associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naive subjects 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.
In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with PREZISTA/ritonavir:
Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/ritonavir.
The use of other active agents with PREZISTA/ritonavir is associated with a greater likelihood of treatment response.
David Nicholson (civil servant)
David Nicholson CBE is an administrator in the English National Health Service, appointed its Chief Executive in September 2006.
Nicholson graduated from Bristol University with a 2:1 in History and Politics. In the 1970s he was a member of the Communist Party and remained so until 1983. 
In 1988, Nicholson was appointed as the Chief Executive in the first wave Doncaster Royal Infirmary NHS Trust. He introduced Clinical Directorates there in 1988 and the Trust was a national pilot for Total Quality Management. In 1997, he moved to the Trent NHS Regional Office as the Regional Director of Performance before being appointed as Regional Director in November 2000.
Nicholson was then made Regional Director for the old Eastern and West Midlands Regions between December 2001 and March 2002, combining these responsibilities with his Trent role whilst shadowing as Director of Health and Social Care (designate) for the Midlands and East of England. In April 2002 he formally took up the post of Director of Health and Social Care for the Midlands and East of England and had responsibility for 8 Strategic Health Authorities covering 20 million population.
In 2003 he was appointed Chief Executive of Birmingham and The Black Country Strategic Health Authority (BBC SHA).  In August 2005 he was asked to take on the additional roles of Chief Executive of neighbouring Shropshire and Staffordshire SHA and West Midlands South SHA.
In April 2006 he was appointed Chief Executive of the newly formed London Strategic Health Authority. However he had little opportunity to make his mark, as it was announced on 27th July 2006 that he would be taking up the role of NHS Chief Executive in September 2006 in charge of a 90bn budget and 1.3m employees.. This became his fifth job-change in a year.
Nicholson was awarded a CBE in the 2004 New Years Honours list, and received the honorary award of Doctor of the University from the University of Central England, Birmingham.
He has two sons (one a recent graduate and one studying at University) and is a passionate supporter of Nottingham Forest Football Club.
Degrees of freedom (statistics)

# Overview
In statistics, the term degrees of freedom has two distinct senses.

# Residuals
In fitting statistical models to data, the vectors of residuals are often constrained to lie in a space of smaller dimension than the number of components in the vector.  That smaller dimension is the number of degrees of freedom for error.
Perhaps the simplest example is this.  Suppose
are random variables each with expected value , and let
be the "sample mean".  Then the quantities
are residuals that may be considered estimates of the errors Xi  .  The sum of the residuals (unlike the sum of the errors) is necessarily 0.  That means they are constrained to lie in a space of dimension n  1.  If one knows the values of any n  1 of the residuals, one can thus find the last one.
One says that "there are n  1 degrees of freedom for error."
An only slightly less simple example is that of least squares estimation of a and b in the model
where i, and hence Yi are random.  Let \widehat{a} and \widehat{b} be the least-squares estimates of a and b.  Then the residuals
are constrained to lie within the space defined by the two equations
One says that there are n  2 degrees of freedom for error.
The capital Y is used in specifying the model, and lower-case y in the definition of the residuals.  That is because the former are hypothesized random variables and the latter are data.
Another simple and frequently seen example arises in multiple comparisons.

# Parameters in probability distributions
The probability distributions of residuals are often parametrized by these numbers of degrees of freedom.  Thus one speaks of a chi-square distribution with a specified number of degrees of freedom, an F-distribution, a Student's t-distribution, or a Wishart distribution with specified numbers of degrees of freedom in the numerator and the denominator respectively.
In the familiar uses of these distributions, the number of degrees of freedom takes only integer values.  The underlying mathematics in most cases allows for fractional degrees of freedom, which can arise in more sophisticated uses.
Diabetes mellitus and pregnancy

# Overview
For women with diabetes mellitus, pregnancy can present some particular challenges for both mother and child. If the woman who is pregnant has diabetes or develops diabetes during pregnancy, it can cause early labor, birth defects, and very large babies.

# Physiology
During a normal pregnancy, a lot of physiological changes occur that influence blood glucose levels, such as a glucose-'drain' to the fetus, slowed emptying of the stomach, increased excretion of glucose by the kidneys and resistance of cells to insulin.

# Risks for the child
Miscarriage, growth restriction, growth acceleration, fetal obesity (macrosomia), polyhydramnios. Birth defects are not currently an identified risk for the child of women with gestational diabetes.

# Risks for the mother
Disturbed blood glucose levels. Hypoglycaemia can occur without warning.

# Treatment of pregnant women with diabetes
Blood glucose levels in the pregnant woman should be regulated as strictly as possible. In diabetes mellitus type 2, oral antidiabetic drugs should be replaced with insulin.
Dihydropyrimidine dehydrogenase
Dihydropyrimidine dehydrogenase (DPD) is an enzyme that is involved in pyrimidine degradation that in humans is encoded by the DPYD gene. It is the initial and rate-limiting step in pyrimidine catabolism. It catalyzes the reduction of uracil and thymine. It is also involved in the degradation of the chemotherapeutic drugs 5-fluorouracil and tegafur.

# Function
The protein is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy.

# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
-  The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Disorders of calcium metabolism

# Overview
Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body.
The amount of biologically active calcium varies with the level of serum albumin, a protein to which calcium is bound, and therefore levels of ionized calcium are better measures than a total calcium; however, one can correct a total calcium if the albumin level is known.
- A normal ionized calcium is 1.12-1.45  mmol/L (4.54-5.61 mg/dL).
- A normal total calcium is 2.2-2.6 mmol/L (9-10.5 mg/dl).
Total calcium of less than 8.0 mg/dL is hypocalcaemia, with levels below 1.59 mmol/L (6 mg/dL) generally fatal.
Total calcium of more than 11.111 mg/dL is hypercalcaemia, with levels over 3.753 mmol/L (15.12 mg/dL) generally fatal.
- Total calcium of less than 8.0 mg/dL is hypocalcaemia, with levels below 1.59 mmol/L (6 mg/dL) generally fatal.
- Total calcium of more than 11.111 mg/dL is hypercalcaemia, with levels over 3.753 mmol/L (15.12 mg/dL) generally fatal.
Doripenem indications and usage

# Indications and Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAX and other antibacterial drugs, DORIBAX should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

## Complicated Intra-Abdominal Infections
DORIBAX (doripenem for injection) is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

## Complicated Urinary Tract Infections, Including Pyelonephritis
DORIBAX (doripenem for injection) is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.
Downregulation and upregulation
Downregulation is the process by which a cell decreases the number of a cellular component, such as RNA or protein, in response to an external variable. An increase of component is called upregulation.
An example of downregulation is that the cell decreases the number of receptors to a given hormone or neurotransmitter to reduce its sensitivity to this molecule. This is a locally acting negative feedback mechanism.
An example of upregulation is that liver cell increases the number of Cytochrome P450 enzymess when xenobiotic molecules, such as dioxin, are detected in order to degrade them.

# Receptor downregulation

## Mechanism
For insulin, the process of downregulation occurs when there are elevated levels of the hormone in the blood.  When insulin binds to its receptors on the surface of a cell, endocytosis of the hormone receptor complex is initiated, only to be subsequently attacked by intracellular lysosomal enzymes.  The internalization is multi-purposed, as it provides the pathway for degradation of the hormone and also a way to regulate the number of sites that are available for binding on the cells surface.  At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding.  The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction.  Over time, this self-induced loss of target cell receptors for insulin reduces the target cells sensitivity to the elevated hormone concentration. 
The process of decreasing the number of receptor sites is virtually the same for all hormones; it only varies in the receptor hormone complex.

## Cases
To illustrate this process we shall look at the insulin receptor sites on the target cells of a type 2 diabetic.  Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the -cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match the demand and return the blood to homeostatic levels.  The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the persons cell to downregulate and decrease the number of receptors for insulin, increasing the subjects resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin.  This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated.  This is the more common process of insulin resistance, which in turn leads to adult onset diabetes in that subject.
Other cases include Diabetes insipidus; here the kidneys become insensitive to arginine vasopressin.

## Reversal
There are ways to counteract this process; using the previous example a type 2 diabetic may increase their sensitivity to insulin through proper diet and regular exercise producing weight loss; some may even return to their pre-diabetic state following this regimen.
Doxycycline calcium description

# Description
Vibramycin is an antibacterial drug synthetically derived from oxytetracycline, and is available as Vibramycin Monohydrate (doxycycline monohydrate); Vibramycin Hyclate and Vibra-Tabs (doxycycline hydrochloride hemiethanolate hemihydrate); and Vibramycin Calcium (doxycycline calcium) for oral administration.
The structural formula of doxycycline monohydrate is
with a molecular formula of C22H24N2O8H2O and a molecular weight of 462.46. The chemical designation for doxycycline is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C22H24N2O8HCl)2C2H6OH2O and the molecular weight is 1025.89. Doxycycline is a light-yellow crystalline powder. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water.
Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.
Inert ingredients in the syrup formulation are: apple flavor; butylparaben; calcium chloride; carmine; glycerin; hydrochloric acid; magnesium aluminum silicate; povidone; propylene glycol; propylparaben; raspberry flavor; simethicone emulsion; sodium hydroxide; sodium metabisulfite; sorbitol solution; water.
Inert ingredients in the capsule formulations are: hard gelatin capsules (which may contain Blue 1 and other inert ingredients); magnesium stearate; microcrystalline cellulose; sodium lauryl sulfate.
Inert ingredients for the oral suspension formulation are: carboxymethylcellulose sodium; Blue 1; methylparaben; microcrystalline cellulose; propylparaben; raspberry flavor; Red 28; simethicone emulsion; sucrose.
Inert ingredients for the tablet formulation are: ethylcellulose; hypromellose; magnesium stearate; microcrystalline cellulose; propylene glycol; sodium lauryl sulfate; talc; titanium dioxide; Yellow 6 Lake.
Doxycycline hyclate description

# Description
Doxycycline for Injection, USP is a sterile, lyophilized powder prepared from a solution of doxycycline hyclate, ascorbic acid and mannitol in Water for Injection.  Doxycycline hyclate is a broad spectrum antibiotic derived from oxytetracycline.  It is meant for INTRAVENOUS use only after reconstitution.  Doxycycline hyclate is a yellowish crystalline powder which is chemically designated 4-(Dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-de monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:
(C22H24N2 O8 - HCl)2 - C2H6O - H2O             1025.89
Doxycycline hyclate is soluble in water and chars at 201C without melting.  The base doxycycline has a high degree of lipid solubility and a low affinity for calcium binding.  It is highly stable in normal human serum.
Each 100 mg vial contains: Doxycycline hyclate equivalent to 100 mg doxycycline; ascorbic acid 480 mg; mannitol 300 mg.  pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.
Each 200 mg vial contains: Doxycycline hyclate equivalent to doxycycline 200 mg; ascorbic acid 960 mg; mannitol 600 mg.  pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.
Estrogen insensitivity syndrome
The estrogen insensitivity syndrome (EIS) is a form of congenital estrogen deficiency caused by a defective estrogen receptor (ER). Thus, estrogens cannot be recognized and initiate their biological action.
In humans, the condition is very rare and occurs sporadic. Only a few cases have been described.  A reported male with EIS was tall as estrogens are not present to close the epiphyseal line, at risk for osteoporosis, and sterile (suggesting that estrogens are necessary for reproduction).

# ERKO mice
Estrogen insensitivity syndrome of  can be experimentally induced in animals, typically mice, by knocking out the estrogen receptor. In so-called ERKO mice different estrogens receptors can be disabled allowing to study the role of such receptors.  ERKO mice show development of  the respective female or male reproductive systems, and are sterile if both, alpha and beta estrogen receptors are defective. The hypoplastic uterus does not respond to exogenous stimulation by estrogens. Males are infertile with atrophy in the testes. Bones age is delayed and bones are more brittle. Variations in these patterns can be achieved by selectively disabling the alpha or beta ERs.

# AIS
In contrast to EIS, the androgen insensitivity syndrome (AIS) where the androgen receptor is defective is relatively common. This can be explained by the genetics of each syndrome. AIS is a X-linked recessive condition and thus carried over into future generations. EIS is not compatible with reproduction, thus each occurrence in humans would have to be a de-novo mutation and is not transmitted to offspring.
Congenital estrogen deficiency can also be caused by a defect in the aromatizing enzyme.
Early prostate cancer antigen-2

# Overview
Early prostate cancer antigen-2 (EPCA-2) is a protein of which blood levels are elevated in prostate cancer. It appears to provide more accuracy in identifying early prostate cancer than the standard prostate cancer marker, PSA.

# EPCA-2 versus PSA
The steady decrease in prostate cancer mortality is indirect evidence that the early detection using serum PSA and rectal examination saves lives.
However using serum PSA in screening for prostate cancer remains controversial, because of its low specificity.
Leman and colleagues describe, in the April 2007 issue of Urology, the performance characteristic of EPCA-2, a novel nuclear protein marker for prostate cancer cells.
A study was initiated which suggested that the EPCA-2 protein serum assay exhibits favorable performance characteristics which are  potentially superior to serum PSA. However more studies are necessary to see if this test will retain its sensitivity when used in a screening population.
Econazole clinical pharmacology

# CLINICAL PHARMACOLOGY

## Mechanism of Action
Ecoza topical foam is an azole antifungal .

## Pharmacodynamics
The pharmacodynamics of Ecoza topical foam, 1% have not been established.

## Pharmacokinetics
The systemic absorption of Ecoza topical foam, 1% following topical application was studied in one clinical trial in adults and one clinical study in pediatric subjects.
In the adult trial, 19 subjects (male and female) with tinea pedis applied Ecoza topical foam, 1% once daily for 29 days.  Subjects applied a mean daily amount of 2.4 g of Ecoza topical foam, 1% to soles, toes, interdigital spaces and tops of both feet up to the ankles. Blood samples were obtained on Day 29 at pre-dose and 1, 2, 4, 6, 8, and 12 hours after application.  Results (mean  SD) showed the time to reach peak plasma concentrations (Tmax) was 6.8  5.1 h with maximum concentration (Cmax) of 417  218 pg/ml. The area under the concentration time curve for the first 12 hours post application on Day 29 (AUC(0-12)) was 3440  1920 pg-h/ml.
In the pediatric trial, 18 subjects (male and female ages 12 to 17) with interdigital tinea pedis and positive fungal cultures were treated with Ecoza topical foam, 1% once daily for 4 weeks.  Subjects applied a mean daily amount of 3.2 g of Ecoza topical foam, 1% to soles, toes, interdigital spaces and tops of both feet up to the ankles.  Blood samples were obtained on Day 28 at pre-dose and 7 h and 11 h post-dose. The mean  SD econazole plasma concentration was 397  289, 534  745 and 575  638 pg/mL at pre-dose and 7 h and 11 h post-dose, respectively.