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Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04727424
Recruitment Status : Recruiting
First Posted : January 27, 2021
Last Update Posted : July 7, 2022
Sponsor:
Collaborators:
Cytel Inc.
McMaster University
Fastgrants
Eiger BioPharmaceuticals
RainWater Foundation
Information provided by (Responsible Party):
Cardresearch

Brief Summary:
The COVID-19 pandemic has been characterized by high morbidity and mortality, especially in certain subgroups of patients. To date, no treatment has been shown to be effective in patients with early-onset disease and mild symptoms. Experimental studies have demonstrated a potential anti-inflammatory role of Fluvoxamine, Fluoxetine, Budesonide and Pegilatrd Interferon Lambda in SARS-CoV-2 infections and observational studies have suggested a reduced complications in patients with COVID-19 disease.

Condition or disease Intervention/treatment Phase
Covid19 SARS-Associated Coronavirus Drug: Fluvoxamine Maleate 100 MG [Luvox] Drug: Budesonide Powder Drug: Placebo (mild disease) Drug: Peginterferon Lambda-1a Drug: Fluoxetine 20 MG Phase 3

Detailed Description:

In December 2019 a series of viral pneumonia cases were reported in the city of Wuhan, China and a new subtype of coronavirus has been identified as the causative agent of this condition. On February 11, 2000 the disease has been characterized as COVID-19 and on March 11 the World Health Organization (WHO) declared a state of worldwide pandemic. On January 25, 2021 there are 98,794,942 cases and 2,124,193 documented deaths (global case-fatality ratio of 2.15%).

To date, no early treatment has been identified as effective in combating this disease which has been identified as with high morbidity and mortality. Epidemiological data suggest that despite development of vaccines we will have hundreds od thousands of cases in the next two years.

Thus, we propose the prospective, double-blinded, randomized evaluation of potential therapies against SARS-CoV2 and some clinical evidence derived from observational studies on reducing complications if used early on the disease, before inflammatory cascade is fully activated.

Important considerations on TOGETHER Trial:

  1. Vaccinated patients were proposed to be an exclusion criteria on amendment 3 which was received final National Ethics Committee (CONEP) decision letter number 4.747.755_E3 dated June 01, 2021. We evaluated vaccination data and outcomes on two large cities involving 150.000 individuals and based on these results we submitted to the IRB a notification request to withdraw the exclusion criteria 4 (vaccination > 14 days) on July 14, 2021, which was granted.
  2. The amendment 5 proposed a collaborative partnership with ANTICOV Consortia and incorporating the fluoxetine + budesonide and its active comparator (paracetamol) arms, as per ANTICOV protocol WHO ERC approval version 13.0. These generated data will be analyzed along with ANTICOV fluoxetine + budesonide and paracetamol arms.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

TOGETHER trial is a Multiplatform, adaptive trial started on 20 Jan 2021. this description is as per amendment five with final Brazilian National Ethics Committee final decision letter issued on 27 January 2022.

Patients with mild disease will be screened at primary and secondary care public health services and randomly allocated to one of four treatment arms in a 1:1:1:1 ratio, as per described in detail in approved protocol version 6.0 dated 03 JAN 2022.

  1. Fluvoxamine + Budesonide
  2. Fluoxetine + Budesonide
  3. Peginterferon Lambda
  4. Placebo

Patients with SpO2 < 94% will be randomly allocated to one of two arms in a 1: ! ratio:

  1. Fluvoxamine
  2. Placebo

We will use a centralized random allocation schedule, generated by computer and stratified by site and age.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

The investigational medical product will be packaged in similar bottles by a third party who will keep the allocation confidential until the end of the study. The bottles will be sealed and identified as "Research Product with no commercial value" and coded. They will be randomly allocated among the participants using a centralized randomization system The research subjects, medical assistance, administrative and health staff will not have access to the contents of the bottles. All arms will have a placebo counterpart with same dose schedule.

All planned Data and Safety Monitoring Board (DSMB) interim analysis will be blinded. If needed a unblinded statistician will be provided if DSMB decides to stop any arm. At the end of the study, or early termination as per DMSB interim analysis plan, the arms will then be identified.

Primary Purpose: Treatment
Official Title: A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Interferon Lambda 1A, Fluvoxamina + Budesonida, Fluoxetina + Budesonida in Mild COVID-19 and High Risk of Complications
Actual Study Start Date : January 19, 2021
Estimated Primary Completion Date : October 1, 2023
Estimated Study Completion Date : November 1, 2023


Arm Intervention/treatment
Active Comparator: Fluvoxamine Maleate + Budesonide Inhalation powder

Fluvoxamine 100 mg oral tablets:

One tablet after randomization (Day 0) followed by 100 mg BID for the following 09 days PLUS

Budesonide Inhalation powder 400 mcg capsule:

One 400 mcg capsule (inhalation) after randomization (Day 0) followed by 400 mcg BID for the following 09 days

Drug: Budesonide Powder

One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS

01 Budesonide powder (inhalation) every 12 hours since randomization through day 09.

Other Name: Fluvoxamine Maleate 100 MG [Luvox]

Active Comparator: Fluvoxamine Maleate

Fluvoxamine 100 mg oral tablets:

One tablet after randomization (Day 0) followed by 100 mg BID for the following 09 days

Drug: Fluvoxamine Maleate 100 MG [Luvox]
One tablet every 12 hours since randomization through day 09.

Placebo Comparator: Placebo (mild disease)

Placebo SC normal saline syringe (single day schedule):

Matching syringes containing 0,5 ml normal saline administered by SC route after randomization Day 0 (single dose SC).

OR

Placebo oral tablets (10-day schedule):

Matching tablets started after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) PLUS

Placebo Inhalation Therapy:

One dosing (inhalation) right after randomization (Day 0) followed by one dose BID for the following 09 days

OR

Paracetamol (07-day schedule - active comparator):

Paracetamol 500 mg tablets started after randomization using the dosing regimen of 01 tablet BID starting at Rand. Day (Day 0) until end of Day 06 (total of 07 days schedule)

OR

Placebo oral tablets (10-day schedule for patients with SPO2 < 94%):

One tablet after randomization (Day 0) followed by 01 tablet BID for the following 09 days (total of 10 days schedule)

Drug: Placebo (mild disease)

Placebo SC normal saline syringe (single day schedule):

Matching syringes containing 0,5 ml normal saline administered by SC route after randomization Day 0 (single dose SC).

OR

Placebo oral tablets (10-day schedule):

Matching tablets started after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) PLUS

Placebo Inhalation Therapy:

One dosing (inhalation) right after randomization (Day 0) followed by one dose BID for the following 09 days

OR

Paracetamol (07-day schedule - active comparator):

Paracetamol 500 mg tablets started after randomization using the dosing regimen of 01 tablet BID starting at Rand. Day (Day 0) until end of Day 06 (total of 07 days schedule)

OR

Placebo oral tablets (10-day schedule for patients with SPO2 < 94%):

One tablet after randomization (Day 0) followed by 01 tablet BID for the following 09 days (total of 10 days schedule)


Active Comparator: Peginterferon Lambda

Peginterferon Lambda 180 mcg syringe:

One syringe of Peginterferon Lambda will be administered by SC route just after randomization (Day 0 - single dose SC administration).

Drug: Peginterferon Lambda-1a
One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).

Active Comparator: Fluxetine + Budesonide Inhalation powder

Fluoxetine 20 mg oral tablets:

Two tablets right after randomization (Day 0) followed by 40 mg MID for the following 06 days PLUS

Budesonide Inhalation powder 400 mcg capsule:

One 400 mcg capsule (inhalation) right after randomization (Day 0) followed by 400 mcg BID for the following 06 days

Drug: Fluoxetine 20 MG

Two Fluoxetine tablets every day starting just after randomization through day 07.

PLUS

01 Budesonide powder (inhalation) every 12 hours since randomization through day 07.





Primary Outcome Measures :
  1. Rate of fluvoxamine + budesonide, fluoxetine + budesonide, peginterferon Lambda, fluvoxamine in changing the need for emergency care AND observation for more than 06 hours due to the worsening of COVID-19; [ Time Frame: 28 days ]
    Evaluation of emergency visits and observation unit stay > 06 hours

  2. Rate of fluvoxamine + budesonide, fluoxetine + budesonide, peginterferon Lambda and fluvoxamine in changing the need for Hospitalization due to COVID-19 progression and related complications, including lower respiratory tract infection (LRTI) [ Time Frame: 28 days ]
    Hospitalization due to COVID-19 progression and related complications

  3. Rate of fluvoxamine + budesonide, fluoxetine + budesonide, peginterferon Lambda and fluvoxamine in changing the COVID-19 associated mortality. [ Time Frame: 28 days ]
    Mortality due to COVID-19 associated complications


Secondary Outcome Measures :
  1. Change in viral load on day 03 and 07 after randomization (interferon lambda arm) [ Time Frame: Day 3 and Day 7 ]
    Viral load

  2. Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms) [ Time Frame: Randomization through day 28 ]
    time to > 50% clinical symptoms changes as reported on baseline visit (self reported)

  3. Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications. [ Time Frame: Randomization through day 28 ]
    Time to hospitalization

  4. Number of days with respiratory symptoms since randomization [ Time Frame: Randomization through day 28 ]
    Days with symptoms

  5. Rate of all-cause hospitalizations [ Time Frame: Randomization through day 28 ]
    All cause hospitalizations

  6. Rate of COVID-19 related hospitalizations [ Time Frame: Randomization through day 28 ]
    COVID-19 hospitalizations

  7. Number of days on Mechanical Ventilator [ Time Frame: Randomization through day 28 ]
    Number of days on mechanical Ventilator

  8. Number of Days on Intensive Care Unit [ Time Frame: Randomization through day 28 ]
    Number of days on Intensive Care Unit

  9. Number of days on hospitalizations [ Time Frame: Randomization through day 28 ]
    Number of days on Hospitalization

  10. Health and Functioning after COVID-19 disease [ Time Frame: Day 14 and Day 28 ]
    Self evaluation of health functioning post COVID using Promis Global Health Score. Short term scale is a 10 item patient-reported questionnaire using response options as a 5-point and one 11 point rating scale. Higher scores means better global health.

  11. WHO ordinal scale for clinical improvement [ Time Frame: Randomization through day 28 ]
    An 8 item Ordinal Scale for clinical status on COVID-19. Higher numbers means worse clinical status.

  12. Number of days on respiratory Symptoms [ Time Frame: randomization through day 28 ]
    Number of days on respiratory symptoms

  13. Adherence of Study drug [ Time Frame: Randomization through day 14 ]
    Percentage of adherence on Study drug



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Gender will be assumed as patient self-reported
Accepts Healthy Volunteers:   No
Criteria

A - Inclusion Criteria (except fluoxetine + budesonide and paracetamol arms):

  1. Patients over 18 years old with the ability to provide free and informed consent
  2. Acute Flu-Like symptoms < 07 days.
  3. Patients with at least ONE enhancement criteria:

    1. Age > 50 years.
    2. Diabetes mellitus requiring oral medication or insulin.
    3. Systemic arterial hypertension requiring at least 01 oral medication for BP control.
    4. Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies).
    5. Symptomatic lung disease (emphysema, chronic bronchitis).
    6. Symptomatic asthma patients requiring chronic use of agents for control of symptoms.
    7. Fever > 38 C at baseline.
    8. Obesity, defined as BMI> 30 kg / m2 body weight.
    9. Transplanted patients.
    10. Patient with stage IV chronic kidney disease or on dialysis.
    11. Immunosuppressed patients/ using corticosteroid therapy (equivalent to maximum 10 mg of prednisone per day) and/ or immunosuppressive therapy).
    12. Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer.
    13. Chronic renal disease KDIGO IV or End-Stage Renal Disease on chronic ambulatory renal replacement therapy.
    14. Patients with important limitation of daily activities due to: Dyspnea, chest pain myalgia (limited to 25% of all randomizations).
  4. Patient with positive rapid test for SARS-CoV2 antigen performed on occasion of the screening or patient with a positive SARS-CoV2 diagnostic test within 07 days of the onset of symptoms.
  5. Willingness to use the proposed investigative treatment and follow the protocol-related procedures foreseen in the research.
  6. Specific inclusion criteria for the fluvoxamine arm: Present significant dyspnea, arterial hypotension, severe dehydration or SpO2 between 85 to 93% in room air at admission and medical decision to discharge patient home, with an observation period at ER not exceeding 12 hours.

B - Inclusion criteria for the Fluoxetine + Budesonide combination arm (07 days of treatment - partnership with the "ANTICOV Consortium"):

  1. Patients over 18 years of age with the ability to provide free and informed consent.
  2. Patients treated at a Basic Health Unit of the Unified Health System (SUS) or patients treated at emergency care units of the SUS or supplementary medicine with an acute clinical condition compatible with COVID 19.
  3. Patients over 18 years of age and a history of at least ONE of the following criteria.

    1. Diabetes mellitus, heart disease, chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular diseases or patients considered to be underweight or overweight according to the investigator's judgment (BMI ≤ 16 or BMI > 25).

      OR

    2. Individuals aged ≥ 60 years without co-morbidities.
  4. COVID-19 confirmed by molecular or antigenic test for SARS-CoV-2 within up to 24 hours prior to screening and a maximum of 2 days after sample collection.
  5. Viral syndrome with or without pneumonia and arterial O2 saturation > 94%.
  6. Signing the Free and Informed Consent Form before any research procedures.
  7. Willingness to use the proposed investigational treatment and follow the procedures provided for in the research.

Exclusion Criteria:

  1. Diagnostic test for negative SARS-CoV2 associated with acute flu symptoms (patient with a negative test collected early and becomes positive a few days later is eligible, as long as it is < 07 days since the onset of flu symptoms).
  2. Patients with an acute respiratory condition compatible with COVID-19 treated in the primary care network and with a decision to be hospitalized.
  3. Patients with acute respiratory symptoms due to other causes.
  4. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg, decompensated COPD, Acute bronchitis, Pneumonia other than viral, Primary pulmonary arterial hypertension).
  5. Patients requiring hospitalization due to COVID-19 or SpO2 ≤ 93%. NOTE: Patients allocated to the fluvoxamine arm alone may be included if SpO2 is below 94%, with no evidence of acute respiratory failure, provided that the attending physician decides to discharge the unit and continue treatment on an outpatient basis.
  6. Exclusion criteria applicable to injectable medication arms:

    a. Patients on chronic use of prednisone, prednisolone or other corticosteroids with doses > 10 mg/day equivalent to prednisone.

  7. Exclusion criteria applicable to 07-day treatment arms:

    1. Abnormal findings on physical examination: Respiratory rate ≥ 25 sisters; blood pressure < 90/60 mmHg or > 160/100 mmHg; Weight < 45 kg; recent episodes of vomiting within the last 24 hours or recurrent diarrhea or serum potassium below 3.5 mEq/L.
    2. Severe organ damage that requires resuscitation and ongoing treatment.
    3. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day
    4. Immunosuppressive treatment in progress
    5. History of known pulmonary arterial hypertension or pulmonary fibrosis
    6. Patients who have received a previous dose of SARS-CoV-2 vaccine
    7. Use of serotonin reuptake inhibitors (all).
  8. Exclusion criteria applicable to 10-day treatment arms:

    1. Chronic use of serotonin reuptake inhibitors other than sertraline
    2. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day;
  9. Continued use of monoamine oxidative inhibitors (MAOI): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazid, moclobemide.
  10. Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar disorders, major depression with suicidal ideation.
  11. Pregnant or breastfeeding patients.
  12. History of severe ventricular cardiac arrhythmia (Ventricular tachycardia, recovered ventricular fibrillation patients) or Long QT Syndrome.
  13. Known history of decompensated heart failure (NYHA III or IV), recent myocardial infarction (event < 90 days of screening), unstable angina, recent coronary bypass surgery (procedure < 90 days of screening), recent stroke ( event < 90 days from screening), symptomatic carotid disease, or moderate to severe mitral or aortic stenosis.
  14. Surgical procedure or hospitalization planned (for other indications) to occur during treatment or up to 5 days after the last dose of study medication.
  15. Current daily and/or uncontrolled alcohol consumption, which, in the investigator's view, could compromise participation in the study.
  16. History of seizures in the last month or uncontrolled seizures.
  17. Clinical history of moderate to severe hepatic impairment or hepatic cirrhosis with Child-Pugh C classification.
  18. Patients with known serious degenerative neurological diseases and/or serious mental illnesses as assessed by the investigator.
  19. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol.
  20. Any clinical conditions, including psychiatric conditions, which, in the investigator's view, could prevent the use of research drugs.
  21. Known hypersensitivity and/or intolerance to Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
  22. Use of drugs which have a known interaction with Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
  23. Inability to use the drugs and formulations provided for in this research.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04727424


Contacts
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Contact: Gilmar Reis, MD, PhD +553132416574 administrador@cardresearch.org
Contact: Eduardo Santos, MD, PhD +553132416574 duduaugusto1@yahoo.com.br

Locations
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Brazil
City of Betim Recruiting
Betim, MG, Brazil, 32550770
Contact: Daniela C Medeiros, MD,PhD         
Contact: Tainara S Vieira         
Hospital e Maternidade Santa Rita Recruiting
Contagem, MG, Brazil, 32215000
Contact: Thiago S Ferreira, MD         
City of Governador Valadares Recruiting
Governador Valadares, MG, Brazil, 35010-000
Contact: Adhemar DF Neto, MD, PhD         
Contact: Marina L Marques, SC         
City of Ibirité Recruiting
Ibirité, MG, Brazil, 30240528
Contact: Aline Milagres, RN         
Contact: Carla Silva, SC       hsfapesq@cardresearch.org   
City of Nova Lima Recruiting
Nova Lima, MG, Brazil, 34000000
Contact: Leticia F Costa, RN         
Contact: Rosemary M Silva         
City of Santa Luzia Recruiting
Santa Luzia, MG, Brazil, 33105160
Contact: Eduardo Augusto SM Silva, MD, PhD         
Contact: Vitoria HS Campos, SC         
City of Sete Lagoas Recruiting
Sete Lagoas, MG, Brazil, 35700-000
Contact: Vinicius A Correa, MD         
Contact: Castilho Vitor Quirino, SC       vitor-quirino@hotmail.com   
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa Recruiting
Belo Horizonte, Minas Gerais, Brazil, 30150240
Contact: Izabel Silva, SC    553132416574    coordpesq@cardresearch.org   
Principal Investigator: Gilmar Reis, MD,PhD         
City of Brumadinho Recruiting
Brumadinho, Minas Gerais, Brazil, 35.460-000
Contact: Eduardo D Calegari, MD         
Principal Investigator: Eduardo Calegari, MD         
City of Igarapé Recruiting
Igarapé, Minas Gerais, Brazil, 32900-000
Contact: Luciene B Ribeiro, RN    +55313657574      
Centro Universitário FIPMOC Recruiting
Montes Claros, Minas Gerais, Brazil, 39.408-007
Contact: Ana Maria, MD         
Principal Investigator: Ana Maria R Nogueira, MD         
Sub-Investigator: Ana Paula FG Alvarenga, MD         
Universidade Federal de Ouro Preto Recruiting
Ouro Preto, Minas Gerais, Brazil, 35400000
Contact: Leonardo CM Savassi, MD, PhD       leosavassi@gmail.com   
Principal Investigator: Leonardo Savassi, MD, PhD         
Sponsors and Collaborators
Cardresearch
Cytel Inc.
McMaster University
Fastgrants
Eiger BioPharmaceuticals
RainWater Foundation
Investigators
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Study Chair: Gilmar Reis, MD,PhD. Cardresearch - Cardiologia Assistencial e de Pesquisa
Study Director: Edward J Mills, FRCP McMaster University
Publications of Results:

Other Publications:

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Responsible Party: Cardresearch
ClinicalTrials.gov Identifier: NCT04727424    
Other Study ID Numbers: TOGETHER_2
First Posted: January 27, 2021    Key Record Dates
Last Update Posted: July 7, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient tables and main data.
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: As of protocol termination
Access Criteria: Upon request

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cardresearch:
COVID-19
Randomized study
Fluvoxamine
Peginterferon Lambda
Budesonide
Fluoxetine
Additional relevant MeSH terms:
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COVID-19
Severe Acute Respiratory Syndrome
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Budesonide
Fluvoxamine
Fluoxetine
Maleic acid
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Serotonin Uptake Inhibitors