Persius/hicric huggingface dataset:
Valproate sodium patient counseling information

# Patient Counseling Information

### Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly .

### Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly .

### Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death .
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

### Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur .

### CNS Depression
Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

### Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately .
Corticosteroid 11-beta-dehydrogenase isozyme 2
Corticosteroid 11--dehydrogenase isozyme 2 also known as 11--hydroxysteroid dehydrogenase 2 is an enzyme that in humans is encoded by the HSD11B2 gene.

# Function
Corticosteroid 11--dehydrogenase isozyme 2 is an NAD+-dependent enzyme expressed in aldosterone-selective epithelial tissues such as the kidney, colon, salivary and sweat glands. HSD211B2 expression is also found in the brainstem in a small, aldosterone-sensitive subset of neurons located in the nucleus of the solitary tract referred to as HSD2 neurons.
In these tissues, HSD11B2 oxidizes the glucocorticoid cortisol to the inactive metabolite cortisone, thus preventing illicit activation of the mineralocorticoid receptor. This protective mechanism is necessary because cortisol circulates at 100-1000-fold higher concentrations than aldosterone, and binds with equal affinity to the mineralocorticoid receptor, thereby out-competing aldosterone in cells that do not produce HSD11B2.
This glucocorticoid-inactivating enzyme is also expressed in tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, as well as parts of the developing brain, including the rhombencephalic progenitor cells that proliferate into cerebellar granule cells. In these tissues, HSD11B2 protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development.

# Clinical significance
Inhibition of this enzyme, for example by a compound in liquorice, results in a condition known as pseudohyperaldosteronism. A genetically inherited deficiency of HSD11B2 is the underlying cause of the syndrome of apparent mineralocorticoid excess.
Aryl hydrocarbon receptor nuclear translocator
The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the beta subunit of a heterodimeric transcription factor, hypoxia-inducible factor 1 (HIF1). A t(1;12)(q21;p13) translocation, which results in a TEL-ARNT fusion protein, is associated with acute myeloblastic leukemia. Three alternatively spliced variants encoding different isoforms have been described for this gene.
The aryl hydrocarbon receptor (AhR) is involved in the induction of several enzymes that participate in xenobiotic metabolism. The ligand-free, cytosolic form of the aryl hydrocarbon receptor is complexed to heat shock protein 90. Binding of ligand, which includes dioxin and polycyclic aromatic hydrocarbons, results in translocation of the ligand-binding subunit only to the nucleus. Induction of enzymes involved in xenobiotic metabolism occurs through binding of the ligand-bound AhR to xenobiotic responsive elements in the promoters of genes for these enzymes.

# Interactions
Aryl hydrocarbon receptor nuclear translocator has been shown to interact with:
- AIP,
- AHR,
- EPAS1,
- HIF1A,
- NCOA2,
- SIM1, and
- SIM2.
ATP-dependent Clp protease proteolytic subunit
ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene. This protein is an essential component to form the protein complex of Clp protease (Endopeptidase Clp).

# Structure
Enzyme ClpP is a highly conserved serine protease present throughout bacterial and also found in the mitochondria  and chloroplasts of eukaryotic cells. The ClpP monomer is folded into three subdomains: the "handle", the globular "head", and the N-terminal region. By itself, ClpP can assemble into a tetradecamer complex (14-members) and form a closed proteolytic chamber. A fully assembled Clp protease complex has a barrel-shaped structure in which two stacked ring of proteolytic subunits (ClpP or ClpQ) are either sandwiched between two rings or single-caped by one ring of ATPase-active chaperon subunits (ClpA, ClpC, ClpE, ClpX or ClpY). ClpXP is presented in almost all bacteria while ClpA is found in the Gram-negative bacteria, ClpC in Gram-Positive bacteria and cyanobacteria. ClpAP,  ClpXP and ClpYQ coexist in E. Coli while only ClpXP complex in present in humans.

# Function
In bacteria, it was shown that ClpP is capable to cleave full-length proteins without being associated with ClpA but the degradation is at a much slower rate. Fully functional Clp protease requires the participation of AAA+ ATPase. These ClpX chaperons recognize, unfold and transfer protein substrates to proteolytic core formed by ClpP tetradecamer. The proteolytic sites of ClpP subunits contain hydrophobic grooves which recruit substrate and host the catalytic triad Asp-His-Ser. 
In several bacteria, such as E. coli, proteins tagged with the SsrA peptide (ANDENYALAA) encoded by tmRNA are digested by Clp proteases.
The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane.

# Clinical Significance
ClpP protease is a major contributor for mitochondrial protein quality control system and removing damaged or misfolded proteins in mitochondrial matrix. Defects in mitochondrial Clp proteases have been associated with the progression of neurodegenerative diseases while upregulation of ClpP proteases has been implicated in preventing premature aging. Recessive CLPP mutations were recently observed in the human Perrault variant associating with ovarian failure and sensorineural hearing loss, in parallel with growth retardation. The clinical phenotype was accompanied by the accumulation of ClpP associating partner chaperon ClpX, mtRNA, and inflammatory factors. The disease pathological cause probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction.
Adult Blood Lead Epidemiology and Surveillance
The National Institute for Occupational Safety and Health funds the Adult Blood Lead Epidemiology and Surveillance (ABLES)program, a state-based surveillance program of laboratory-reported adult blood lead levels. The goal of ABLES is to reduce the rate of adults(age 16 or older) who have blood lead levels of 25 micrograms per deciliter (mcg/dL) or greater (objective 20.7 in Healthy People 2010) . The ABLES program objective is to build state capacity to initiate or improve adult blood lead surveillance programs which can accurately measure trends in adult blood lead levels and which can effectively intervene to prevent lead over-exposures.

# Health Effects
Elevated blood lead levels (BLL's) in adults can damage the nervous, hematologic, reproductive, renal, cardiovascular, and gastrointestinal systems. The majority of cases are workplace-related. During 2003--2004, the industry sectors with the highest annual average numbers of resident adults with elevated BLLs were manufacturing, 4,622 (69%); construction, 1,252 (19%); and mining, 488 (7%). The specific industries with the highest numbers were manufacture of storage batteries, 2,499; painting, paperhanging, and decorating, 626; and mining of lead ores, 482.   U.S. Department of Health and Human Services recommends that BLLs among all adults be reduced to <25 g/dL. The highest BLL acceptable by standards of the U.S. Occupational Safety and Health Administration is 40 g/dL.
 The geometric mean BLL of all adults in the United States is <3 g/dL.

# Program Description
ABLES state interventions to prevent lead over-exposures include: (1) conducting follow-up interviews with physicians, employers, and workers; (2) investigating work sites; (3) providing technical assistance; (4) providing referrals for consultation and/or enforcement; and (5) developing and disseminating educational materials and outreach programs.
ABLES states are required to have a mandatory state requirement that laboratories report blood lead level results to the state health department or designee. The lowest blood lead level to be reported varies from state to state.
Lead may be taken home from the workplace on clothes or in cars potentially exposing spouses and children. Children who come in contact with lead-exposed workers should be targeted for blood lead screening.

# ABLES States
The ABLES program collects data from 40 funded states:
Alabama,
Alaska,
Arizona,
California,
Connecticut,
Florida,
Georgia,
Hawaii,
Illinois,
Indiana,
Iowa,
Kansas,
Kentucky,
Louisiana,
Maine, 
Maryland,
Massachusetts,
Michigan,
Maine,
Missouri,
Montana,
Nebraska,
New Hampshire,
New Jersey,
New Mexico,
New York,
North Carolina,
Ohio,
Oklahoma,
Oregon,
Pennsylvania,
Rhode Island,
South Carolina,
Tennessee,
Texas,
Utah,
Vermont,
Washington,
Wisconsin, and
Wyoming.
Advances in catheter based physical treatments

# Overview

# Advances in catheter based physical treatments
Interventional procedures have been plagued by restenosis due to the formation of endothelial tissue overgrowth at the lesion site. Restenosis is the body's response to the injury of the vessel wall from angioplasty and to the stent as a foreign body. As assessed in clinical trials during the late 1980 and 1990s, using only balloon angioplasty (POBA, plain old balloon angioplasty), up to 50% of patients suffered significant restenosis but that percentage has dropped to the single to lower two digit range with the introduction of drug-eluting stents. Sirolimus and paclitaxel are the two drugs used in coatings which are currently FDA approved in the United States. As opposed to bare metal, drug eluting stents are covered with a medicine that is slowly dispersed with the goal of suppressing the restenosis reaction.
The key to the success of drug coating has been;
- choosing effective agents,
- developing ways of adequately binding the drugs to the stainless surface of the stent struts (the coating must stay bound despite marked handling and stent deformation stresses) and
- developing coating controlled release mechanisms that release the drug slowly over about 30 days.
Amphotericin B cholesteryl sulfate description

# Description
AMPHOTEC is a sterile, pyrogen-free, lyophilized powder for reconstitution and intravenous (IV) administration. AMPHOTEC consists of a 1:1 (molar ratio) complex of amphotericin B and cholesteryl sulfate. Upon reconstitution, AMPHOTEC forms a colloidal dispersion of microscopic disc-shaped particles.
Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drugs functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products.
Amphotericin B is an antifungal polyene antibiotic produced by a strain of Streptomyces nodosus.
Amphotericin B, which is the established name for -33--1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo nonatriaconta-19,21,23,25,27, 29,31-heptaene-36-carboxylic acid, has the following structure:
The molecular formula of the drug is C47H73NO17; its molecular weight is 924.10.
AMPHOTEC is available in 50 mg and 100 mg single dose vials. Each 50 mg single dose vial contains amphotericin B, 50 mg; sodium cholesteryl sulfate, 26.4 mg; tromethamine, 5.64 mg; disodium edetate dihydrate, 0.372 mg; lactose monohydrate, 950 mg; and hydrochloric acid, qs, as a sterile, nonpyrogenic, lyophilized powder. Each 100 mg single dose vial contains amphotericin B, 100 mg; sodium cholesteryl sulfate, 52.8 mg; tromethamine, 11.28 mg; disodium edetate dihydrate, 0.744 mg; lactose monohydrate, 1900 mg; and hydrochloric acid, qs, as a sterile, nonpyrogenic, lyophilized powder.
Amphotericin B lipid complex adverse reactions

# Adverse Reactions
The total safety data base is composed of 921 patients treated with ABELCET (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with ABELCET, 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.
In general, the adverse events most commonly reported with ABELCET were transient chills and/or fever during infusion of the drug.
The following adverse events have also been reported in patients using ABELCET in open-label, uncontrolled clinical studies. However, the causal association between these adverse events and ABELCET is uncertain.
Body as a whole: malaise, weight loss, deafness, injection site reaction including inflammation
Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions
Cardiopulmonary: cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.
Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme
Gastrointestinal: acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis
Hematologic: coagulation defects, leukocytosis, blood dyscrasias including eosinophilia
Musculoskeletal: myasthenia, including bone, muscle, and joint pains
Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms
Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria
Serum electrolyte abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia
Liver function test abnormalities: increased AST, ALT, alkaline phosphatase, LDH
Renal function test abnormalities: increased BUN
Other test abnormalities: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia
To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 or by email at drugsafety@sigmatau.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.
Amphotericin B liposomal clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics
The assay used to measure amphotericin B in the serum after administration of AmBisome does not distinguish amphotericin B that is complexed with the phospholipids of AmBisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of AmBisome is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day AmBisome for 3 to 20 days.
The pharmacokinetics of amphotericin B after administration of AmBisome is nonlinear such that there is a greater than proportional increase in serum concentrations with an increase in dose from 1 to 5 mg/kg/day. The pharmacokinetic parameters of total amphotericin B (mean  SD) after the first dose and at steady state are shown in the table below.

## Distribution
Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of AmBisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of AmBisome, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing.
Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum.

## Metabolism
The metabolic pathways of amphotericin B after administration of AmBisome are not known.

## Excretion
The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied.

## Pharmacokinetics in Special Populations
Renal Impairment
The effect of renal impairment on the disposition of amphotericin B after administration of AmBisome has not been studied. However, AmBisome has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES).
Hepatic Impairment
The effect of hepatic impairment on the disposition of amphotericin B after administration of AmBisome is not known.
Pediatric and Elderly Patients
The pharmacokinetics of amphotericin B after administration of AmBisome in pediatric and elderly patients has not been studied; however, AmBisome has been used in pediatric and elderly patients (see DESCRIPTION OF CLINICAL STUDIES).
Gender and Ethnicity
The effect of gender or ethnicity on the pharmacokinetics of amphotericin B after administration of AmBisome is not known.
Amphotericin B liposomal indications and usage

# Indications and Usage
AmBisome is indicated for the following:
- Empirical therapy for presumed fungal infection in febrile, neutropenic fever patients.
- Treatment of cryptococcal meningitis in HIV infected patients.
- Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
- Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with AmBisome, relapse rates were high following initial clearance of parasites.
Ampicillin sulbactam dosage and administration

# Dosage and Administration
The pharmacy bulk package is for preparation of solutions for IV infusion only. ampicillin/sulbactam should be administered by slow intravenous injection over at least 1015 minutes or can also be delivered in greater dilutions with 50100 mL of a compatible diluent as an intravenous infusion over 1530 minutes.
The recommended adult dosage of ampicillin/sulbactam is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of ampicillin/sulbactam, and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.
The recommended daily dose of ampicillin/sulbactam in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of ampicillin/sulbactam, and corresponds to 200 mg ampicillin/
100 mg sulbactam per kg per day. The safety and efficacy of ampicillin/sulbactam administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous ampicillin/sulbactam.
In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of ampicillin/sulbactam in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:
When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.
Atovaquone proguanil dosage and administration

# Dosage And Administration
The daily dose should be taken at the same time each day with food or a milky drink. In the event of vomiting within 1 hour after dosing, a repeat dose should be taken.
Atovaquone proguanil may be crushed and mixed with condensed milk just prior to administration to patients who may have difficulty swallowing tablets.

## Prevention of Malaria
Start prophylactic treatment with Atovaquone proguanil 1 or 2 days before entering a malariaendemic area and continue daily during the stay and for 7 days after return.

### Adults
One Atovaquone proguanil Tablet (adult strength = 250 mg atovaquone/100 mg proguanil hydrochloride) per day.

### Pediatric Patients
The dosage for prevention of malaria in pediatric patients is based upon body weight (Table 1).

## Treatment of Acute Malaria

### Adults
Four Atovaquone proguanil Tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) as a single daily dose for 3 consecutive days.

### Pediatric Patients
The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 2).

### Renal Impairment
Do not use Atovaquone proguanil for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min) . Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment.