We all focused on one topic throughout 2020: Covid-19. No single day passed without news on the pandemic as we counted numbers of positive cases and the death toll while anticipating for a vaccine. In the meantime, we got more familiar with some of the medical processes, like phases, clinical trials, mutations, etc. for all this had to deal with the most precious gift we are given: life.

In our last issue, we touched upon the history of pharmacology and how modern-day drugs are made in an article titled “Pharmacology: The Journey of a Chemical Compound into a Drug.” Now, we will explore the multiple, lengthy phases of clinical trials that drugs must undergo and why they are imperative in order for new medicines to get approved for the marketplace.

Clinical trials are a way to test new methods of diagnosing, treating, or preventing health conditions. The goal is to determine whether a substance is both safe and effective. A clinical trial is only done when there is strong reason to believe that a new test or treatment may improve the care of patients.

A variety of treatment methods such as medications, medication combinations, new uses for existing medications, and medical devices are evaluated through clinical trials. In the United States, all new treatments must go through these trials before being approved for public sale by the Food and Drug Administration (FDA).

At the discovery and development stages, thousands of compounds may be potential candidates for development into a “drug”. After early testing, however, only a small number of compounds look promising and call for further study. The entire process of developing a drug from its pre-clinical research stage to its final marketing phase can take approximately 12 to 18 years and often costs well over $1 billion [3, 4].

Clinical trials show us what works and what does not in the realm of healthcare and are designed to answer some important questions such as:

• Does the new treatment work in people? If it does, how effective is it?
• Is it better than currently used treatments?
• If it is not better, is it just as good and cause fewer side effects?
• Does it work in some people who do not benefit from current treatments?
• Is the new treatment relatively safe? There is virtually no treatment or procedure that is without risk, but do the benefits of the new treatment outweigh the risks?

Answering these questions, while giving as few people as possible an unknown treatment, often requires several clinical trials in different phases. Each phase is designed to answer certain questions while keeping trial participants as safe as possible.

Preclinical phase

Before clinical trials can begin in humans, tests and treatments are assessed in pre-clinical research, which can involve extensive laboratory research over several years of testing on animals and human cells. This research may aim to learn the chemical compound of a drug [1]. If the initial laboratory research is successful, researchers send the data to health authorities for approval in order to begin research and testing on humans.

Once pre-clinical research results are approved, human testing of experimental drugs can begin and is typically conducted in four phases that are denoted by Roman numerals (Phase I, II, III and IV). Each phase is considered a separate trial and, after completion of a phase over many years, researchers are required to submit their data to, and then wait for approval from their local health agency (the FDA in the US) before continuing onto the next phase. If the drug successfully passes through Phases I, II, and III then it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are “post-marketing” or “surveillance” studies that are conducted to monitor how safe the product is over several years [2].

Phase I

This is the first clinical phase that involves humans. Phase I trials most often include healthy volunteers, however there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV. These treatments possess a much higher risk for healthy individuals and could cause to become ill and contract serious adverse side effects.

In a Phase I clinical trial, doctors collect information on:

• The dose or treatment
• When it should be taken, and how often
• Any side effects or complications
• How the treatment affects patients and their preexisting conditions

One of the primary goals of Phase I studies is to find the highest dose of a new treatment that can be given safely without causing severe side effects. Although the treatment has been tested in laboratory and most likely been used in animal studies, the side effects in people cannot be known for sure. During Phase I of a clinical trial, researchers spend several months to evaluate safety, side effects, optimal dosage amounts, and formulation method for the drug on about 20 to 80 people who have no underlying health conditions.

In addition to evaluating safety and ideal dosage, specialists also look at the best way to administer the drug such as orally, intravenously, or topically. These trials are often conducted in a clinical trial clinic where the subject can be observed by full-time staff. Safety always remains the foremost concern in Phase I. The research team keeps a close eye on the people and watches for any severe side effects.

Researchers start by giving very low doses of the drug to a few patients while higher doses are given to other patients until side effects become too severe or desired effects are seen. The drug may help patients, but Phase I trials are to test a drug’s safety. If a drug is found to be safe enough, it can be tested in a Phase II clinical trial. According to the FDA, approximately 70 percent of medications move on to Phase II.

Phase 2

Phase II of a clinical trial usually involves anywhere from 50 to several hundred who are living with the condition that the new medication is meant to treat. They are usually given the same dose that was found to be safe in the previous phase. Investigators monitor participants for several months, or years, to see how effective the medication is and to gather more information about any side effects it might cause.

Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second “control” group receives a standard treatment or placebo. These studies are mostly “blinded” which means that neither the patients nor the researchers know who has received the experimental drug in order to avoid from bias. Doctors use a computer program to randomly sort volunteers into these two separate groups. Each volunteer has an equal chance of ending up in any of the groups and are randomly put in any group.

This allows investigators to provide the pharmaceutical company and the health authority with comparative information about the relative safety and effectiveness of the new drug. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered to not to work as planned or to have toxic effects. The FDA estimates that roughly one-third of experimental drugs successfully complete both Phase I and Phase II studies.

Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18% [5] and only 31% of developmental candidates advanced from Phase II to Phase III in a large study of clinical trials conducted during the period of 2006 – 2015 [6].

Phase III

Phase III of a clinical trial usually involves up to 3,000 participants who have the condition that the new medication is meant to treat. These participants must include men, women, and people of different ages and ethnic groups in many places across the country (or even around the world) at the same time. This helps doctors learn how treatment works in different people with different genetic backgrounds, races, and ethnicity. These studies tend to last longer – up to several years – than Phase I and II studies.

One of the additional purposes of Phase III is to evaluate how the new medication works in comparison to existing medications for the same condition. To move forward with the trial, investigators need to demonstrate that the medication is at least as safe and effective as existing treatment options. Due to the larger number of participants and longer duration of Phase III, rare and long-term side effects are more likely to show up during this phase.

There can be more than two treatment groups in Phase III trials. The control group may receive the current standard-of-care treatment for their illness while other groups receive the new treatment on trial. Phase III trials are usually double blinded to eliminate bias when interpreting results.

Placebos may be used in some Phase III studies, but they are never used alone if there is a treatment available that works. Sometimes, a patient who is randomly assigned to the placebo for part of the study will at some point be offered the standard treatment as well. As with other trials, patients in Phase III clinical trials are watched closely for side effects, and treatment is stopped if they become too hard to manage.

Every patient in a Phase III study is watched closely, and the study will be stopped early if the side effects of the new drug are too severe or if one group has significantly better results. Phase III clinical trials are often needed before the FDA will approve the use of a new drug for the general public. If researchers demonstrate that the medication is at least as safe and effective as others already on the market, then the FDA will usually approve the medication.

In the United States, when Phase III clinical trials (or sometimes Phase II trials) show a new drug is more effective or safer than the current treatment, a new drug application (NDA) is submitted to the FDA for approval. The FDA reviews the results from the clinical trials and other relevant information.

Based upon the review, the FDA then decides whether to approve the treatment for use in patients with the illness the drug was tested on. If approved, the new treatment often becomes a standard of care and newer drugs may be tested against it before they can be approved. If the FDA feels that more evidence is needed to show that the new treatment’s benefits outweigh its risks, it may ask for more information or even require that more studies be done. Once Phase III is complete, a pharmaceutical company can request FDA approval to begin marketing the drug. Roughly 25 to 30 percent of medications move on to Phase IV.

Phase IV

Phase IV trials test new drugs that are approved by health authorities and often are called Post Marketing Surveillance Trials. The drugs are available for doctors to prescribe to patients, but Phase IV studies might still be needed to answer important questions. In previous clinical phases the drug may not have been tested for interactions with other drugs, or on certain population groups, such as pregnant women, who are unlikely to subject themselves to trials. This phase involves thousands of participants and can last for many years. Investigators use this phase to get more information about the medication’s long-term safety, effectiveness, and any other benefits.

This is often the safest type of clinical trial because the treatment has already been studied a lot and has likely been given to many people. Phase IV studies look at safety over time. These studies may also look at other aspects of the treatment, such as quality of life or cost effectiveness.

Phase IV studies can result in a drug or device being taken off the market or restricted depending on the findings in the study. Unless an adverse effect of the approved drug is shown or the drug is accepted as safe, it will stay on the market and also in Phase IV forever.

This clinical trial algorithm has come out after many scientific studies. Every point of the clinical trials, and possible problems, have been clarified by policies which may differ from country to country. At the end, clinical trials are a very safe and cautious method of finding out the safest and most effective treatment, or diagnostic method, for people. During clinical trials, scientists are very careful about ethical issues and try not to harm any living organisms, be them animals or humans. There is an ongoing public debate over pharmaceutical companies. While some think they play a major role in the emergence of many methods and scientific developments to benefit human health, others doubt their motivations and questions their contribution to the public good. This debate will surely continue for a long time, but under the current circumstances, pharmaceutical companies are found in the center of all these clinical trials described in this article. Regardless of the truth behind these doubts, it is important to be always aware of the priceless value of life, that it has been given to us and all living things as an inalienable right and a precious gift, and that it is a major responsibility take care of it well and seek healing when needed.

• https://www.nccn.org/patients/resources/clinical_trials/phases.aspx
• “The drug development process”. US Food and Drug Administration. 4 January 2018. Retrieved 17 August 2020
• Holland J (2013). “Fixing a broken drug development process”. Journal of Commercial Biotechnology. 19. doi:10.5912/jcb588.
• Adams CP, Brantner VV (2006). “Estimating the cost of new drug development: is it really 802 million dollars?”. Health Affairs. 25 (2): 420–8. doi:10.1377/hlthaff.25.2.420. PMID 16522582.
• “New drugs failing Phase II and III clinical trials”. MedCity News. 2011-06-02.
• “Clinical Development Success Rates 2006-2015” (PDF). bio.org. Retrieved 2018-02-11.

Most of us have taken, or at least interacted with, medicine at some point or another in our lives. This can range from more “simple” over-the-counter drugs to more complex medicines specifically designed for exact illnesses. Considering the Covid-19 era we are going through and as search for a vaccine is at the highest possible speed, it is important to have at least a general idea on how medicines are developed for our use. This article aims to explore how a complicated mix of chemical compounds in a laboratory end up as pills on a shelf in your local pharmacy. We will also explore a brief history of pharmacology, where drugs get their names, how drugs come into fruition, the various affects that drugs can have on our bodies, along with the discrepancies that exist between them in regard to when, how, and why they should be taken.

Pharmacology is the study of the interactions that occur between a living organism and the chemicals that affect normal or abnormal biochemical functions. It includes the study of how a drugs can affect our biological systems, such as individual organs or an entire part of the body, and how the body overall responds to the drug. The discipline encompasses the sources, chemical properties, biological effects and, therapeutic uses of drugs. Substances with medicinal properties are considered pharmaceuticals, whereas drugs given for therapeutic purposes are usually called medications. Drug therapy, which is also called pharmacotherapy, is the use of drugs to prevent, diagnose, and treat signs, symptoms, and disease processes. When prevention or cure is not a reasonable goal, relief of symptoms can greatly improve quality of life and the ability to function properly on a day-to-day basis. Developing an understanding of this craft can allow us to better appreciate how molecules interact to form the drugs and medicines that can change our lives, and perhaps even allow us to contemplate their complex creation and existence.

In its most simplistic definition, a medication is a substance that is ingested or placed onto the body in order to cure a disease or condition (antibiotics are given to cure an infection), treat a medical condition (anti-depressants are given to treat depression), relieve symptoms of an illness (pain relievers are given to reduce pain), given to prevent diseases (flu vaccine helps to prevent the person from complications of having the flu).

Source of drugs

Historically, drugs were mainly derived from plants, animals, and minerals. Morphine, insulin, and iron are all commonly used examples of their respective sources. Belief in the curative powers of plants and certain substances rested exclusively upon traditional knowledge. But empirical information was not subjected to critical examination. Until the end of the 19th century, medicines were made by natural organic or inorganic products including mostly dried or fresh plants and their parts. These compounds might contain substances that possess healing properties or reactions that exert a toxic effect. It is important to remember that many fruits, vegetables, and plants still possess great power despite not having a “modern” origin.

Most drugs used nowadays are synthetic chemical compounds manufactured in laboratories which are synthesized by altering the chemical structure of an existing drug. The first drug of a particular group of drugs are called prototypes. For example, morphine is the prototype of opioid analgesics, and penicillin is the prototype of antibacterial drugs. Drug classifications and prototypes are defined and most new drugs can be assigned to a group. We must be hopeful and continue to search far and wide for cures for all  diseases, whether they be organic or synthetic, since our world is full of an infinite amount of possibilities and discoveries.

Drug names

The systematic naming of pharmaceutical drugs is called “drug nomenclature.” Drugs primarily have three types of names: chemical names, generic names, and trade names. The chemical names are the scientific names that often sound complex and are based upon the molecular structure of a drug. During development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, such as the U.S. Food and Drug Administration (FDA), and will be granted a generic name for it. Generic names usually indicate, via their stems, what drug class the drug belongs to. For example, oseltamivir is an antiviral drug because its name ends in the -vir suffix.

After development, testing, and regulatory acceptance of a drug, the pharmaceutical company gives the drug a trade name, which is a standard term in the pharmaceutical industry for a brand name or trademark name. Many drugs have multiple trade names which can reflect separate marketing strategies in different countries, manufactured by different companies, or both.

Drug investigation

A new drug investigation is the beginning of the journey of a chemical compound to a drug that will be used in clinics. The testing process of a chemical compound begins with animal studies to determine potential beneficial uses and also potential toxic side effects of the candidate compound.  The results from these animal studies are reviewed, and if the results are satisfactory, the compound then undergoes clinical trials in humans that people can voluntarily sign up for. Most clinical trials use a randomized, controlled experimental design that involves selection of subjects according to established criteria, random assignment of subjects to experimental groups, and administration of the test drug to one group and a control substance to another group.

Patent protection

New drugs that are developed by pharmaceutical companies will be covered under patent protection. This means that only the pharmaceutical company that holds the patent is allowed to manufacture, market, and eventually profit from the drug. This is seen as a return on the company’s investment that it took to develop the drug, which may require years of work and millions of dollars, along with an incentive for developing other drugs. Other pharmaceutical companies cannot manufacture and market the drug during the patent period.

Usually, the drug patent is awarded for around twenty years in the United States, however the number of years varies across countries and drugs. Pharmaceutical companies apply for a patent long before the clinical trial period even begins. The effective patent period after the drug has finally received approval is often around seven to twelve years. After the patented period expires the drug can be manufactured and sold by other companies. The drug is referred to as a generic drug at this point, and they are required to be therapeutically equivalent and much less expensive than trade name drugs.

Pharmacoeconomics

Pharmacoeconomics involves all of the costs that are accrued due to drug therapy and experimentation including those related to purchasing supplies, dispensing the drug, storing it, administrative fees, laboratory and other tests that are used to monitor patient responses, and losses from expiration. The length of a patient’s illness or hospitalization is also considered. While the most important factor is the health of the patient the costs for treatment are increasingly being considered as a major factor when choosing medications, and research projects that compare costs have greatly increased in recent years. The goal is to make it easier for patients to choose the most cost-effective drugs that combine high quality treatment at an affordable price. For drugs or regimens of similar efficacy and toxicity, there is considerable pressure upon doctors and pharmacies to prescribe less costly drugs for shorter duration.

Prescription and non-prescription drugs

In many countries, consumers have two legal routes of access to therapeutic drugs. One route involves a prescription or order from a licensed health care provider, such as a physician, dentist, or nurse practitioner. The other route is by over-the-counter (OTC) purchase of drugs that do not require a prescription. Both of these routes are regulated by various drug laws that change from country to country. Acquiring and using prescription drugs for non-therapeutic purposes, by persons who are not authorized to have the drugs or for whom they are not prescribed, is illegal.

The rejection of drugs in modern society

Nowadays, there are some people who deny various kinds of treatments because of their religious beliefs. This category of people is only a minority, as the majority of religions advocate for people to be healthy and to take care of their health as much as they can. In almost all belief traditions, the human body is believed to be a trust, and in case of any disease, the most appropriate and fastest treatment methods should be used. Even substances that are not normally permitted are allowed by scholars to be used if the person’s safety is concerned. For believers, the most important goal in life is to worship God, and for this to be possible the body must be healthy.

One day, people asked Prophet Muhammad, peace be upon him:

“Should we make use of medical treatment?”

He replied: “Make use of medical treatment, for God has not made a disease without appointing a remedy for it, with the exception of one disease, namely old age.”

People are encouraged to seek out those remedies and to use them with skill and kindness. Let us also remember that Jesus, peace be upon him, too, was very active in his ministry of healing. He showed by God’s permission miracles like curing the blind and the deaf, and bringing the dead back to life. Thus, religions do not refuse treatment with any available methods, and they even strongly encourage treatment and prevention of diseases.

Religions are also well known to treat stress, which wreaks havoc on the mind and body. It is still not known exactly how stress harms our health, but researchers have found that chronic psychological stress is associated with body’s losing its ability to regulate the inflammatory response. It has been shown that the effects of psychological stress on the body’s ability to regulate inflammation can promote the development and progression of disease. We know that religions and beliefs give people hope and significantly decrease the stress.

Human beings are the most precious creation, and health is necessary for us to achieve the purpose of our existence. Using scientific medicine together with faith and religion can help people to protect their health. Being the science of drugs and by investigating new drug therapies, pharmacology helps us exactly with that.

History of Pharmacology

Claudius Galen (129–200 A.D.) was the first person who attempted to consider the theoretical background of pharmacology.

Ali al-Tabari (838 A.D.) Medieval Islamic physicians used natural substances such as Papaver somniferum Linnaeus, poppy, and Cannabis sativa Linnaeus, hemp as a source of medicinal drugs. Although poppy had medicinal benefits, Ali al-Tabari explained that the extract of poppy leaves was lethal, and the extracts and opium should be considered poisons (4).

Theophrastus von Hohenheim (1493–1541), also known as “Paracelsus”, began to question doctrines from antiquity. He prescribed chemically defined substances with such success that professional enemies had him prosecuted as a poisoner. Against such accusations, he defended himself with the thesis that has become an axiom of pharmacology:

“If you want to explain any poison properly, what then isn‘t a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison.”

Johann Jakob Wepfer (1620–1695) was the first to use animal experimentation for pharmacological or toxicological actions.

Rudolf Buchheim (1820–1879) founded the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, which firstly made pharmacology as an independent scientific discipline. In addition to a description of effects, he strove to explain the chemical properties of drugs.

Oswald Schmiedeberg (1838–1921), together with his many disciples, helped to establish the high  reputation of pharmacology. He partnered with pathologist Bernhard Naunyn (1839–1925) to found the first journal of pharmacology, which has since been published without interruption.

After 1920, the pharmacological industry had their own pharmacology laboratories outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry.

References

1. Clinical Drug Therapy: Rationales for Nursing Practice – Seventh 7th Edition, Lippincott Williams &Wilkins.
2. Basic&Clinical Pharmacology, 12^th Edition, McGrawHill Lange.
3. Modern Pharmacology with Clinical Applications, Sixth Edition, Charles R. Craig and Robert E. Stitzel, Lippincott Williams &Wilkins.

Depression can have a profound impact on a person’s psyche as their mind slowly cascades down a slippery slope towards irrationality. It can cause them to lose all sense of hope, enjoyment, and excitement in life. Activities that usually bring joy and vitality begin to feel unappealing and pointless. Family members and loved ones that normally bring happiness may instead be seen as a burden due to the corrupt lens that they are being viewed from. Life, as it is known, changes dramatically.

If a person uses some of the following sentences, then they may possibly be experiencing a state of depression: “I wouldn’t get out of bed if it weren’t for my cats.” “I go to bed, but I don’t really sleep.” “What I eat has no taste.” “I am useless. What good can I do anyway.” “I have no use for my children.” “I don’t remember how long I haven’t communicated with my wife.” “Nobody calls me, and I don’t want to talk to anyone anyway.” “I could not be a good person so far. I don’t think I’ll be of any use in the future, either.” “Everything around me seems to be bleak and dark.” “Everything I used to like, that I thought made me happy, is meaningless now.” “My feelings seem to be taken away.” “I want to move, but I feel like I don’t have the energy.” “I’m distracted, it’s like a battlefield in my head.” “Sometimes I ask myself why I live.”

What is depression?

Depression is a common psychiatric disorder that is often characterized by a sense of incapacity that affects not only the individual but their whole family and even has effects on their broader societies. Throughout daily life, we often hear the phrase “I am depressed.” However, depression is not an illness that can be “entered” and “exited” so easily; it is a disorder that needs to be diagnosed by experts. It is normal for us to undergo mood swings throughout our days, and these differing experiences of sadness, sorrow, or lack of excitement do not necessarily qualify as depression. It is important for us to do our best to understand ourselves and our emotions, specifically what causes us to feel unwell and to learn from these mood swings.

Nowadays, there is a perception as if life should always be experienced in joy and that emotions such as sadness and sorrow are completely pointless and should be avoided at all costs. However, people mature when they face difficulties and can learn to confront their problems, instead of running away from them, as they endure hardship. In fact, most of the time, we discover different aspects and abilities about ourselves during such periods.

Am I depressed?

It is most important to first and foremost state that any person seeking to learn if they do or do not have depression should consult a physician for a professional diagnosis. In order to be diagnosed with depression, a depressive mood and the inability to enjoy life must have been present for more than 15 days. Furthermore, at least four of the below symptoms should coexist:

• feeling of worthlessness and guilt
• lack of energy, tiredness
• sleep disturbance (decrease or increase)
• appetite disturbance (decrease or increase)
• concentration disorder
• loss of interest
• recurrent thoughts of death

Just as depression worsens the course of chronic diseases, chronic diseases also make it difficult to treat depression. It should be investigated whether an organic disease accompanies the symptoms at the diagnosis stage. For this purpose, thyroid function tests should be performed and anemia, vitamin B12 and D levels should be checked. Any diseases or problems related to the body should be treated simultaneously.

Causes of depression

Modern science has not yet been able to fully explain the mechanism by which depression occurs. The general view is that it is related to the molecules that are involved with communication between cells in the brain. Biologically, differences in the levels of molecules such as serotonin and noradrenaline change our perceptions. In addition, the finding that depression in first-degree relatives triples the risk of disease suggests that depression may have a genetic basis. Not being able to think properly, and exposure to intense stress, can also lead to depression.

Risk groups

Factors that facilitate the development of depression vary. It has been found that twice as many women compared to men are afflicted. Among risk groups are being in the middle age group; not being married (depression rates are higher among widows, the divorced, and singles); having a low income; alcohol or substance addiction; and chronic illness.

Treatment

Medication and psychotherapy options are available as the current treatment options for depression. For an effective recovery, both approaches should be used together. Depression is a disease and medication must be used in its treatment; therefore, the initial depression diagnosis means that the decision has already been made to start taking medication. Liver and kidney function tests should be done before a patient begins using medication.

Patients should be advised that drug treatment will take a long time and it may take up to six weeks before the actual effect is noticed. This time is necessary for the adaptation of our brain cells. As the drug starts to produce visible benefit, the person may opt to stop taking the drug thinking that they are out of depression and that the drug is no longer needed. Discontinuing drug treatment leads to the continuation of the disease and therefore causes further despair.

Since depression does not start in only a few days, treatment should not take place in a short time either. Depression is shaped in relation to the perceptions, interpretations, and relationships of the person’s environment, and its treatment is a comprehensive process. Since the decision to start treatment is made by the doctor and the patient together, the decision to discontinue the drug should be taken together as well. Psychotherapy is an important stage that contributes to the healing process. In addition to this therapy, the patient is taught the methods of how to cope with the illness to prevent recurrence of it.

It is necessary to think of stress as a microbe entering our body. Even though we try not to get sick, our immune systems and bodies are renewed and become more resistant to different seasonal diseases two or three times a year. We do not say we should not get sick, as we consider disease conditions such as a sore throat, ear infection, and flu to be normal. However, we generally do not want to be exposed to stress and we do not tolerate the changes that stress will make in our body and the effects that it will have on our outlook on life.

Things to keep in mind

• Depression should be diagnosed by a doctor.
• You should be prepared for a long treatment process.
• Serious life decisions should be postponed until after treatment ends (such as undergoing a divorce, job change, moving).
• Comparing your quality of life to the life of others should be avoided.
• Physical exercise, like walking, is necessary, a balanced diet should be kept, attention should be paid to maintain adequate and quality sleep, and a regulated lifestyle should be adopted.
• Listening to soothing music and reading books 15-20 minutes before bedtime can be helpful.
• As we go to bed, statements of determination, like “I will take this small step tomorrow” should be repeated. Such conditioning can help strengthen our willpower and win the war against depression.

Depression should not be feared. Every small step taken in the treatment process will positively grow gradually. Not rushing through treatment is very important, as the process is more of a marathon than it is a sprint.

As with any illness, it is important to follow the advice of a specialist. These doctors will give their patients legitimate advice that help to turn the patient away from exaggeration and understatements and more towards balance, appreciation, and gratitude. Evaluating a problem as a means of test from God and knowing that the world is not a place of taste and remuneration, will change our view towards life. This perspective will also make a difference in our reactions towards all of our problems.

Spirituality has the potential to aid people in their fight against depression and grappling with life can bring great psychological duress upon a person. Human beings are able to “read” and understand, to a degree, our changing universe and the events that come into existence. Contemplating and striving to understand the comprehensive rules that exist in the universe can allow us to develop an appreciation for existence through a believer’s lens. This appreciation can lead us to a greater sense of harmony and purpose in life, and the simple fact of having a solid foundation that we feel comfortable with can bring great tranquility to people whose minds are more concerned with the questions regarding life, creation, and the universe. We may instead feel lost, purposeless, demotivated, and more concerned with trivial worldly matters without this knowledge.

Life is in the center of existence, and food is in the center of life. All living things are in pursuit of their sustenance to continue their lives. Failing this pursuit means the end of it all. Yet, it is not only the lack or scarcity of food, but also its abuse that is a major cause for disorders. Consuming food without any criteria of lawfulness, or with no heed to virtues like contentedness or gratitude, but with greed and wastefulness, leads to many health problems – mental and physical – at both individual and societal levels. Among these problems are many notorious eating disorders such as obesity, anorexia, and bulimia nervosa. Illnesses that relate to overeating, such as obesity, are now beginning to be considered as food addictions, even as a type of substance abuse, in some medical literature [1].

One serious consequence of eating and food addictions is a clinical condition that is called “metabolic syndrome” (MetS). Characterized by multiple cardiovascular disease risk factors such as obesity and high blood pressure, this syndrome has been recognized as a crucial public health problem worldwide. Characteristics such as geography, race, age and gender are influential in the frequency of the disease, which spreads daily as a pandemic that affects approximately 20-30% of the global adult population [2]. Among US adults aged 18 years or older, the prevalence of metabolic syndrome rose by more than 35% from 1988–1994 to 2007–2012, increasing from 25.3% to 34.2% [3].

First described by Dr. Gerald Reaven, MD, in 1988, metabolic syndrome is also referred to as “insulin resistance syndrome,” “deadly quartet,” and “civilization syndrome” [4]. In 2001, the Adult Treatment Panel (NCEP-ATP III) defined metabolic syndrome in adults as the combination of central obesity (waist circumference >102 cm in men, >88 cm in women), hypertriglyceridemia (>150 mg/dl), low HDL (<40 mg/dl in men, <50 mg/dl in women), hypertension (blood pressure> 130-85 mm-Hg), and hyperglycemia (fasting blood sugar >110 mg/dl). In 2005, the International Diabetes Federation (IDF) published a global guideline describing different thresholds for different ethnic groups. According to this guideline, the diagnosis of metabolic syndrome should be based upon central obesity and high triglyceride, low HDL, high blood pressure, and high fasting glucose. The IDF also reported that the presence of at least two factors sufficed for diagnosing anyone as a patient of metabolic syndrome.

as one of the likely pathological findings in metabolic syndrome, central obesity is observed in one in three adults. Hypertension, another crucial factor, is generally acknowledged to be originating from insulin resistance in metabolic syndrome, but the actual features of its development mechanism still remains controversial. Global awareness about hypertension, its treatment, and how to control it is low, and there are significant differences in between people worldwide. A National Health Examination Survey (NHANES) spanning 2011-2014 revealed that 34% of US adults aged 20 years and older are hypertensive and NHANES 2013-2014 data showed that 15.9% of these hypertensive adults are unaware they are hypertensive [5].

Dyslipidemia, which increases as a result of central obesity and insulin resistance in patients with metabolic syndrome, is characterized by low HDL cholesterol and high triglycerides, the most crucial factors that increase the risk of cardiovascular disease. In one study done in 2008, the average total cholesterol levels for American men and women were found to be 197 mg/dl [6].

The presence of overt diabetes or impaired glucose tolerance (fasting blood sugar above 110 mg/dl) indicates the first step of the diagnostic criteria of the metabolic syndrome, and insulin resistance is not sought for further. People diagnosed with metabolic syndrome are 2.34 times more likely to contract diabetes [7]. A 2011 study conducted in America reported that roughly half of all adults have impaired glucose metabolism as a result of type 1 diabetes, type 2 diabetes, and prediabetes. Diabetes has been a prevalent global ailment similar to asthma, autoimmune diseases, and cancer [6].

Insulin resistance, which can be observed in metabolic syndrome, increases the risk of cardiovascular disease by 2.35 times, deaths by cardiovascular disease by 2.40 times, risk of myocardial infarction by 1.99 times, and stroke by 2.27 times, as independent of other risk factors. However, the presence of metabolic syndrome, not obesity, increases the risk of cardiovascular disease [7]. Another significant result is that women with metabolic syndrome have a higher risk of cardiovascular disease than men. Women are more likely to have central obesity than men, have a different cholesterol profile, and higher triglyceride levels that cause more coronary artery disease, while polycystic ovary syndrome, hormone support therapies, and pregnancy diabetes pose additional risk for women [8]. Fatty liver disease, cirrhosis, chronic kidney disease, polycystic ovary syndrome, gout, dementia, and decreased cognitive functions are more common in individuals with metabolic syndrome than the normal population [7].

Treatment of Metabolic Syndrome

Since metabolic syndrome is caused by environmental and genetic factors, and is appearing in people with increasing frequency, the best treatment approaches involve a well-regulated lifestyle, with the main objective being to prevent diabetes and cardiovascular diseases that cause fatal or disabling conditions. Weight loss that results from an appropriate nutrition and exercise program has a corrective effect on almost all disorders observed in metabolic syndrome.

In the treatment of metabolic syndrome, prevention of central obesity seems to be a priority solution. This can be achieved by a lifestyle planning that provides and maintains a 7-10% reduction in total body weight by limiting caloric intake and increasing physical activity. Even methods that increase weekly physical activity by 150-300 minutes and provide only a 5-7% reduction in body weight are considered sufficient to correct the metabolic syndrome. This has especially been reported to have a positive effect on lipid disorders, glucose intolerance, and hypertension, with a 58% reduction in the risk of diabetes with additional lifestyle changes [9].

Since a well-regulated diet is one of the focal points of life style change for people with metabolic syndrome, dietary models that are limited to saturated fats and cholesterol, rich in complex carbohydrates, based upon an abundant consumption of fruits and vegetables, and a restricted use of salt (for those with hypertension) are strongly recommended.

Even though the traditional Mediterranean diet is lauded as one of the vibrant treatment options in the prevention of coronary heart disease and metabolic syndrome, it is not sufficient to correct the metabolic syndrome unless the diet is in tandem with significant weight loss [10]. According to numerous studies, increasing the consumption of nutrients such as fish, vegetables, fruits, dried legumes, and unrefined grains that are rich in olive oil, omega-3 fatty acids, and antioxidants reduce the risk of coronary diseases and death. It goes without saying, that smoking and alcohol use may increase cardiovascular, metabolic and hepatic complications in patients with metabolic syndrome.

Patients with metabolic syndrome should have their blood lipids checked annually, and should be determined to keep low-density lipoprotein (LDL) cholesterol lower than 100 mg/dL, high density lipoprotein (HDL) cholesterol higher than 40 mg/dL, and triglyceride levels lower than 150 mg/dL. Diabetic patients should set their blood pressure target as lower than 130/80 mm-Hg. Changes in lifestyle such as regular exercise and a controlled diet are extremely vital. The use of low-dose aspirin to prevent complications in patients with coronary artery disease is also among treatment recommendations.

The basic sustenance that is provided to us in the form of fruits, animals, grains, and other bounties is such a precious, rich and full-fledged treasure, for which we should be grateful for. However, gluttony and wastefulness pave the way for thanklessness, disease, and even conflicts with the wisdom in the universe.

Almost all living beings are engaged in the pursuit of sustenance and revolve around this goal. We humans have been equipped with the ability to taste and appreciate all kinds of food, and can draw an appreciation for the Divine through these gifts. Just as everything revolves around sustenance, thankfulness has been placed in the center of sustenance. That is, gratitude should be at the center of all sustenance. Through gratitude, we live healthier physical, spiritual, and mental lives.

Notes

1. Meule A, Rezori V, Blechert J. Food addiction and bulimia nervosa. Eur Eat Disord Rev. 2014;22:331–337.
2. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008; 28: 629-36.
3. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev Chronic Dis 2017;14:160287
4. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
5. Alexander, Matthew R.; Eric H. Yang. “What is the prevalence of hypertension (high blood pressure) awareness of in the US?” https://emedicine.medscape.com/article/241381-overview#a2
6. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.
7. Balcı M.K, Metabolik Sendrom, Türkiye Klinikleri J Med Sci 2008;28:102-106.
8. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-32
9. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403
10. Carbonneau É1, Royer MM2, Richard C3, Couture P4, Desroches S5, Lemieux S6, Lamarche B7. Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome. Nutrients. 2017 Mar 19;9(3).

Nooriye is a 39-year-old Iraqi female. She had a pretty normal life until a group of terrorists knocked on her door. Her two sons were killed in front of her. She was abused and tortured for days, as was her husband. Rebels eventually took her husband and left. Some neighbors helped her to bury her sons and provided her with shelter and food. She was about to kill herself when, miraculously, her husband came back 57 days later. He never told her what he went through during those 57 days. They were both in extreme pain but able to hold onto each other.

They immigrated to the U.S. a year later. Her husband found a job and is still working. They are safe now, but it has not been enough to heal them. Both still have nightmares and flashbacks. She spends all her time in her home. She stares at walls, feels numb and very fearful, and cries every day. Her speech is sparse, and she never smiles. She goes out with husband once a day but grabs his hand and won’t let him go when they are out. When faced with stress, she often passes out.

Her husband “has to be strong because she is the only thing he has,” although he also has extreme pain. He hides his tears from his wife, is unable to sleep at night, feels guilty, and misses his sons. He is afraid to make any Iraqi friends and stays away from mosques.

Obviously, providing a safe place, food, and a job is not enough to heal these people’s pain. Invisible wounds and problems are much harder to treat than visible ones.

In this article we will try to elucidate some elements of what Nooriye and thousands of other families have been exposed to all around the world.

Mass trauma

When a group of people, regardless of size, experience psychological effects after a trauma that was suffered collectively, this is called a mass trauma. Sometimes an entire society witnesses the same trauma, and this may cause a collective sentiment, often resulting in a shift in that society’s culture and mass actions.^1,2

Wars, political violence, natural disasters, exile, torture, and terrorism are examples of mass trauma. The Holocaust, the Atomic bombing of Hiroshima and Nagasaki, slavery in the United States, and the 9/11 attacks are well-known collective traumas.

Collective traumas have been shown to play a key role in group identity formation. Having the same problems, suffering from the same pain, and being under the same pressures bring individuals together. This togetherness eventually helps to build a community, a group, and sometimes a nation. Almost every nation has traumatic events in their history. Even the concept of “nation” is extensively affected by these events.

Nevertheless, despite its role in building group identity, mass trauma is still individually painful. In fact, the effects of mass trauma can be very deep and transferred through the generations. In 1966, clinicians observed that large numbers of children of Holocaust survivors were seeking treatment in psychiatric clinics in Canada. Moreover, when compared to the general population, the grandchildren of Holocaust survivors were three times more likely to seek clinical psychiatric help.³

Post-Traumatic Stress Disorder

According to the National Center for Posttraumatic Stress Disorder, the most common stress reactions in the wake of disaster may include the following:

Emotional reactions, including shock, fear, grief, anger, guilt, shame, feeling helpless, feeling numb, and sadness.

Cognitive reactions, including confusion, indecisiveness, worrying, shortened attention span, and trouble concentrating.

Physical reactions, including tension, fatigue, edginess, insomnia, bodily aches and pains, startling easily, racing heartbeat, nausea, change in appetite, and changes in other bodily desires.

Interpersonal reactions, including distrust, conflict, withdrawal, work or school problems, irritability, loss of intimacy, and feeling rejected or abandoned.⁴

Several factors present in the acute-phase recovery environment of a disaster have been found to aggravate stress reactions and therefore increase survivors’ risk of developing negative outcomes. These include:

• Lack of emotional and social support
• Presence of other stressors such as fatigue, cold, hunger, fear, uncertainty, loss, dislocation, and other psychologically stressful experiences
• Difficulties at the scene
• Lack of information about the nature and reasons for the event
• Lack of, or interference with, self-determination and self-management
• Treatment [given] in an authoritarian or impersonal manner
• Lack of follow-up support in the weeks following the exposure

Protective factors that may mitigate negative effects include:

• Social support
• Higher income and education
• Successful mastery of past disasters and traumatic events
• Limitation or reduction of exposure to any of the aggravating factors listed above
• Provision of information about expectations and availability of recovery services
• Care, concern and understanding on the part of the recovery services personnel
• Provision of regular and appropriate information concerning the emergency and reasons for action.⁵

In most cases, the symptoms of trauma eventually disappear, but unfortunately, some of the survivors of the mass trauma will eventually develop Post-Traumatic Stress Disorder (PTSD). PTSD is a mental disorder resulting from exposure to an extreme traumatic stressor.

The National Comorbidity Survey Replication (NCS-R), conducted between February 2001 and April 2003 in the U.S., estimated the lifetime prevalence of PTSD among adult Americans to be 6.8%.⁶ The lifetime prevalence of PTSD among men was found to be 3.6% and among women 9.7%. ⁷

PTSD is described in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM 5) which is published by the American Psychiatric Association, as:

Criterion A (at least one required): The person was exposed to: death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence, in the following way(s):

• Direct exposure
• Witnessing the trauma
• Learning that a relative or close friend was exposed to a trauma
• Indirect exposure to aversive details of the trauma, usually in the course of professional duties (e.g., first responders, medics)

Criterion B (at least one required): The traumatic event is persistently re-experienced, in the following way(s):

• Intrusive thoughts
• Nightmares
• Flashbacks
• Emotional distress after exposure to traumatic reminders
• Physical reactivity after exposure to traumatic reminders

Criterion C (at least one required): Avoidance of trauma-related stimuli after the trauma, in the following way(s):

• Trauma-related thoughts or feelings
• Trauma-related reminders

Criterion D (at least two required): Negative thoughts or feelings that began or worsened after the trauma, in the following way(s):

• Inability to recall key features of the trauma
• Overly negative thoughts and assumptions about oneself or the world
• Exaggerated blame of self or others for causing the trauma
• Negative affect
• Decreased interest in activities
• Feeling isolated
• Difficulty experiencing positive affect

Criterion E (two required): Trauma-related arousal and reactivity that began or worsened after the trauma, in the following way(s):

• Irritability or aggression
• Risky or destructive behavior
• Hypervigilance
• Heightened startle reaction
• Difficulty concentrating
• Difficulty sleeping

Criterion F (required): Symptoms last for more than 1 month.

Criterion G (required): Symptoms create distress or functional impairment (e.g., social, occupational).

Criterion H (required): Symptoms are not due to medication, substance use, or other illness.⁸

Treatment for mass trauma:

Treatment for mass trauma should be delivered at two different levels: the community level and the individual level.

1. Community level:

Dr. Frantz Omar Fanon gives the recipe for mass trauma treatment at the community level: “Mass trauma can be alleviated through cohesive and collective efforts such as recognition, remembrance, solidarity, communal therapy and massive cooperation.”

The statement above can be a topic for a separate article. Here, we would like to express the importance of the remembrance days. People comes together on remembrance days and remind the victims that they are not alone and not forgotten. This can be therapeutic for the victims and alleviate their pain.

2. Individual level

PTSD treatment includes pharmacotherapy (medical treatment) and psychotherapy. Some of the medications which have been helpful combatting depression are selective serotonin reuptake inhibitors (SSRIs), such as Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil), and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as Venlafaxine (Effexor) and Duloxetine (Cymbalta).

There are several therapy types that have been shown to be effective at treating PTSD. Trauma-focused psychotherapies are the most highly recommended psychotherapies for PTSD. In these therapy types the treatment focuses on the memory of the traumatic event or its meaning. These treatments use different techniques to help a victim process their traumatic experience. Some involve visualizing, talking, or thinking about the traumatic memory. Others focus on changing unhelpful beliefs about the trauma. Prolonged exposure therapy, Cognitive Processing Therapy, Eye-Movement Desensitization and Reprocessing, Brief Eclectic Psychotherapy, and Narrative Exposure Therapy are the some of the therapies that have been found to be helpful for PTSD patients.

Additionally, spirituality might help treat PTSD, too. A study of Bosnia-Herzegovina war veterans suggested that veterans who prayed had significantly higher levels of incorporation, self-protection, and reactive formation and significantly lower levels of regression, compensation, transferring, lack of control, and aggressiveness than their peers who did not pray. ⁹

In brief, providing shelter, food, and a safe environment are mandatory for trauma patients, but they aren’t nearly enough. Psychological traumas are very hard to treat, and treatment may take years. It has been shown that soldiers who have somebody to share their war experience/trauma with, have a lower risk for PTSD when compared with the ones who can’t talk to anybody. Victims need professional help along with community support. Trauma can be alleviated through cohesive and collective efforts and cooperation. Praying for the trauma victims, as politicians suggested for recent hurricane victims, definitely has some social impact. It has also been shown that medication/prayers decrease PTSD symptoms ¹⁰; however, showing support and empathy, listening to victims, and acts of remembrance are the other key elements of community support.

References

1. Lisa Gale Garrigues, “Slave and Slave Holders Break Free of History’s Trauma“, Yes Magazine, August 2, 2013
2. Updegraff, Silvler, Holman, “Searching for and Finding Meaning in Collective Trauma, Journal of Personal and Social Psychology, September 2008
3. Coffey, R. (1998). Unspeakable truths and happy endings. Sidran Press. ISBN1-886968-05-5
4. https://www.ptsd.va.gov/professional/pages/handouts-pdf/Reactions.pdf
5. NSW Institute of Psychiatry and Centre for Mental Health. (2000). Disaster Mental Health Response Handbook.North Sydney: NSW Health.
6. Kessler, R.C., Berglund, P., Delmer, O., Jin, R., Merikangas, K.R., & Walters, E.E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6): 593-602.
7. National Comorbidity Survey. (2005). NCS-R appendix tables: Table 1. Lifetime prevalence of DSM-IV/WMH-CIDI disorders by sex and cohort. Table 2. Twelve-month prevalence of DSM-IV/WMH-CIDI disorders by sex and cohort. Accessed at: http://www.hcp.med.harvard.edu/ncs/publications.php
8. American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders, (5th ed.). Washington, DC.
9. Pajević I, Sinanović O, Hasanović M. Association of Islamic Prayer with Psychological Stability in Bosnian War Veterans. J Relig Health. 2017 Dec;56(6):2317-2329. doi: 10.1007/s10943-017-0431-z.
10. Gallegos AM, Crean HF, Pigeon WR, Heffner KL. Meditationand yoga for posttraumatic stress disorder: A meta-analytic review of randomized controlled trials. Clin Psychol Rev. 2017 Dec; 58:115-124. doi: 10.1016/j.cpr.2017.10.004.

Fear of obesity may sometimes lead people to an extreme diet, and this may cause a deadly disease: anorexia nervosa. The sufferer initially tries to lose weight by going on a diet, but the illness soon reaches the point of no return as the result of extreme dieting. At this point, weight loss cannot be stopped; the person can no longer eat, even if he or she may want to. If they do manage to eat a little food, they throw it up. This disease and many other health conditions are connected with how our bodily functions like appetite are regulated with the secretions in our brain.

Discovered in 1998, orexin is a neuropeptide, or protein-like substance secreted by the brain. It is responsible for regulating states like wakefulness, appetite, and arousal. There are tens of thousands of neurons in the lateral hypothalamus of the human brain that secrete orexin. It was first discovered to increase appetite, but later other functions – especially in relation internal organs – were identified, including regulating the body’s energy use.

Orexins play very important roles in the development and maturation of the brown adipose tissue, which is especially important for infants. The fats in this tissue are directly converted into heat. It is the duty of the adipose tissue to protect the body from illnesses in cold weather. Experiments on lab rats have revealed that body temperature decreases in animals without orexin in their body, and they fail to consume fats. The conclusion is that orexins help boost energy consumption, protect the body from cold-related illnesses by raising the body temperature, and prevent obesity.

Orexins also help regulate metabolic activity and its speed. They are also responsible for regulating the circadian rhythm, or the daily sleep-wake cycle, especially by helping us stay awake. Orexins help increase the secretion of dopamine, norepinephrin, histamine, and acetylcholine hormones, which are in charge of the proper functioning of the daily sleep-wake cycle. All these hormones are substances that increase wakefulness.

The destruction of neurons responsible for producing orexin leads to a severe illness called narcolepsy, which is a serious sleep disorder. Patients suffer from sudden fits of involuntary and extreme sleepiness, irregular nighttime sleep, sleep apnea, various hallucinations, and muscular paralysis called cataplexy. They may suddenly fall into REM asleep while driving and watching television. The muscular paralysis accompanied by REM sleep makes sufferers collapse wherever they may be. They sometimes cannot move and remain motionless, even when they wake up. The fits of sleep strike with or without forewarning and make the need for sleep impossible to fight off. Since frequent uncontrollable collapses may cause injury, narcoleptics know they have to take precautions when they perform daily tasks. Generally appearing in a person’s twenties, the disorder may result from organic factors such as inflammation or a tumor in the brain or other underlying hostile causes.

Narcolepsy is untreatable. It can sever patients from real life and incapacitate them, leaving them unable to perform routine daily tasks. Treatments that are available can only make patients’ lives bearable.

Cataplexy is a condition in which muscles become dysfunctional, speech becomes incomprehensible, and the body collapses due to loss of strength in the neck or knees. Fits may also appear in the form of emotional responses such as excessive laughter, anger, or fear. The duration of cataplexy may last from a few seconds to a few minutes. Patients do not become unconscious during the attack; they just lose control of their physical functions. More often than not, people who have a cataplexy attack in public places seem to be under the influence of alcohol or drugs. They can see and hear others, but they cannot respond.

Sleep paralysis is a temporary state of inability to speak or move during sleep. Although it may look frightening, it is in fact not dangerous. Hypnotic hallucinations, on the other hand, are extremely vivid and frightening dream-like states experienced when falling asleep or waking. An extreme tendency for daytime sleep and hypnotic hallucinations are consequences suffered by people who have not had enough sleep, whereas cataplexy is unique to narcoleptic patients.

Orexins are also responsible for increasing the amount of nutrition a body consumes. This duty is not about meeting the body’s daily diet. Orexins tend to increase appetite, even when the body does not need feeding. They suppress the feeling of satiety, causing the person to continue eating. The willpower should kick in at this point, and the person should use it to stop eating.

The secretion of orexin is influenced by two opposite hormones. The first is leptin, secreted in obese people. Leptin’s duty is to prevent the person from overeating by reducing orexin secretion. The second is ghrelin, a digestive hormone secreted when the stomach is empty. Ghrelin increases orexin secretion, causing an increase in appetite.

It has also been discovered that orexins are connected with smoking and drug addiction. Medicines that reduce orexin secretion are used in addiction treatment. Orexins stimulate the neurons of pleasure in the brain, the reward centers, and impact a person’s happiness or sadness. A reduction in orexin secretion leads to unhappiness and sadness.

References

• Herring W. J. et al. “Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications”, J Sleep Res., 2018; e12782. doi.org/10.1111/jsr.12782.
• Kaushik, M. K. et al. “Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy”, PNAS, June 5, 2018 115 (23) 6046–605.
• Zhou, W. et al. “Activation of orexin system facilitates anesthesia emergence and pain control”, PNAS, November 6, 2018 115 (45) E10740–E10747.

It is estimated that there are approximately 100 trillion cells in the human body. They fulfill their duties harmoniously with all the systems, organs, and tissues manifesting innumerable signs of wonder and wisdom. If a disruption occurs to the working of cells or the coordination among cells, the process leading to cancer starts to develop in the body’s tissue.

The recent increase in cancer occurrences has led researchers to look into its development. The phrase “cellular anarchy” is sometimes used to refer to cancer’s development. Indeed, when we examine the mechanism of cancer development, we see that cells engage in irregular – anarchic – activities in addition to regular ones.

Abnormalities emerge in cancerous cells during cell division and differentiation (when they transform into specialized cells according to different tissues). Cancer cells divide uncontrollably. Under normal circumstances, numerous genes are active in cell division. In cancerous cells, however, failures occur in the mechanisms that control division. Moreover, due to differentiation flaws in cancerous cells, undifferentiated cells, which fail to acquire features that enable them to function in a tissue or organ, form groups of cells that constrain and damage other cells because of the space they occupy.

Checkpoints in cell division and tumor suppressing genes

How is cell division controlled in a normal cell?

Our cells go through numerous stages as they divide. The beginning of each stage is called a “checkpoint” because it is where errors in cell divisions are checked. At each checkpoint (called G1, S and G2) are proteins with certain duties. One of these proteins, P53, suppresses development of cancer. In other words, P53’s job is to prevent failures during cell division, hence blocking the path to cancer’s development in the cell. Whether there is a flaw in the DNA it is checked over and over again at each checkpoint. If no error is identified, the next stage proceeds. In this way, it is ensured that there is not any genetic error in the cells formed as a result of division. If there is an error, cell division is stopped. First an attempt is made to correct this genetic error. If it can be corrected, cell division is resumed. If the error is too big to be corrected, then the cell is scheduled to die; this is called apoptosis. It is worth remembering at this point that proteins that are too minute to be observed even by microscopes are tasked to perform these stupendous mechanisms. It is remarkable that they were designed to work so effectively.

Because these systems are disrupted during the development of cancer, genetically flawed cells form and multiply. Proteins produced with the genetic codes of the flawed cells are also flawed, and these flawed proteins cause a failure of the mechanisms that constrain cell division. Unconstrained cells have an abnormal capacity for division and they divide continuously, which is why cancerous cells have a greater ability to divide than normal cells.

Proto-oncogenes and oncogenes

It is essential that the parts of our body that grow, develop, or get damaged be repaired. In such cases, our cells synthesize certain “signal” molecules which are responsible for carrying to the nucleus the information that our cells should divide. As a result of the incoming information, some DNA regions called proto-oncogenes are stimulated and cell division gets underway. Proto-oncogenes are genes responsible for checking the start of cell division. When the human body encounters various cancer-making elements, damages occur in proto-oncogenes, which transform into oncogenes, or genes with the potential to cause cancer. Oncogenes lead a cell to develop cancer because cell division does not stop where it should and continues endlessly in the absence of healthy proto-oncogenes. Underlying abnormal tissue growth and spread to other organs is the fact that the control over cell division is lost.

Genetic treatment of cancer

It became apparent that age-old treatment methods proved wrong once it was discovered that the biological foundations of cancer stemmed from genetic disruptions. Despite its increase in the last century, cancer has in fact been seen throughout the history of mankind; even ancient Egyptian papyri talked about it. Because there was not a definite treatment for cancer, radical treatments were used, such as burning or cauterizing the tumor. In the first half of the twentieth century, only surgical methods were implemented in cancer treatments. Desired results could not be obtained by surgical procedures, which ended up with the excision of entire organs.

Research studies were launched in the second half of the twentieth century into whether it was possible to treat cancer using drugs. These studies revealed that cancer stemmed from genetic flaws (like the ones in oncogenes and tumor suppressing genes), which led to questions about types of treatment. Treatments of flaws at the genetic level are based on genes themselves. These treatments use such methods as stopping genes that work abnormally, eliminating the products of these genes, and killing cancer cells by making use of their genetic mechanisms.

New incidents of cancer are likely to continue to develop, for people are exposed to factors that cause disruptions of the makeup of genes. To prevent cancer, it is critically important that one should have a conscious, natural, and balanced lifestyle. People should be well-informed about the effects of smoking, genetically modified food, radiation, stress, and chemicals, so that they can lessen exposure to such risk factors. Moreover, more frequent implementation of screening tests will make early diagnosis easier. More effective methods with fewer adverse effects should also be developed for higher success rates in cancer treatment. Genetic treatment of cancer is a relatively new field but an increasing number of studies focus on it. These studies aim to kill only cancerous cells and spare healthy ones. It can be expected that research into this field will produce promising outcomes in coming years.

We are all aware of the fact that there is certain rhythm and order in the movement of the sun and the earth, as well as other planets along their pre-assigned orbits. This order has ongoing without a glitch for possibly billions of years. The day and the night become longer and shorter on a schedule, and this is how we can develop calendars by calculating seasons, months, and days.

The movements of celestial bodies impact in multiple ways the biosphere in which we live. Trees shed leaves or bloom, some animals hibernate, and others enter reproduction season.

Time advances not linearly but in cycles. The internal systems by which the metabolisms of living things are organized are made to work according to numerous biological clocks that depend on the cyclical nature of time. These biological clocks are sometimes based on the length of a day and sometimes on long cyclical patterns that may span years. Periods of sunspots followed by explosions on the surface of the sun, for example, cause the reproduction cycles of populations of lynx and hare to peak every 11 years. This cycle is also tied to an increase in the production of wheat and certain species of fish breeding in abundance. The internal clock of the human metabolism is likewise organized during the day.

Scientists have long since noticed and started to research the different reactions of the human body to different time intervals throughout the day. It was realized that pains eased during certain times of day and intensified during others. There are also rising and falling cycles for hormones and the nervous system. These coincided with periods of hunger, meals, and sleep.

It has been found that certain changes occur in the physical and mental makeup of humans during the year, seasons, month and day. Researchers agree that every human has a unique physical and mental clock, but there are generally broad similarities. The scientific field researching these is called chronobiology. Researchers in chronobiology have demonstrated that certain changes occur, according to time periods, in the endocrine and autonomic nervous system as well as the body’s water and salt balance.

Other studies have focused on biological changes with respect to space. The regulation of the body’s biological rhythm is found to be influenced by the movements and positions of the earth on its own axis, the moon around the earth, and the earth around the sun. As the atmospheric environment changes, so do living things.

Towards the end of the 1960s, scientists found that a synthetic corticosteroid drug called methylprednisolone was more reliable for treatment of arthritis and asthma when taken in the morning rather than at other times. “These rhythms might affect responses to cancer treatment,” says Eric Holland, a neurosurgeon at Fred Hutchinson Cancer Research Center, adding that there are optimal times for administrating radiation in mice.

A forty-three-year-old patient with 27 tumors in her liver whose drug treatment for colon cancer did not work volunteered for a trial and recovered from cancer after rescheduling the administration of her drugs. Oncologist Francis Lévi was so amazed by this effect on the patient that he became a supporter of chronotherapy, or time-cycled treatment. To Lévi, who works at Warwick Medical School in the United Kingdom, timing can prove even more important than dose. In the trial, the patient was first wired up to a device like a clock so that metabolic rhythms could be better monitored. The patient had extremely regular sleep-wake cycles, which Dr. Lévi believed was likely to have contributed to the success of the treatment. This novel understanding did not spread before because researchers could not explain molecular foundations of daily rhythms, or circadian cycles, until 10 years ago, and clinical data was inconsistent.

Lévi and his team randomly divided 186 chemotherapy patients into two groups. They administered medicine to one group in accordance with the participants’ biological clocks and to the other group according to the standard procedure. More than 50% of the former responded well, whereas the rate remained at only 29% for the latter. Another study found that 298 patients who had heart operations in the morning were twice as likely to have unsuccessful operations and develop complications as compared to 298 patients who had operations in the afternoon. To prevent the effects of the surgeon’s selection of patients, the same surgeons operated both in the morning and in the afternoon.

The 2017 Nobel Prize for the field of physiology was awarded to three American biologists, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, for their study into biological rhythms. Their research presents remarkable insights into the reasons why the biological rhythms of plants, animals and humans are created in coordination with the movements of the earth. The researchers used the fruit fly, an exemplary organism, and found the genes that controlled its daily biological rhythm. Discovering that these genes initiate the secretion of a protein that accumulated overnight and dwindled during the day, the researchers revealed that these proteins caused a mechanism made to work in a certain rhythm when the time was right. It was like a watch had been set inside the fruit flies’ cell.

It is estimated that approximately 80% of our genes follow night and day rhythms (and also possibly seasonal rhythms). Indeed, it has been identified that fits of asthma and epileptic seizures develop according to certain daily rhythms. The products expressed by the genes that are active in most tissues peak early in the day and in the afternoon and reach lows after dinner and before bedtime. All these activities are carried out by the “molecular biological watches” written in our genes. If we can better understand our internal clocks, researchers believe they could discover breakthroughs in the treatment of up to 150 diseases, including cancer.

The time machine

Many tissues in the body have their own time schedules arranged by regular cycles in which numerous innate “clock genes” envelop the body like a net. The timing of all these clocks can have a powerful impact on metabolic activity, the increase in the number of immune cells, and many other things. “The best advice I can offer is don’t mess with your body clock,” says Professor Derk-Jan Dijk, director of the Surrey Sleep Research Center in the city of Guildford, England. [1]

The biological clock is an extraordinary system. A group of neurons in the hypothalamus in the brain, called the suprachiasmatic nucleus, are assigned as the central clock for all these activities in the body. The signals from this region play a role in initiating and finalizing the activities of the genes, which channel drugs to their molecular targets and help produce enzymes that destroy drugs. “Clock” genes are found virtually in every organ and tissue, and they are particularly important during cancer treatments, because interventions performed during such critical processes as the cycle of cellular division and growth and repair of DNA damage become significant for killing cancerous cells.

Cisplatin, an effective drug used for almost 50% of solid tissue cancers, kills malignant cells by binding to their certain parts, yet because the drug is toxic to the kidneys, lungs, and nervous system, efforts have been made to develop less toxic versions. Just as a cell develops cancer due to DNA damage, so is the destruction of the cancerous cell started by damaging the cell’s DNA. For this reason, some drug trials focus on blocking the DNA repair of the cancerous cell.

Observations made on the appearance and repair of DNA damage showed, as expected, that DNA damage was repaired more easily during certain periods of the day, leading to the hope that cancer can be treated through DNA repair if drugs are administered in tandem with this cycle. If optimal periods could be established for numerous normal cells to repair their DNA damage, administration of drugs can both optimize the useful effects of drugs and minimize toxicity of drugs with toxic properties.

The human organism and cells are not static, but dynamic. The behavior of our cells changes dramatically before and after a meal. Similarly, the movement and frequency of numerous materials circulated in our body when we are sleeping are different from when we are awake. Therefore, if the amount of a material doubles after lunch followed by a cup of coffee and if the material negates a drug taken by a patient, then that drug can be administered when this material is at its lowest in the body. For example, if the material is at a minimum at two in the morning, the drug can be given at that time, ensuring that the effect is maximized.

The studies into “man, the unknown” are bound to lead to many more discoveries about both treatments of diseases and the knowledge, power, and wisdom waiting to be found in the creation.

Note

1. https://woolcock.org.au/new-2/why-you-shouldnt-mess-with-your-body-clock-expert

References

• Leder, K., Pitter, K., LaPlant, Q. (2014). Mathematical Modeling of PDGF-Driven Glioblastoma Reveals Optimized Radiation Dosing Schedules. Cell. Cilt 156, Sayı 3, s. 603-616.
• Lévi, F., Zidani, R. & Misset, J.-L. (1997): Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350, 681–686.
• Peeples , L. (2018). Medicine’s secret ingredient — it’s in the timing. Synchronizing drug delivery with a patient’s body clock can yield clear benefits. But will the data be enough to overcome long-standing hurdles? Nature 556, 290-292 (2018).
• “Why You Shouldn’t Mess with Your Body Clock: Expert,” woolcock.org.au. August 7, 2018.

There are two types of pain. One is called sharp or acute pain, which for example might be caused by the prick of a needle, an injury from broken glass or a sharp object like a knife, or contact of skin with a hot object like an element. Such sharp pain is especially important to protect the body through reflex. Similarly, sharp pain in internal organs such as the stomach or intestines may result from a puncture or blockage that prevents the transport of oxygen, or leakage of toxic material such as the stomach acid.

Another type of pain is continuous or chronic pain, of which one obvious example is rheumatic pain. Cancer pain is mostly chronic, although cancer may also cause sharp pain. Whether chronic or sharp, cancer pain can be unbearable, and only endurable with morphine.

What can we do about pain?

Medication should be our last resort when dealing with pain. We should remember that every drug is potentially a poison, and drugs, especially when used for a long time and in high doses, can have numerous adverse effects. Thus no drug, including aspirin, is fully innocent.

The cause of pain must first be diagnosed by a physician. A pain in the chest may simply be a muscle pain, or conversely may be as deadly as a heart attack.

After diagnosis comes the required treatment or operation. Intense pain from appendicitis, for example, is easily treated with an operation. Pain from a heart attack, which causes pain in the left part of the chest, left shoulder and left arm, must be dealt with very seriously under the supervision of a cardiologist.

The first measure to be taken in case of a headache, backache, or neck ache is to avoid the position or movement that causes the pain. Consider the following analogy: the wheels of your car are not properly aligned. One side of the tire is worn due to friction, and thus blows out or loses traction. This result is inevitable, unless one corrects the misalignment leading to friction and wear. The damage cannot be prevented by putting on ear plugs and pretending it doesn’t exist.

If your neck has an ache, you should consult a physician to diagnose the cause. The pain may be related to how you use your pillow; so you can get rid of the pain by simply adjusting the pillow based on your preferred sleeping position, or you may need to buy a new pillow. The pain may also be caused by keeping the head in the same direction for prolonged periods to watch TV or looking into the monitor, we may just need to do some simple physical exercise and sit up right. Desk jobs and extended cell phone use are primary causes of neck aches. Resorting to painkillers immediately is not the right thing to do in such cases. A drug may ease the pain temporarily, but as in the car analogy, we may end up with a flat tire. Painkillers do not resolve the injury to the neck and what is worse, despite the intensifying pain you may not be aware of the body’s warnings, and finally have a serious case of hernia that may require an operation that runs the risk for death or paralysis.

The most important cause of backache is a vicious circle of inactivity and obesity. If a person does not exercise, they will put on weight and as one puts on weight they cannot exercise. Carelessness when picking up something is one of the most common causes of backaches. Obesity is one of the most common causes of herniated disc. Obesity prevents doing exercise; back muscles weaken as one does not exercise, and this leads to a herniated disc. If we do not take necessary care about these and look to drugs for treatment, we may not feel the pain, but the injury and hernia continue to exist. The risk is much lower among those who observe meditation and other religious practices that include physical activity like bowing, prostrating, sitting and standing upright. Eating little and leaving the table before being full are among many prophetic advices that are useful for our health.

The same is true for knee injuries such as meniscus tears and ligament sprains. Our knees are some of our most precious assets. We should be careful about our knees when standing up from a squat or getting on or off a car so that they will not slip sideways. Dangerous, rigorous exercises or movements that may harm the bones and cartilage in the knees, such as lifting heavy weights and jumping off a height, should be avoided, especially after a certain age. Sitting crossed-legged or squatting for long periods may stretch cruciate ligaments too much, and a slight move may cause their rupture.

One of the most common types of headaches is stress-related headaches. In these headaches the muscles in the head become tense, causing the vessels to contract and leaving tissues without oxygen. If we learn how to deal with stress, we can ease the headache and become happier. We should fight stress consciously and actively. We can overcome headaches not by sitting idly but by mental preparation and activity targeting stress.

Cupping and other complementary treatments can be tried before medication. Performing regular prayers may help relieve the aches in the head, neck, and knees, because these prayers reduce stress and are a form of exercise. Washing yourself as a part of prayers includes exercise, cleaning, and getting rid of the stress-related static electricity through water. Cleaning the top of the head, massaging the ears inside out, and washing the face and feet are known to reduce stress and discharge static electricity.

Endorphins, a group of hormones secreted within the brain, are in fact given the task of acting as painkillers in our body. They are thousands of times more powerful than morphine and help us fight headaches. Most of the ache, especially in chronic pains, is eliminated by the “pain-control systems” which were installed in our brains; what we feel as pain is in fact whatever remains after this elimination. Were it not for this mechanism, which is a sign of great compassion, life would be insufferable because of pains.

It’s not just modern medicine that utilizes bees and their products for healing. A clay tablet that dates back to 2000-2100 BC describes the healing properties of bee venom. In 1935, Forapin, which was isolated from bee venom, was introduced into the market. It’s still being used. Bee venom is collected by placing a small panel, which looks like a grill, in front of the bee hive. The panel is composed of metal wires in which low voltage electric currents flow. The entrance to the hive is through these wires. The bees that are entering or exiting the hive are subjected to a mild electric shock, and sting the panel with their needle as self defense. Meanwhile, the bee venom flows into the glass plate underneath the panel. Bee venom is collected and turned into a powder form without harming the bee.

The chemical composition and effects of bee venom

Bee venom is a colorless, odorless, clear, and water soluble liquid that is resistant to cold and hot temperatures. In normal seasonal temperatures, this venom dries up in 20 minutes and loses 65-70% of its weight. It takes a yellowish brown color after it is dry. 10,000 bee needles are needed for one gram of bee venom.

18 different bioactive molecules were found in the composition of bee venom. Some of these are: Melittin, adolapin, apamin, mast cell degranulation, histamine, phospholipase A, peptide, dopamine and hyaluronidase. These molecules show the characteristics of amino acid, protein, fat, sugar, and enzyme. Melittin and adolapin protein are anti-inflammatory; apamin increases nerve transmission; and mast cell degranulation is equipped with characteristics to help reduce allergies. Mellition, which is composed of 26 amino acids, is the main toxin molecule of the bee venom. Melittin triggers the synthesis of the cortisol hormone that suppresses inflammation and increases the resistance of cell walls. Melittin also triggers the immune system cells that prevent the formation of free radicals, which normally damage cells and tissue. As well as being antipyretic (fever decreasing), adolapin is also a pain reliever and also plays a role in the prevention of cyclooxygenase that are a cause of infection. Apaminin, which consists of 10 peptides, is thought to play a role in healing a damaged nervous system.

Low concentrations of mast cell degranulation proteins cause the synthesis of histamine, which triggers an allergic reaction; whereas high concentrations of it play a role in preventing these reactions. Although these molecules are called venom, they are provided with remarkable healing characteristics.

Treatment with bee venom

The fact that treatments for rheumatism are not completely effective has persuaded patients and healers to look into complimentary treatment techniques. Bee venom has gained acceptance as a complementary healing technique in China, the US, and Europe. Apitherapy centers have been popping up in these places – and the best method to apply apitherapy is by using bee venom.

The bee sting is mimicked by injecting bee venom into or underneath the skin, though creams or capsules of bee venom also exist. The injections function in a way similar to an actual sting, or to acupuncture. Acupuncture prevents pain by blocking the brain and spine paths (opioid and alpha 2 adrenergic receptors) that cause pain. Similarly, a bee sting stimulates the secretion of endorphins, which are a pain relief molecule. Therefore, in Chinese medicine, it is more common to apply the bee venom through acupuncture. In some cases, api-acupuncture is practiced by combining both treatments.

The treatment is started by injecting a small amount of bee venom underneath the skin to see if the patient will respond with an allergic reaction. If no allergic reaction occurs, the treatment is continued with one or two bee stings or injections. The treatment is carried out three times a week, by increasing the number of bee stings and injections each time. The treatment may cause allergic reactions in the patient that result in pain, swelling, itching, redness, or – very rarely – death. Therefore, as with every practice, treatment with bee venom should only be practiced by experts, and should not be tried by inexperienced healers.

As well as rheumatic complaints, bee venom is used for the treatment of arthritis (rheumatoid arthritis), joint calcification (osteoarthritis), bone weakening after climacteric, muscular rheumatism (fibromyalgia), and chronic pain.

In a study conducted with 80 inflamed articular rheumatism patients, 40 of them were treated with bee venom twice a week for two months. The rest of the patients were injected with physiological serum. The first group showed significant improvements on sensitive and inflamed joints, morning stiffness, and pain.

In a similar study, patients with inflamed joint rheumatism were injected with bee venom three times a week for three months, and there was a significant decrease in patient complaints. This study also proved that bee venom can be used for the treatment of inflamed joint rheumatism.

The healing quality of bees has long been noted. If we ruminate on this gift, it’s hard not to admire its wise design.