How does loneliness affect your brain?

Spreng et al. The default network of the human brain is associated with perceived social isolation. Nature Communications. December 2020.

A recent study found fundamental structural and functional differences in the brains of lonely people. Researchers examined the magnetic resonance imaging (MRI) data, genetics, and psychological self-assessments of over 40,000 middle-aged and older adults in the UK Biobank medical database. They then compared the MRI data of participants who reported often feeling lonely with those who did not. There were several major differences in the brains of lonely people which were primarily found in what is called the “default brain network,” a group of brain regions that are involved in inner thoughts such as remembering, future planning, imagining, and thinking about others. Detailed analyses of these regions showed that surprisingly, the default networks of lonely people were more strongly wired together and their grey matter volume in regions of the default network was greater. Moreover, bundles of nerve fibers called fornix that connects the hippocampus to the default network were better preserved in the brains of lonely people. These findings suggest that since lonely people are more likely to use imagination, memories of the past, or envisioning the future to overcome their social isolation they strengthen memory-based functions of their default networks through internally-directed thoughts and imagining social experiences. Loneliness has been increasingly turned into a major health problem, as other studies showed that older people who experience loneliness have a higher risk of cognitive decline and dementia. As COVID-19 related social distancing continues, isolation and loneliness could affect our society even more dramatically. Understanding how loneliness manifests itself in the brain at the structural and functional level, and how these paradoxical findings translate into late-onset brain pathologies, would be critical to prevent both neurological diseases and related social problems.

Human-made mass is about to exceed total global living biomass

Elhacham et al. Global human-made mass exceeds all living biomass. Nature. December 2020.

Humanity is rapidly approaching a new milestone in the history of our planet. The amount of manmade objects on Earth will soon outweigh all living biomass. A new study finds that each person alive today produces approximately the amount of manmade mass equivalent to their bodyweight every week. Our daily life objects such as roads, houses, cars, and clothes now weigh in at around 1.1 trillion metric tons, which is equal to the combined dry weight of all plants, animals and microorganisms on the planet. The production and accumulation of manmade objects, also known as anthropogenic mass, has accelerated since the early 1900s. The world’s plastics alone now weigh twice as much as the planet’s marine and terrestrial animals.

About 50% of the current anthropogenic mass is concrete. Bricks, asphalt, metals, plastic, and other materials make up about 19% of the total. Three major problems will arise from the outproduction of antropogenic mass. First, manufacturing consumes resources which will not be available for future generations unless objects are recycled or new raw materials are discovered. Second, even if we can achieve 100% recycling, pollution is generated and energy is used during manufacturing, so resources are still consumed. Third, many of the manufactured items will eventually be discarded which will cause serious disposal issues in the future. This is particularly alarming for the future. Nature is not infinite like so many of us would like to believe. If the current trend continues, anthropogenic mass will grow to three times the world’s biomass by 2040. In the next 20 years, we will generate as much waste as from the last 110 years together. These huge waste flows could lead to massive environmental catastrophes. This study demonstrates the brutal scale and impact of human activities on our planet. Humans are modifying the planet to such an extent that we might have already started a new geologic epoch likely called the Anthropocene.

Drug repurposing by artificial intelligence

Liu et al. A deep learning framework for drug repurposing via emulating clinical trials on real-world patient data, Nature Machine Intelligence. January 2021.

Researchers have developed a machine-learning method that analyzes very large datasets to discover which existing medications could work for diseases for which they were not prescribed. This process is called “drug repurposing,” a popular strategy to find new purposes for existing drugs that offers a rapid transition from research to clinical care. Drug repurposing can lower the risk associated with safety testing of new medications and dramatically reduce the time and money required to get a drug into the marketplace for clinical use. However, discovering new uses for existing medications still requires time-consuming and expensive randomized controlled trials to prove that a drug that is effective for one disorder will also be useful to treat another disorder. To overcome this challenge, a team designed a computational framework that works in two steps. First, it searches enormous patient care-related datasets with high-powered computation to arrive at repurposed drug candidates for a given disease. Second, it calculates and estimates effects of those existing medications on a defined set of clinical outcomes. As a proof-of-principle, researchers decided to focus on repurposing of drugs to prevent heart failure and strokes in patients with coronary artery disease. The edge of the machine learning approach is that it can analyze and compare thousands of human differences within a large population that could influence how a drug will work in the body. These confounding factors such as age, gender, race, and disease severity function as parameters in the deep learning computer algorithm on which the framework is based. This information is streamed from “real-world evidence,” which consists of longitudinal observational data about millions of patients captured by various sorts of electronic medical records. The team used insurance data for more than 1.2 million heart-disease patients. The algorithm analyzed each patient’s drug prescriptions and diagnostic tests for every visit and models input for drugs based on their active ingredients. The model yielded a total of 9 drugs with potential therapeutic benefits, three of which are currently in use and six new candidates for drug repurposing. Interestingly, two diabetes medications, metformin and escitalopram, have been found to lower the risk of heart failure and stroke in the model patient population. This study shows how artificial intelligence can speed up hypothesis generation and clinical trial processes. While this study focused on heart failure and stroke, the framework is flexible and could be applied to most complex diseases.

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.

Muslim psychologists and psychiatrists recently published an eye-opening book titled Applying Islamic Principles to Clinical Mental Health Care. I had learned about Dr. Rania Awaad and her work in mental health at a talk hosted by Salaam Islamic Center. She is a Clinical Associate Professor of Psychiatry at the Stanford University School of Medicine and the Director of the Muslim Mental Health Lab. Discussing how traditional Islamic texts meet with the modern disciplines of psychology and psychiatry, Dr. Awaad uses the “biopsychosocial” approach; she claims that psychology, mental health, spirituality, and religion cannot be separated. As someone who shares the same understanding, I was deeply impressed with her and her team’s clinical treatment methods and their new book. It is a book about introducing Traditional Islamically Integrated Psychotherapy (TIIP), which is the culminating result of the Khalil Center’s research.

I attach importance to this book because I truly believe in the power of holistic approaches to healing. I am also involved in the Association for Psychological and Spiritual Sciences (APSS), which is similar to the Khalil Center because it also encourages psychologists, psychiatrists, students of medicine, theologians, and researchers of human sciences to discuss and conduct studies to solve many problems of individuals and societies. Additionally, the APSS mirrors the Khalil Center due to its similar work of analyzing conceptual religious and spiritual sources of oriental history with an emphasis on Sufism. Thus, predominantly Islamic sources are discussed to develop universally applicable theories, concepts, and therapeutic strategies.

Two halves of a coin

The recently published book, Applying Islamic Principles to Clinical Mental Health Care, is built upon three profound principles. First, researchers combed through traditional and foundational Islamic texts, such as the holy Qur’an, sayings of the Prophet Muhammad (hadith), actions of the Prophet (sunnah), and other general Islamic guidelines for spiritual and material well-being. Then, this well-established and prosperous literature review was evaluated, and then combined, with modern psychology. Last but not least, practical methods were then synthesized by using traditional Islamic literature in the psychology field and current modern psychotherapy techniques.

The book delivers a detailed and lucid account of the differences between the approaches utilized by modern psychiatry and the TIIP. Contemporary psychiatry is largely based upon “The Diagnostic and Statistical Manual of Mental disorders” (DSM) and “The International Classification of Disorders,” (ICD) which are used for diagnosing mental disorders. The TIIP utilizes these texts and the vast amount of clinical research that they possess, but on the other hand it also takes the Qur’an, hadith, sunnah, and other Islamic spiritual traditions into consideration. The critical difference in between the two is that the TIIP advocates for a more holistic approach to mental health that includes a person’s spiritual well-being, while modern psychiatry does not consider a person’s spiritual pathological character in order for them to require clinical treatment. 

The TIIP’s perspective is that the concept of health and pathology cannot be adequately addressed with current clinical diagnoses. According to Islam, proper psycho-spiritual health is heavily associated with each person achieving a strong understanding of their own unique ethereal purpose, and the proper treatments for gaining and maintaining psycho-spiritual health can be achieved through training. For instance, a person that suffers from an abundance of arrogance, which negatively affects various aspects of their life, does not require modern psychiatric clinical treatment. Since arrogance is mentioned as a spiritual disease in Islamic sources, a TIIP practitioner addresses this condition with a psycho-spiritual integrative approach.

The APSS explains this concept in more detail by arguing that the human being is a vast, profound, and complicated creation that longs for a sense of eternity, permanence, understanding behind creation and life, and connection to one’s Creator. Spiritual health is seen to be equally important as one’s physical and mental health since neglecting one’s spiritual health can have adverse consequences upon many facets of a person’s life. Thus, eternal satisfaction may be gained via spiritual contentment. 

Furthermore, these techniques are not exclusive only to Muslims despite their backing in Islamic theology; they could be applied to non-religious and religious individuals alike, regardless of their belief system, since Islam aims to take a holistic look at life in a way that everyone can relate to in some form.

Our “inner senses” cannot be ignored

Humans have external senses and internal senses. External senses include sight, hearing, smell, taste, and touch, and we communicate with the external world via these senses. On the other hand, internal senses are spiritual senses and are used to communicate with the inner world. They include metaphysical concepts such as the spiritual heart (qalb), soul (ruh), and different modes of cognition (sır), (hafi), and (ahfa), and much more. They are the separate depth of the heart. Humans have a wide range of uses for internal dynamics and mechanisms, and our internal and external senses should work together like two wings on a bird. Just like how we take vitamins to strengthen our physical body, we strengthen our spiritual “body” by honing our inner senses.

All of the chapters of the book are very intriguing, and it has a compelling and inspiring effect on readers to understand and apply TIIP practices. For instance, the whole chapter about “Intellect” and its methodization in Islamic Psychotherapy is remarkable. One of the most impressive indications is that the word “intellect,” which is mentioned about 50 times in the Qur’an and across various hadiths, is referred to the link between intellect and well-being. Thus, the importance of the mind is explained through a different lens. Cognitive-behavioral therapy (CBT) looks at our thoughts, feelings, and the roles that they have when it comes to how they affect our behavior. There is a direct correlation in between our thoughts, emotional health, mental wellbeing, and then our actions. The book refers to the writings of Islamic philosopher, jurist, and mystic Abu Hamid al-Ghazali and his modality in Islamic literature. Al-Ghazali offered to implement interventions among stages by addressing faulty thoughts, negative feelings, and actions. For instance, the Islamic ablution, which is often performed once before each of the five daily prayers, is given as an example during two of the stages. Those interventions would help change the focus on faulty thought and shift the state of emotion.

While the TIIP discusses the intellect it also includes three stages of “self” (nafs); the evil commanding lower self and the animalistic impulses (nafs ammarah), self-criticizing blaming stages (nafs lawwamah), and tranquil stage (nafs mutma’innah). These stages are interpreted as the spiritual elevation of the human spirit. A TIIP practitioner aims to achieve a tranquil stage for the client. TIIP gradually works with cognitive science by identifying and challenging a person’s faulty thought and then reconstructing situations, thoughts, and feelings. 

The seven stages of thought progression

In addition to the book’s description of intellect, the APSS mentions seven stages of the mind’s metacognitive dimensions and functioning system that are important information processing steps.

The first one is “imagination” (tahayyul); in this stage, false thoughts occur. The mind starts overreacting by imagining false thoughts, such as worrying about getting sick due to Covid-19 even if a person is self-quarantined and has almost no chance of getting it. In this phase, negative thoughts and apprehension happen. Then, the “envisage” (tasawwur) stage comes. Thoughts are conceptualized and shaped in this stage. An individual could start believing, or perhaps even convince themselves, that they have contracted the virus if they are constantly being exposed to negative news surrounding it. When both the imagination and envisage phases activate then thoughts start to attack an individual’s inner world. Toxic thoughts can begin entering the brain and can wreak havoc on a person in the form of abnormal behavior, anxiety, stress, and obsessive thoughts.

The fourth stage is “comprehending” (ta’aqqul), which also assess our thoughts with the goal of more clearly understanding them. Then, the “approval” (tasdiq) stage comes, and in this stage individuals understand and confirm positive thoughts in their heart. The next stage is foresight (iz’an) which starts where individuals begin to understand themselves very well and act according to their understanding. Next is favoring (iltizam). The last stage is faith (i’tikad), which involves having sincere belief, firmness, and not hesitating to act upon what a person believes to be right. The first two stages, imagination and envisage, compose the thought process and the outcomes of this process. To change faulty thoughts, individuals need to consciously intervene upon the first and second steps by “getting rid of habits.” Directly attacking the source of these negative thoughts allows a person to begin to change their faulty thinking processes. One should start with staying abstinent from being exposed to too much unhelpful information. Habits always need to be replaced in order to fill the void that is consequently made, and it is therefore recommended to engage in otherwise beneficial activities, such as reading the holy book, praying, spending time outside, engaging with people that bring joy and positive emotions, or pursuing a subject or hobby of interest.

Applying Islamic Principles to Clinical Mental Health Care: Introducing TIIP qualifies as a bedside book that every professional working with the Muslim population should read. The book structurally clarifies and demonstrates how Traditional Islamically Integrated Psychotherapy is utilized in therapy by discussing an overview of modern psychology and the traditional Islamic bibliography. Case examples are spectacularly and elaborately explained. After reading the whole concept and its case studies, readers will find answers to their questions. Whether the readers are an emotionally focused therapist, a cognitive-behavioral therapist, a behavioral therapist, or a spiritual therapy practitioner, they will benefit from this book. The book covers all four approaches under the “Treatment of the Domains of the Human Psyche” part. Therapeutic interventions can be practically implemented.

Almost all of us are familiar with the fact that our bodily organs are composed of tissues, which are made of cells. The perfect machinery of the cells is controlled by our genes; i.e. DNA and RNA. Therefore, a minor defect or mutation in the genetic code may affect either partial or entire systems within the body. Some of these genetic diseases are inherited from our parents or relatives. Others may be introduced into our body through environmental mutagens, such as ionizing radiation, ultraviolet rays, or different chemicals within our food and drink; these can result in cancer or cardiovascular diseases. We can protect ourselves from the latter by using appropriate outfits, taking care with our diet, etc. However, inherited genetic disorders are usually unavoidable and sometimes have fatal consequences. Modern medicine is striving to find a way to treat these diseases. Although there are some medical procedures that may lessen the pain of patients or extend their life expectancy, there is no available comprehensive curative therapy for genetic disorders.

Gene therapy has become one of the rising stars in the field of molecular medicine during the last decade, with more than 1500 proposed or ongoing clinical trials worldwide. Gene therapy promises to provide curative therapies for a large number of inherited or acquired diseases, such as monogenic disorders, cancer, or cardiovascular disease. Gene therapy is universally defined as the replacement of an abnormal/dysfunctional gene in the cells of an individual with its correct and functional version. Mechanics use a number of tools to fix our cars for us when they give us trouble; in the same way, gene therapy can be used by doctors to alleviate or completely eradicate some diseases from our bodies.

Gene therapy is classified into two categories based on the target cells that are to be treated. The transduction of the differentiated cells of an individual, i.e. the somatic cells, is known as somatic gene therapy; the transduction of reproductive cells, i.e. gametes (sperm or ova), is known as germ-line gene therapy. Currently, there are many regulations in place that limit the likelihood of the modification of the germline in any gene therapy approach. This is because fear exists that the ability to alter the germline will result in the widespread application of gene therapy to achieve eugenic genetic enhancements, such as improvement of intelligence or physical characteristics. On the other hand, transgenic animals, which are used to detect the function of the genes within an organism, can be generated by modifying the germ-line. Furthermore, gene therapy is also classified into two groups: adult and fetal (in utero) gene therapy, according to the individual to be treated. There are several advantages and disadvantages to these methods, such as immune response, the pooling of mitotic cells, the amount of vector that is required, etc.; however, these are matters for a different article.

Gene therapy is achieved by using special exogenous genetic material transfer agents which are called vectors; these can be compared to the special tools used by auto mechanics. Over the years, a number of gene transfer vehicles, i.e. vectors, have been developed and these can be divided into two principal categories: non-viral (synthetic) and viral (virus-based) gene delivery systems.

Non-viral gene transfer can be achieved by using both physical and chemical methods. The physical methods include: i) Electroporation, in which areas of the cell membrane break down as result of an applied electric pulse, thus allowing DNA to enter the cell, ii) Ballistic gene transfer (the Gene Gun), which bombards particles coated with DNA into the cells, and iii) Microinjection, in which DNA is transferred through microcapillaries into the cells [1]. In terms of chemical gene transfer, lipofection is the most promising method; in this method negatively-charged DNA molecules bind to cationic lipid particles through electrostatic interaction and the DNA–lipid complex enters the cell through endocytosis/pinocytosis. Although these non-viral delivery systems exhibit low toxicity and can be easily produced in high concentrations on a commercial scale, in general, gene transfer using these agents is inefficient and often transient. Therefore, as a result of the viral vectors’ ability to efficiently deliver and integrate genes into the host genome, they are being engineered extensively to achieve a sustained and high-level expression of the gene of interest (transgene).

Viral vectors

Have you ever thought that one of the major pathological agents that cause catastrophic and even fatal diseases could be used to treat the same or a similar disease?

Viruses are equipped with specialized molecular mechanisms that allow them to efficiently transport the genomes into the cells they infect and use the cell’s machinery for their own reproduction. Molecular biologists first harnessed this machinery of transduction in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage lambda to infect monkey kidney cells that were being maintained in culture. Viral delivery systems are based on replicating viruses that have the ability to deliver genetic information into the host cell, a process known as transduction [2]. Due to the fact that there are several advantages to viral vectors, these are the vehicles being employed in approximately 75% of all ongoing clinical trials worldwide. Numerous viruses are being used as the basis for the vectors, including, but not limited to, adenovirus (24%, n=377), retrovirus (20.9%, n=329), adeno-associated virus (4.3%, n=67), herpes simplex virus (3.2%, n=51), vaccinia virus (7.9%, n=124), poxvirus (5.8%, n=91), and baculovirus (more detailed information is available at www.wiley.co.uk/genmed/clinical). The first step to construct a viral vector for transferring the gene of interest involves the identification of the viral sequences that are necessary for replication and pathogenesis. Then some of the genes are removed to make room for the transgene and to render the viral vector replication-incompetent. Consequently, the vector is unable to replicate within the host, and therefore is safe for delivering genes to human cells or tissues (Figure 1).

There are advantages and disadvantages to all of the currently available vectors; the suitability of the vector, therefore, actually depends on the disease or condition that is being treated. For instance, if the goal of the gene therapy is to increase bone marrow engraftment with the transient expression of a growth factor, the use of chemical transfection or naked DNA transfer methods would suffice. However, if the objective is to provide long-term treatment for an inherited disease, then the use of an integrating viral vector is more desirable. Thus, a vector that might be ideal for treating one defect may not be ideal for another. Driven by the desire to develop the “perfect” vector, scientists are continually striving for novel forms of gene delivery that might become the “magic bullet.” Somia and Verma [3] have proposed that the ideal gene therapy vector should include all of the following properties: 1) easy production at a high titer on a commercial scale with a reasonable shelf-life for transport and distribution 2) sustained or regulated expression of the transgene product that is adjustable to the nature of the disease, 3) absence of immune response against the vector and the transgene product, 4) ability to target specific tissues and/or cell types while avoiding professional antigen-presenting cells, 5) absence of size limitations for the genetic material to be delivered by the vector, 6) site-specific integration of the transgene into the chromosome of the target cell to avoid insertional mutagenesis, or faithful division and segregation if it is to reside in the nucleus as an episome independent of local chromatin environments, and 7) an ability to infect dividing and post-mitotic cells. Unfortunately, none of the currently available gene delivery vectors carry all of these features; however, many vectors have enough of the attributes to make them promising for clinical use.

Candidate diseases

During the last 4 decades, gene therapy for many diseases has progressed from preclinical to clinical studies; these range from monogenic recessive disorders such as hemophilia and cystic fibrosis to more complex diseases such as cancer, cardiovascular disorders, human immunodeficiency virus (HIV), neurological and ocular pathologies. The prevalence of diseases that fall under the scope of gene therapy is enormous and most of them have catastrophic or fatal outcomes. Therefore, gene therapy approach for almost any of the diseases mentioned above has an obvious appeal and rationale. To date, more than 1,540 gene therapy clinical trials have been initiated, and these are continuing or have been completed in 28 countries, using more than 100 genes, including antigens, cytokines, tumor suppressors, growth factors, and deficiency genes [4].

Candidate monogenic disorders that are considered to be good candidates for treatment by gene therapy include the hemoglobinopathies, X-linked genetic disorders, amino acid metabolism disorders, and lysosomal and other storage diseases. Currently, there are more than 4000 monogenic diseases registered in the OMIM database. The ultimate aim in treating monogenic diseases with gene therapy is the correction of the disorder by the stable transfer of the functioning gene into dividing cells (stem/progenitor cells), which will ensure the permanence of the correction [5]. The first recognized successful clinical gene therapy trial involved the treatment of 11 children who suffered from SCID-X1 (Severe Combined Immunodeficiency), an X-linked inherited monogenic disorder caused due to a mutation in the common cytokine receptor gamma chain (γc). In these patients, immunity was not fully developed due to the blocking of T-cell and natural killer cell development as a result of mutation. Unfortunately, the trial in SCID-X1 also exemplified one of the potentially serious side effects of gene therapy. Three of the children developed uncontrolled clonal T-cell proliferation, that is, leukemia, almost 3 years after treatment. This case was associated with the integration of the retroviral vector close to the promoter of the LMO-2 proto-oncogene. As a result, LMO-2 protein expression was up-regulated in an abnormal way and resulted in leukemia [7]. Another candidate monogenic disorder for gene therapy is cystic fibrosis (CF), in which abnormally thick mucus is produced in the lungs of the patients, causing difficulty in breathing and increasing the frequency of serious lung infections. CF is known as the most common inherited genetic disease in Europe and USA, especially within the Ashkenazi Jewish population. The average life expectancy of patients with CF is less than 40 years; hence the treatment of this disease has become one of the prime targets of gene therapy research.

In addition to its use in the treatment of monogenic diseases, gene therapy is also becoming a therapeutic alternative for the treatment of various forms of cancer. Indeed, almost 65% of ongoing clinical trials are related to cancer (more detailed information is available at www.wiley.co.uk/genmed/clinical), an area in which much more promise can be seen; this is also a reflection of the urgent need for new therapies to tackle the escalating incidence of this disease. Several different principles are used to treat cancer, including gene therapy that is targeted at tumor suppressor genes, such as p53, or central signaling molecules, as well as “suicide gene” therapy, in which the transgene is capable of converting pro-drugs (selectively less active drugs) into drugs that are toxic for tumor cells. Furthermore, various gene therapy protocols have been developed to strengthen the host’s anti-tumor immune responses by immunotherapy. Most of these studies have been early clinical trials designed primarily as studies of the safety, applicability, and toxicity of gene therapy. Several of these phase I and II studies have, however, shown partial remission of tumors and, in rare cases, complete remission. However, complete cure of the tumor has not yet been achieved. In some trials, including TP53 gene therapy trials, regression in tumor size has been observed in up to 50% of patients. China has become the first country to license gene therapy as a regular treatment for neck and head cancer; here Gendicine, a replication-defective Ad5 vector expressing p53 from a Rous sarcoma virus (RSV) promoter, is used for therapy [6].

In addition to its applications for cancer and monogenic diseases, gene therapy has become one of the favorite methods in cardiovascular research field. This is in step with the rise in clinical trials for cardiovascular gene therapy from 8.3% to 9.1% during the last few years, becoming the second most popular application for gene therapy. In accordance with the variety and occurrence of cardiovascular diseases, different gene therapy strategies have been developed to tackle each disease on its own terms. The expectation is that gene therapy will provide a new avenue for therapeutic applications in the growth of blood vessels, as well as the protection, regeneration, and repair of heart tissue, the prevention of the reoccurrence of constricted or narrowed arteries following cardiovascular intervention, the prevention of the rejection of a bypass, and risk-factor management [4]. Long-term therapeutic gene expression is required in some diseases, such as hypertension research, where reversal and prevention are the key targets. On the other hand, for some other types of cardiovascular diseases, such as ischemia, atherosclerosis, and restenosis, shorter-term gene control will be sufficient to prevent further progress of the symptoms. Therefore, different gene-therapy vectors have to be considered for the treatment of each specific cardiovascular disorder.

Consequently, gene therapy offers new avenues of treatment for diseases including monogenic disorders, cancer, cardiovascular diseases, infectious pathologies and many more. As we follow the tradition, “God did not send down any illness for which He did not also send a cure (Bukhari)”, gene therapy using either viral, non-viral, or any other novel methods may pave the way for the cure of many diseases that are highly prevalent in the world and which for decades have been perceived as untreatable.

Dr. Ferhat Ozturk is a postdoctoral research associate at University of Nebraska Medical Center.

References

1. Wells DJ. “Gene therapy progress and prospects: electroporation and other physical methods.” Gene Ther. 2004 Sep;11(18):1363-9.
2. Kootstra, N.A. and I.M. Verma, “Gene therapy with viral vectors.” Annu Rev Pharmacol Toxicol, 2003. 43: p. 413-39.
3. Somia, N. and I.M. Verma, “Gene therapy: trials and tribulations.” Nat Rev Genet, 2000. 1(2): p. 91-9.
4. Edelstein, M.L., M.R. Abedi, and J. Wixon, “Gene therapy clinical trials worldwide to 2007–an update. J Gene Med, 2007. 9(10): p. 833-42.
5. http://www.biomedisch.nl/en/gene_therapy_targeted_diseases.php
6. Peng, Z., “Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers.” Hum Gene Ther, 2005. 16(9): p. 1016-27.
7. Cavazzana-Calvo M, Fischer A, Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007 June. 117(6):1456-65

American Indians applied its leaves as a poultice to heal wounds, and brewed a cough mixture from its roots. Now its seeds are claimed to have medicinal uses ranging from relieving pre-menstrual syndrome to management of multiple sclerosis, alcoholism and atopic eczema.

The seeds contain approximately 15% protein, 24% oil and 43% cellulose and lignin. The fatty acids in the oil are thought to be important to health because the oil contains 65-85% linoleic acid (LA) and 7-15% gamma linoleic acid (GLA): LA is an essential fatty acid for the body which it cannot make but which it converts to GLA. GLA is one of the components of cells and a precursor of prostaglandins which regulate many body functions. However, the LA GLA conversion step may be blocked by a range of factors including excessive levels of blood cholesterol, a high proportion of certain fatty acids in the diet, ageing, alcohol intake and diabetes.

Supplementing the diet with evening primrose oil (EPO) by-passes the conversion step, thus providing for the presence of GLA in the body. A recent World Health Organisation report suggested that 3% of the total calorific intake of adults should be in the form of essential fatty acids, this figure rising to 5-6% for children and pregnant and lactating women. GLA can be provided by several other sources as well, e.g. borage oil and blackcurrant oil, both of which contain a higher concentration of GLA than EPO but not as much LA.

The quality and composition of EPO used in commercial manufacturing is currently the subject of much research and monitoring work. In the UK research is concentrated on obtaining GLA from other sources e.g. by fermentation from the fungus mucor javanicus.

A concentrated oil from evening primrose, borage and blackcurrant seeds, is now undergoing clinical trials and may be used in second generation oil products of the future. EPO is already used in a variety of beauty and hygiene products, including cosmetic and skin care products, shampoos and soaps.

Trials have been curried out to investigate claims of the effectiveness of EPO in treating many diseases and conditions, including multiple sclerosis, cardiovascular disease, asthma, atopic eczema, cancer, obesity and premenstrual syndrome. So far the results have been variable but some genuine clinical effects have been seen.

Millions of dollars have been and are being spent on developing new methods of extracting useful natural products for the benefit of mankind. We are now seeing a widespread desire to return to natural resources to cure various ailments. Let us hope that, before mankind destroy their environment, they will come to realize the importance of nature’s medicine-cabinet, and give thanks where it is due. Without that giving of thanks, mankind will not practise the humility and compassion necessary if our common resources are to be preserved both for ourselves and for future generations.