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Undereducated about the Unknowns

I know, I know. So far this hasn’t been a very positive post and for a condition that effects a large proportion of people, I don’t want to scare anyone. Like always, my goal is to educate and that is why I go into detail about these things—for some people they need to know the why before they understand the solution. As such, let’s go into the way we approach Obesity and weight loss and see how we solve it. Short answer: it's very difficult, not easy, and requires lots of encouragement and motivation for everyone involved but the payoff is huge. As a pharmacist working in addiction and psychiatry, part of my job is to recommend agents to assist someone’s treatment. Because of my background I feel that I have a unique perspective on medical issues because I am the drug expert and so I can balance the drug benefit with the side effects of other drugs OR complications of other conditions. That being said, no size fits all and everyone needs a different approach.
Currently I work with many individuals with weight loss challenges due to behavioral conditions (such as Binge Eating Disorder), their medication regimens, or genetics. One of the most important aspects of recommending a weight loss agent is understanding the mechanism of why that person’s calorie intake is more than their calorie expenditure. This section refers to a person who may not be aware of what goes into a proper calorie intake and how to balance intake and output. In a sense this is the field of Nutrition and is where Dieticians come in (please note that registered Dieticians are medical professionals with a degree in Nutrition which enables them to perform medical nutrition counseling and diagnose or treat nutritional illnesses. Depending on the state, a nutritionist does not have a license to practice Medical Nutrition).
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• The essentials of Nutrition come down to the idea of Energy Balance or how energy is taken into the body, generated, and then expended. A positive energy balance is when more energy is taken in and then stored resulting in weight gain while a negative energy balance is where less energy is taken in than used so fat stores must be used. Remember that the goal of eating food is to make energy which is represented by the molecule ATP (produced by the Mitochondria!). However, depending on the kind of activity done, we may not have enough stored ATP in the body to cover the activity and thus have to use other means of ATP production.
  • When we are at rest, the activities we do such as swiping your thumb on a screen and moving your eyeballs to read do rapidly deplete the amount of stored ATP—this is why you can sit all day without feeling winded. If we perform a more intense activity, such as walking, the stored ATP is used incredibly quickly (lasts <10sec) and we have to use Aerobic Metabolism to create ATP while doing the activity. Aerobic Metabolism utilizes oxygen to make ATP and is incredibly efficient which enables us to do low-impact activities for an extended period, like walking down a hallway. As the impact level of the activity increases or the length of time increases the body switches from Aerobic Metabolism to Anaerobic Metabolism which is ATP production when oxygen is not available. This isn’t to say that your muscles have 0 oxygen when you are running but more that oxygen demand (moving the muscle) is much higher than oxygen supply (oxygen capacity of red blood cells). As such, the body utilizes Anaerobic Metabolism which produces ATP for energy but also Lactic Acid which causes that muscle pain after exercising.

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• To make it simple, Aerobic Metabolism is used in low-impact activities while Anaerobic is used short bursts of high-impact (like a 2-min workout) OR prolonged high impact activity (like crossfit or HIIT exercises). Now that we understand that, we can see what kind of energy source is used in what kind of metabolism. As you can see, Fatty Acids are part of Aerobic Metabolism but only after about 1.5-2hrs of activity. What this means is that in order to burn fat you need to burn your Liver glucose stores (called Glycogen) first and then you can start burning fat. So the 20 minute treadmill run while great for raising your mood and improving blood vessel health may not touch the fat in your belly.
• This brings us to the other aspect of Nutrition—diet. Now this is where the lack of words to describe the science is cumbersome. Someone’s food intake, aka their diet, is different from dieting (cutting out certain foods) which is different from following a Diet (capital D), a more strict set of food guidelines. I don’t have the training to discuss what is a good Diet but I can talk about what are the necessary components of what makes up a good diet (lower case d). In general, it is all about ensuring you have the essential nutrients and reduce the intake of weight gaining foods. Essential nutrients like Vitamins, Minerals, Trace Elements, essential Amino Acids are required from our food in order to live and there are lots of sources online about which foods create balanced meals that fit your preferences. What is nonessential is carbohydrates, proteins, and fats (except omega-3 fatty acids). Yeah, kinda weird to think that the main components of our foods are nonessential but what that means is that we can change it up as needed to fit your current need.
  • Carbohydrates are a group of macromolecules that consist of carbon, hydrogen, and oxygen and are very energy rich. Carbs come in two flavors: nondigestible and digestible. Nondigestible carbs are the dietary fiber we need to ensure that our stools can form solidly and move along the intestines. There are lots of types of fibers but the one for weight specifically is Viscous Fiber which forms a gel in the intestines to reduce sugar and fat absorption. Unprocessed oats, flaxseeds, asparagus, beans, and Psyllium Husk are great sources of Viscous Fiber which help reduce the amount of fat and sugar we take in from our food. Digestible carbs on the other hand are the sugar we normally think, the sweet stuff like glucose, sucrose, fructose, and starches. All digestible carbs can result in weight gain but it all depends on the amount you eat. The essential of a diet is not what you eat but how much you eat; so yes you can have some cake one day but you should abstain for the next few days.
  • Unsurprisingly the fat we eat can be absorbed into the body and used to make fat that is stored. Animal products and processed foods are highest in fats that are likely to be stored while plant based fats and oils are less likely to be stored (more likely to be immediately used as energy).
  • Finally proteins which are not required for weight loss but are essential for muscle gain and the best way to promote further energy expenditure after exercise is to promote muscle synthesis. Essentially, when we exercise the muscle is damaged either by the flexing of the muscle or by the lactic acid produced and so needs to recover with protein in our diet. In order to use the protein the body needs to spend energy which can be done in the form of using more stored fat. Thus, eating protein while trying to lose weight can provide additional benefits.
  • So what does this all mean in terms of the exercise we were talking about before? Well remember that in order to burn fat someone needs to exercise about 1.5 hours to burn through stored glucose stores. Now this can be really cumbersome but the way around this is to starve the Liver of glucose to rebuild those glucose stores. By keeping a low-carb diet, your liver wouldn’t be able to use dietary glucose to rebuild the Glycogen stores and instead have to use more fat! As such, keeping the amount of glucose in your diet low aids in getting to the 1.5 hours sooner and can facilitate using fat as a main energy source when you are at rest.
• Now diet and exercise is all well and good but there is a big factor here that we have to consider: ability to diet and exercise. Yes physical ability is a major aspect but this is why this section is titled Undereducated—for individuals who are lower socioeconomic status (SES) they have a harder time achieving the necessary diet and exercise goals to find significant weight loss. Is this because they are uneducated? No, most Obese people of any SES know that eating better and exercising will make them lose weight, but performing those actions uses another major commodity: time. Unfortunately, those of lower SES face several challenges that make it extremely difficult to lose weight: often they are working lower wage jobs meaning that more time is spent working and less time available for exercise. Combine this with the higher cost of living, especially when caring for children, and lower SES correlates heavily with buying cheaper foods which are often not the most nutritious. If a parent has to feed 4 children with a few dollars, they will use sources of food that maximize the value of that dollar—this means processed foods filled with salt and fat to make them taste good. This is part of the benefit of food stamp programs which enable lower earning families to purchase more nutritious foods. But this is where the undereducated part comes in.
  • For many people they think that a weight loss meal is salad, and while its not wrong, its a lot of what is in the meal. Part of my work in college working in a food kitchen was helping families understand how to maximize the benefit of the canned or frozen vegetables and fruits they have access to rather than feeling that healthy food is only fresh produce. A person can accomplish the same nutritive goals on frozen or canned vegetables as they can on fresh or raw foods and often on a smaller budget. I highly encourage those who are on a limited budget to get in touch with their local food bank—often they can connect you with a dietician who can guide you through how to cook nutritious meals on a small budget and for a large family. Please know that diet and exercise is extremely possible even with added time constraints.

And a quick buck was made

Okay I think we have come to the part that people were really waiting for—the drugs! Please take this next section as educational only and to merely inform you of the thinking behind weight loss agents. You must talk to your doctor or pharmacist before starting, stopping, or changing any medications including herbals, supplements, or illicit substances. The first group of medications we will look at are those with an FDA approved indication for weight loss:
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• First up we have Orlistat, a medication that does not require a prescription in the United States to use. Orlistat is an inhibitor of stomach and pancreas Lipases, a type of enzyme responsible for breaking down dietary fats. This means that when someone takes Orlistat the fats they eat are unable to be broken down for absorption and instead stay in the stool for excretion. When used correctly, about ¼ to ⅓ of dietary fat isn’t absorbed and there is a sizeable reduction in LDL (bad cholesterol). While its nice its over the counter, Orlistat has some…major drawbacks. The biggest is it’s tolerability—because Orlistat prevent fat digestion, most of the fat stays in the intestines causing oily stools, urgent diarrhea, and smelly flatulence. In its official documentation the term “explosive diarrhea” is used. Now, to avoid these unfortunate side effects a person should meals that are high in fat (no more than 30% of their daily recommended fat amount). Now this begs the question: is Orlistat effective in losing weight because of how it works or because people avoid fat like its poison to prevent explosive diarrhea? Either way someone should expect to lose around 15 lbs at 6 months of regular use which is nothing to sneeze at.
  • Speaking of over the counter weight loss aids we should talk about a few. One of the biggest ingredients included in these supplements is Caffeine. Caffeine is thought to work by increasing someone’s metabolic rate or in other words to increase the amount of energy someone uses while at rest. Part of this is because the heart is working harder (Caffeine increases heart rate) but there is some more systemic effects that are not explained by simple increased fight or flight effects. I can’t find the source I heard this from, because I believe I learned it during a seminar, but somewhere near 65% of OTC weight loss supplements have some form of Caffeine in them. Caffeine can be listed by itself or be hidden in an herb like green tea, yerba mate, green coffee beans, kola, guarana, yaupon, and dozens more. I'm not anti-caffeine, I drink plenty of it everyday but these supplements often have people exceeding the safety limit of caffeine by combining these herbs together. Caffeine can worsen anxiety, put significant strain on the heart, and isn’t recommended for pregnant women. Just be careful!

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• One supplement that used to be on the market in the US and is now banned is Ephedra. Ephedra is preparation of the chinese herb Ma Huang which contains the alkaloid Ephedrine and Pseudoephedrine. Both chemicals are part of the stimulant class of medications and when used in large enough doses will cause appetite suppression. Essentially these chemicals stimulate the fight or flight region of the nervous system which suppress the urge to eat. This is actually the reason why stimulants like Amphetamine (Adderall) and Methylphenidate (Ritalin) are used off-label to treat Binge Eating Disorder and help weight loss. Suppressing the urge to eat helps the person eat correct portion of food or prevent binge episodes thus reducing calorie intake. One OTC product that was extremely popular in the late 1990s and early 2000s was Hydroxycut which heavily marketed itself on TV and on the unregulated internet. In 2003 the Missouri Attorney General sued the company over their claims that Hydroxycut was “clinically proven” to burn fat but the case was settled out of court. Later in 2003 the NYT uncovered hidden documents that showed Hydroxycut knew its product didn’t work and have tampered with documents in another lawsuit in Oklahoma to show otherwise. Regardless, the usage of Hydroxycut wasn’t significantly hampered but due to its widespread use and unscrupulous advertising, the FDA banned Ephedra in 2004 after 155 deaths were attributed to the herb. It was the first time a supplement was banned in the US. Hydroxycut then switched to using Hydroxycitric Acid which required a lower dose than the Ephedra based formulations. The company failed to advertise the change in dosing and dozens of cases of serious liver failure resulting in liver transplant were reported and at least one death (19yo male). Hydroxycut is now mostly Caffeine.

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• Similar to the stimulants is Bupropion which is combined with the opiate antagonist Naltrexone in the product Contrave. Bupropion is an antidepressant that causes a raise in Dopamine and Norepinephrine in the brain while Naltrexone works by preventing endorphins from binding to the opioid receptor in the brain. Together its thought that Contrave works in Hypothalamus to reduce pro-eating stimulation as well working in the Mesolimbic Dopamine Circuit to reduce the reward feedback someone feels when eating. In a sense, the drugs work by causing someone to be less hungry and then reduce the pleasurability of eating. Contrave can be incredibly useful in people who are mindless snackers (such as eating large quantities of food when not paying attention) or for binge eating disorder. The benefit of using this medication over the stimulants like Adderall or Ritalin because it helps treat the cause of the Obesity (overeating) rather than just preventing the symptom (weight gain). Generally people see around a 25lb weight loss around 6 months.
  • Similar to Contrave is another combination product: Phentermine and Topiramate in the branded product Qsymia. This combo pill utilizes the stimulant Phentermine which comes from the same class as Adderall and Methylphenidate to suppress appetite and Topiramate, originally an anti-epilepsy medication that is thought to suppress appetite, increase satiety, and reducing pleasure from eating. Qsymia produces similar results to Contrave.

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• Okay, this brings us to a very controversial medication in the pharmacy world: GLP-1 agonists. If you remember from earlier I described how White Fat releases the appetite-suppressing hormone Leptin due to the stomach and intestine releasing GLP-1. GLP-1 is released when the GI tract detects carbohydrate or fat rich foods and their release triggers a cascade resulting in long term appetite suppression. LIkewise it is believed that the very common side effect of nausea and vomiting reduces the desire to eat. So in a lot of ways, they are working the same as the stimulants are—reducing appetite but not really touching the reason for overeating. GLP-1 agonists like Semaglutide (Wegovy) and Liraglutide (Saxenda) are used primarily for their influence on Insulin in Type 2 Diabetics to help lower blood sugar levels and reduce A1c, a marker of overall health in Diabetes. In diabetes, the clinical benefits of GLP-1s cannot be understated on the heart, kidney, liver and many other organs. In non-Diabetes weight loss? Well…don’t get me wrong they do work—people usually see a 15 lb loss at about 6 months but they miss the mark in the same way that the stimulants do. They prevent symptoms but don’t really help the underlying cause for why someone might be Obese.
  • The other aspect that I am always weary of is when drugs become “popular” in the media and especially with celebrities. Many celebrities and social media influencers are touting the benefits of GLP-1 agonists, i.e. the weight loss, but the consequence of this fad is that Diabetics who rely on this drug are unable to get it anymore. There is a massive shortage in GLP-1 agonists for people who could use another agent with similar efficacy but are using GLP-1s due to the social media presence. Likewise the weight loss isn’t sustained—at about 1 year the weight loss plateaus and after stopping only around 50% maintained the weight loss. Compare this to the other agents we’ve talked about who had a sustained weight loss around 80% and the choice is clear. Another aspect I have against these drugs for weight loss is the use of a side effect as a selling point—the rate of nausea is about 44% which means that someone is making themselves sick in order to lose weight. This is not a life I would put my patients on.

Finally, I have to talk about the pills mills, or I guess injection stations since the GLP1s are injectable medications, that have popped up around Wegoxy and Saxenda. Weight loss is an extremely tough, emotional, and sometimes unbearable process. For some individuals it is the worst trigger to think about and I really do feel for the people who have tried good eating and exercising but are unable to do it. This is why I believe that weight loss agents should be used just prior to or at the same time diet and exercise routines are implemented. While the drugs are effective, the true power in sustained and increased weight loss is by learning to eat properly and exercise consistently. That being said, I am the kind of person who is results driven and to be encouraged to lose weight I would need to see the pounds come off first before I would feel comfortable starting a diet or exercise. For some its that initial loss due to the drug that pushes them to go for the walk around the block, take the stairs, or choose an apple over a bakery item. I believe in the drug’s ability as much as I believe in the initial push to get the process going. But, and this is the sticking point for me, the process should be an active collaboration between the patient and the healthcare provider. I don't think giving a weight loss agent with a) educating the person on how to diet and exercise, b) follow up on the challenges of implementing those lifestyle modifications, and c) allowing weight loss despite a sedentary lifestyle is okay. I want the best for my patients and sometimes that means giving a boost in the beginning, guiding through the process, and encouraging when things get tough.
One of the trends we are seeing right now is telehealth doctors prescribing GLP-1s. Telehealth is awesome because it connects people to healthcare providers when local doctors aren’t available—but in these cases it is just a formality for a drug to be prescribed. Weight loss needs to be a concerted effort on both people and unfortunately those only prescribing GLP1 agonists are doing it to make money at the expense of the patient. This was the same for doctors that prey on men searching for erectile dysfunction medications, the same for doctors preying on people who believe they have ADHD but haven’t gotten a formal neurologist or psychiatrist and are put on unnecessary stimulants, and now it is the same for weight loss. Drug companies are using social media influencers to push drugs on people—imagine if that was OxyContin. There are dozens of online health clinics and telehealth companies whose sole goal is to get people on high cost drugs to make money. I’d hate to see a wave of pancreatitis and gallstones because due diligence wasn’t being applied.
Okay, I’m off my soapbox. Regardless, weight loss is a difficult topic because there is no easy solution. There is no drug that cures Obesity and it takes time and effort to have the sustained benefit that people are looking for. Remember that weight loss is the first goal, the second is preventing the weight from coming back. Drugs do the first, diet and exercise do the second. Both work together.
Cheers!

If you want to stay fit and healthy, then you should always ensure that you are well prepared before starting a new fitness regime. This means having the right equipment and clothing, knowing the correct exercises, and understanding the importance of rest and recovery. Nonetheless, it should only be carried out under medical supervision. There is a timeframe for noticing results, as well.
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IV drip therapy for weight loss has become very popular over the last couple of years. Some celebrities swear by it. The idea behind IV drip therapy is simple—it involves giving patients intravenous fluids and nutrients directly into their bloodstream. It means they get a constant supply of calories and nutrients. It's safe, natural, and 100% legal. There are various things you must know before choosing this therapy for weight loss.
The solution is simple; drink water mixed with caffeine and ephedra.
How Does The Process Work?
We are born with the ability to heal ourselves. Our bodies can fight off disease and injury through their innate immune system when we get sick or injured. This system consists of two major components: the innate (or non-specific) immune response and the humoral (or specific) immune response.
● When we inject fluids into the bloodstream, they enter the lymphatic vessels and travel to the lymph nodes, where they drain into the bloodstream.
● The fluid is delivered slowly over time, allowing the body to absorb nutrients from the fluid.
● As such, IV drip therapy is a form of lymphatic drainage, which helps reduce swelling and inflammation in the body.
● By injecting various fluids intravenously, doctors can effectively treat conditions ranging from arthritis to lymphedema.
● Drip therapy helps reduce patient risk from infection, improve blood pressure control, and prevent complications such as pulmonary edema.
Types of IV Therapies
Several types of intravenous (IV) drip therapies claim to help patients lose weight. They include saline drips, ketone drops, amino acid solutions, and even bromelain.
For example, studies show that ketones can improve insulin sensitivity, but they don’t seem to affect appetite or body composition. Moreover, some research suggests that ketosis causes metabolic changes that could result in muscle wasting.
Recovering From The Injuries
Sports injuries are common and can last weeks, months, or even years. They also affect millions of Americans every year. If you suffer from sports injuries, you should see a doctor for treatment.
After working out, your muscles get sore. This is normal because exercise causes microtears in the muscle fibers. Your body then starts repairing these tears and rebuilding them into stronger muscle fibers. The healing process takes several days, depending on the severity of the injury. The facilities of athletic recovery in North Richland Hills accommodate one’s busy lifestyle.

Hello and welcome back to SAR! I have been working on a few projects where I’d stay up late working and as those projects finished up I was thinking of a next topic and realized that sleep disorders would be a great place to start. Sleep is a physiological process that is an important part of life and not having enough sleep can lead to decreased function, cognition, and even death. While we tend to think of insomnia as the only sleep disorder, there are a few others like narcolepsy, restless legs syndrome, and obstructive sleep apnea.
Disclaimer: this post is not designed to be medical advice. It is merely a look at the chemistry of medications and their general effect on the body. Each person responds differently to antidepressant therapy. Please talk to your doctor about starting, stopping, or changing medical treatment.

We all sleep but we don't know why

When you think about sleep from an evolutionary standpoint, we just aren’t sure why it became such an important physiologic process—afterall, having an animal unconscious for 6-8 hours completely exposed is kinda nuts. Regardless sleep is here to stay and while we humans don’t need to worry about lions and bears attacking us at night, we need sleep each night to perform even the most remote tasks the next day. Sleep is a reversible process in which sensory and motor activity decreases significantly but that doesn’t mean the brain is turned off. While cortical activity (such as decision making and operations you’d do while awake) decreases, the rest of your brain is working hard to either regulate sleep or do certain operations to make you refreshed for the next day.

• When we image the brain with EEG during sleep, we see that there is a specific cycle of electrical activity inside the brain that correlates to five stages of sleep which we can see with different types of brain waves:

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• When someone is awake and alert (eyes open), their brain would show Beta waves but as soon as you close your eyes, the brain waves decrease to Alpha waves due to decreased sensory input (you’re not looking at anything).
  • When someone is ready to sleep, they enter into the initial period of sleep called stage 1 which lasts about 5 to 15 minutes. This period represents the transition from being awake to falling asleep and is that period of time when you can remember falling asleep but nothing thereafter until you wake up. During this transition period, alpha waves (from closed eyes) transition to Theta waves which show a slowing of electrical activity in the brain as it relaxes. This would be considered light or drowsy sleep.
    • Stage 2 sleep lasts between 15 and 20 minutes and is mostly the theta waves of light sleep with spikes/bursts of longer sleep waves characteristic of deep sleep. While there isn’t much change in the brain, the brain disengages the body’s control over skeletal muscle, disabling your ability to fling your arms and legs during the night. If you’ve ever been woken during this stage, you might have experienced sleep paralysis—your body lags behind your brain waking up from sleep and you aren’t able to control your limbs.
    • Stages 3 and 4 are referred to as slow wave sleep and show high amplitude, slower frequency Delta waves. This is considered the deepest sleep and is the least similar to being awake. The brain has the smallest amount of activity it will have during the sleeping period and the body is rejuvenating.
    • Finally, we reach stage 5 which most people know as REM sleep. REM stands for Rapid Eye Movement which is named after the phenomenon of the eyes moving quickly back and forth under the eyelids. Likewise breathing increases but the brain activity remains in delta waves. The increase in brain activity is when dreaming increases, the muscles are paralyzed the most, and metabolic changes occur (such as the creation of muscle and fat, bones elongating during puberty, etc.) Due to this, we commonly refer to REM sleep as active sleep.
  • Sleep cycles normally repeat every 90-100 minutes throughout the night but sleep doesn’t necessarily go through each stage of sleep in order. A healthy adult usually enters sleep through the progression of stages with the first REM stage occurring after 75-90 minutes and then cycling through stages 2 and 3. As the sleep progresses, the amount of time spent in REM increases so that an 8 hours sleep period is about 60% stage 1 and 2 (light sleep), 20% stage 3 and 4 (deep sleep), and 20% stage 5 (REM).

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Often you’ll hear people talk about the circadian rhythm which most people think of as the cycle that regulates when we should go to bed, in actuality its a bit more complex. The circadian rhythm is a cycle over 24 hours where the body regulates feeding, hormone production, body temperature, and sleep. Generally there are two hormones we think are implicated in the regulation of sleep over the day: cortisol, the stress hormone, and melatonin, the sleep promoting chemical.

• Sleep all begins with a decrease in light that is detected by the photosensitive melanopsin-containing retinal ganglion cells (mRGCs). Melanopsin is a photopigment that is found in the light containing cells called rods and cones inside the retina of the eye. mRGCs are sensitive to the amount of light exposure and can send signals depending on the intensity of light, what kind of light, and how long they have been exposed. That light exposure stimulus is sent along the retinohypothalamic tract (RTH) where it travels from the eye to the suprachiasmatic nuclei (SCN) via the optic nerve. The SCN is the ‘body block’ that coordinates the regulation of sleep.
  • Once the SCN realizes that a) there is a decrease in light and b) it is time for sleep, it release norepinephrine onto the hypothalamus. The hypothalamus is the control center of the body—it regulates the release of neurohormones that make sure your arteries and heart work right, your sugar and fat stores are adjusted, you have enough oxygen in your blood, and so much more. In sleep, the hypothalamus tells the pineal gland to release Melatonin, the first domino in the initiation of sleep. From there many other hormones get involved that allow sleep to progress through the cycles, namely by preventing Cortisol from being released which would wake you up.

Not all sleep disorders are created equal

As previously said, not all sleep disorders are just lack of sleep, although that is one of the most common forms of disruptive sleep disorders. Sleep disorders are classified into two categories:

• Dyssomnias: a person who has difficulty falling asleep, staying asleep, or excessive daytime sleeping.
  • Circadian rhythm sleep-wake disorder—a group of disorders characterized by persistent sleepiness, insomnia, or sleep disruption due to alteration of the circadian system. This could be due to a disconnect in light levels and what the body thinks the time should be (such as seasonal changes or jet lag) or a change in the body’s internal clock and the individuals need (such as 3rd shift workers who awake at night and sleep during the day).
  • Insomnia which is broken into 3 different types:
    • Inability to initiate sleep
    • Inability to stay asleep (sleep-maintenance insomnia)
    • Waking up early the next morning
  • Hypersomnolence—increased sleeping throughout the day
  • Narcolepsy—a neurological disorder in which the person has sleep attacks. The person will literally drop and be instantly asleep making daily living extremely difficult.
  • Sleep apnea—blockage of the airways during sleep resulting in decreased oxygen during the night waking someone up. This can be central sleep apnea due to a respiratory center issue or obstructive sleep apnea due to blockage of the trachea during sleep (normally by the tongue).
• Parasomnias: a group of disorders that exhibit abnormal behaviors or experiences while falling asleep, during sleep, or when waking up from sleep.
  • Non-REM parasomnia—repeated episodes of brief but incomplete awakenings
    • Sleepwalking disorder
    • Sleep terror disorder
  • REM-related—a dissociation between REM sleep and awake state
    • Nightmare disorder
    • REM sleep behavior disorder
    • Recurrent isolated sleep paralysis
  • Restless legs syndrome
• Are these all the sleep disorder? No! There are many more but these are what are referred to as primary sleep disorders, meaning that these are generally not the result of another diseases. Mental health illnesses are often causes of secondary sleep disorders such a depression/anxiety and insomnia or hypersomnolence.

Solving sleep has been important since we’ve been awake

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Ibn Sina’s Diagram of Sleep, 1030 AD
The beginnings of sleep medications are a great example of trial and error and once again I find myself saying, “how the fuck did we make it as a species?” Alright, fasten your seat belts as we dive into the entire history of sleep!

• Egyptian scrolls written in 1600 BC and 1350 BC dictate the connection between sleep and dreams as contrary predictions—if you dreamed of death you were going to live a long life. Ancient Egyptians believed that the gods Thoth and Imhotep were responsible for sleep and praying to them would help cleanse the Metu, a series of channels inside the body that all bodily fluids flowed through (sound familiar).
  • The Egyptians were extremely concerned with cleanliness and believed that the metu could be contaminated, particularly by…ahem…feces. As such, vomitives and enemas were used frequently to clear the body of the offending feces and restore sleep. How did they accomplish this vomiting or diarrhea? Well of course with the good ol’ favorites: purposefully infecting yourself with malaria, parasites, smallpox, or leprosy. If that didn't work, alcohol always worked and medicinal plants like belladonna and deadly nightshade (which contain hyoscyamine and scopolamine which you can read about here) and Papver somniferum—the opium poppy.
  • Unsurprisingly, the Egyptians weren’t the only civilization to use plants to induce a more restful night. Over 700 vegetables have been identified as Indian sleep aids, nominally Rauwolfia serpentina which contains Reserpine (read more here!).
  • Ancient Chinese viewed sleep as a balance of the universe: “everything is one; during sleep the soul undistracted, is absorbed into the unity; when awake, distracted it sees the different beings (Chinese philosopher Chuang Tzu, 300 BC”. The most important medical compendium of ancient Chinese medicine, Nei Ching by Yu Hsiung (2600 BC) notes two herbs as important remedies for sleep: Ephedra (where ephedrine is derived from) which helps treat breathing disorders related to sleep and Ginseng which was used as a cureall for many ailments.

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Star of Life with the Staff of Asclepius vs Preparation of Theriac

• The Greeks and Romans also had many ideas of what dictated good sleep and what was interruptive sleep. Much of what we know of early Greek medicine is due to Homer’s Illiad (900 BC) in which Hypnos would deliver sleep to the soldiers. Homer also mentions Asclepios (the god of healing) and his two sons Machaon (the father of surgery) and Podalirius (the father of internal medicine). Greek physician Alcmaeon of Croton (b. 510 BC) hypothesized that sleep was due to lack of circulation to the brain or the drop in body temperature during sleep caused sleep. Aristotle (384 BC - 322 BC) thought that sleep was a lack of ‘consciousness’ of the heart since the heart beat decreased while Roman physician Galen (129-216 AD) correctly identified that sleep originated in the brain.
  • During the Medieval period when Europe was fighting, Arabic scholars became the center of the scientific world. Moses ben Maimon (known as Maimonides, 1135-1204) combined the thoughts of Hippocrates, Galen, and Avicenna to see sleep as: “The day and night consist of 24 hours. It is sufficient for a person to sleep one third thereof which is eight hours. These should [preferably] be at the end of the night so that from the beginning of sleep until the rising of the sun will be eight hours. Thus he will arise from his bed before the sun rises (Mishneh Torah, Hilchoth De’oth, ch. IV, no. 4).”
    • By the end of the dark ages (around 1100 AD), monastic medicine was using mysticism to treat illnesses. One of the most important medicines was Theriac, a mixture of 64 plants and animals, some of which were helpful additives like ginger (calming), Valerian (sedative), water germander (calming), St. John’s Wort (sedative), anise (calming), wine (y’know alcohol), and some not so beneficial items like bitumen (literally asphalt), boli armen. Verae (clay), castoreum (beaver anus), Cypriot turpentine (toxic when ingested), spicy peppers, and spoiled almonds (which contain cyanide!!!!!). By the 1600s, many of the additives were replaced by opium until eventually it was just opium for obvious reasons.
  • Sleep changed dramatically in the 1800s when medicine shifted away from the theory of humors to a more biological focus. Previously, insomnia would be treated with mercury, bloodletting, and purgatives (read more here!) but now the idea of organs and glands needing treatment started to take over. Now, don’t get me wrong, opium was still a mainstay therapy during this time and purging and bloodletting would have a resurgence in the mid 1800s, but hey, progress. In fact, Linnaeus (1707-1778) created the theory of cyclical sleep patterns after observing flowers opening and closing throughout the day.

Welcome to modern times, you may never wake up again!

Woah feel that whiplash rushing through time? If you want to read the whole comprehensive history of sleep, I highly recommend reading this paper by Michael J. Thorpy. Now that we have arrived in the previous century, we can start looking at the modern treatment of insomnia. There are two categories of drugs to consider: sedatives whose purpose is to reduce anxiety by depressing brain activity and hypnotics whose job is to put the person to sleep.
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• The latter half of the 1800s is referred to as the ‘alkaloid era’ due to the reliance on chemicals derived from plants that follow a specific backbone. The most famous is opium, which continued to be a mainstay therapy due to its ability to relieve anxiety and induce sleep. Other alkaloids like hyoscyamine, atropine, and scopolamine along with opium were common cocktails to administer to agitated and manic patients in psychiatric institutions. These would be considered sedatives though since their intent was to decrease agitation rather than cause a more restful sleep.

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• The first true hypnotic was Chloral Hydrate, discovered in 1832 by Justus von Liebig but not used until 1869 by Oskar LIbreich. Inside the body, Chloral Hydrate is quickly broken down into formaldehyde (toxic) and chloroform which puts the person to sleep. Originally it was a medicated gas that needed to be inhaled but later formulations allowed for capsules (huge 7.5 gram pills; about the size of small baby carrot). Chloral hydrate was preferred over opium because it didn't need to be injected making it easier to administer to resistant and psychotic patients.
  • Chloral Hydrate would be replaced by the Bromides, a wide range of inhalants introduced by Sir Charles Locock in 1857. As an obstetrician, Locock was influential in the treatment of women diagnosed with hysteriaform—a form of psychosis where women would have such silly ideas like wanting to vote, be independent, and hold property.

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[Left] Barbital, [Right] Elixir Veronal from Dr Bustamante’s Laboratories it is a “Practical treatment of insomnia” that is “Safe and Harmless” and “it tastes good and acts smoothly, being absorbed by the organism.”

• By 1900, the toxicities associated with 19th century drugs was catching up to patients which pushed physicians to find safer alternatives. One such alternative was Barbituric Acid (named after the discoverer’s wife, Barbara), a sedative or hypnotic depending on the dose, which wasn’t outwardly toxic! First synthesized by Adolf von Baeyer in 1864, it would be perfected by the French in 1879 before becoming a main staple of Bayer Chemical Co.’s list of products by 1890. von Baeyer would win the Nobel Prize in 1905 for this discovery. In 1904 the first true Barbiturate was synthesized, Barbital which was brought to market as Veronal. By making small changes to the structure of Barbital, over 2500 different compounds where synthesized.

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A collection of Barbiturates

• Barbiturates’ success was pushed by their use in psychiatric institutions looking for faster acting and longer acting agents to sedative patients. By 1915, Phenobarbital (Luminal) was being administered regularly to patients to get them to calm down, sleep, and be out of everyone’s way. You'll notice that the di-substitution at C5 is really what makes barbiturates different. The type of substituent changes the duration of action of the drugs which makes them short acting or long acting. The duration is based on how easy it is for the body to metabolize (deactivate) the drug and remove it from the body. In general there are two trends:
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1. Aliphatic Hydroxylation - metabolizing alkyl chains. This is done by adding an OH to the chain turning it from a hydrophilic non-polar region to a hydrophilic polar region. Thus deactivating it!

• 2) Aromatic Hydroxylation - metabolizing aryl rings. This is done by adding an OH to the ring turning it from a hydrophilic non-polar region to a hydrophilic polar region. Thus deactivating it!
  • While having the aromatic ring may seem larger and cause it to fall under the above rule, aromatic centers generally resist reacting due to stability. The overall resonance of the structure stabilizes the substituent preventing reaction. So, the presence of an aromatic functional group resists hydroxylation which means a longer acting drug.
  • Phenobarbital's duration of action is about 15 hours
• So what about thiopental? Will it be long acting due to the smaller side chain? Drum roll please........ its ultra-short acting (3 hours)! What? Why?
  • The reason has nothing to do with chemistry and everything to do with biology (damn you biology! Always ruining our rules). Although metabolism rate is a big factor in duration of action, the ability for the drug to penetrate tissues is another huge factor. Most other barbiturates are able to be stored in the fat (high lipophilicity) and so hide from being metabolized. Thiopental however has low fat tissue penetration and so cannot hide. Can't hide → faster metabolism.

So what happened? We had useful drugs that would patients to sleep in minutes and could be swallowed orally instead of injected. There were two main issues: firstly the half of the drugs were around 15 to 20 hours meaning that patients woke up tired (or did not wake up) and secondly tolerance built quickly. Barbiturates are known to induce their own metabolism, causing them to become less effective over time meaning that higher doses needed to be used. This put people into CNS depression (coma), respiratory depression (stopped breathing), and circulatory collapse not to mention that any mixture with alcohol could be deadly (like with Marilyn Monroe).
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Benzodiazepine backbone vs Chlordiazepoxide

• Their replacement came in 1960 with Chlordiazepoxide (Librium), the first benzodiazepine. BZDs would change the face of insomnia treatment for one reason: they are MUCH safer than barbiturates. They aren’t without risks but in terms of the risk of accidental overdose or toxicity is much much lower. However barbiturates would remain in use until 1971, with more than half of insomnia prescriptions being barbiturates. In 1973 they were classified as schedule II (controlled medications) and by the end of the decade, barbiturate use fell to less than 20%. Benzodiazepines would become the mainstay insomnia treatment throughout the 80s supplemented with sedating antidepressants (which work through Histamine).

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GABA-a receptor binding sites

• Unlike the hydantoin backbone of barbiturates, BZDs featured a bicyclic backbone with a phenyl substituent. This change in structure had a surprising effect on how BZDs work on the GABA-a receptor versus Barbiturates. Both classes of drugs bind to the GABA receptor but in different ways which is why they can have similar effects but much different safety profiles. The GABA receptor is an inhibitory Chloride channel whose function is to decrease the activity of the brain. Both barbiturates and BZDs open this channel which calms the brain so much that the person feels like they should sleep—hence the fact they are sedating agents.
  • Barbiturates are full agonists at the GABA-a receptor. When they bind, they keep the channel open allowing for more chloride to flow and for more brain activity to be suppressed. If someone takes too much Phenobarbital, they quickly progress from being sedated (sleepy but arousable) to anesthetized (sleeping and unrousable) to medullary depression (lungs and heart stop working) and eventually coma. Mix in alcohol (which you’ll notice also binds to GABA-a) and less barbiturate is required to get there. Not good.
  • Benzodiazepines however have a max ceiling since they are positive allosteric modulators. Essentially, they make it easier for the endogenous GABA to do its job but not so much that its crazy. On the graph you’ll notice that the effect of BZDs eventually flattens although a person can still stop breathing when overdosing on benzodiazepines. Again, alcohol is terrible mix with BZDs since it can easily push someone to stop breathing or coma.

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• There are at least 30 known benzodiazepines with many more being created all the time. As much as I would love to go through each and every structure I think it would get incredibly repetitive. As such, lets cover some important features of BZDs!
  • Firstly in blue, you’ll notice the two most important features of the benzodiazepine: the C5 Phenyl and the C7 Chlorine. The phenyl group allows for the benzodiazepine to interact with the the hydrophobic region of the allosteric site while the chlorine increases affinity for the receptor.
  • In red we have a methyl group attached to a nitrogen as seen in Diazepam. This methyl is actually deactivating and so Diazepam is completely inert and has no action! The body removes the methyl group which activates the metabolite, Nordiazepam, allowing it to function. Both Diazepam and Clonazepam are some of our longest acting BZDs.
  • In purple we have a C3 Hydroxyl group. This group doesn’t affect affinity for the receptor but makes it so the drug can be metabolized and eliminated quicker! This means drugs containing this C3 OH group are much shorter acting than drugs that do not have this OH.
  • Finally in orange we have the imidazole basic center with that incredibly deactivating methyl group. Drugs that have this combination of aromatic center with a methyl are the shortest acting drugs on the market and are the preferred agent if needed for sleep. Why? Well we want the person to fall asleep quickly but have the drug leave their system by the time they need to wake up. The half life of the drugs are about 1-4 hours, perfect for inducing sleep.

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• Benzodiazepines are extremely effective at putting people to asleep but are also dangerous if used incorrectly and without medical supervision. Particularly with the risk of drug dependence that drug companies under reported when they were manufacturing the drug. By the 90s it was clear that BZDs were addictive and could cause withdrawal symptoms and resulted in the largest ever class-action lawsuit in UK history against the drug manufacturers. Due to this the overuse of BZDs was scaled back dramatically and are used when the situation is pretty dire and specific for their need. Benzodiazepine illicit use is on the rise in the United States, particularly among teens, with much of it being laced with Fentanyl—not good. That being said, if used correctly BZDs are often life-changing medications for the betterment of the patient whether they are being used in insomnia, anxiety, or another condition!

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Insomnia by u/Insurgi

Attempting to take the addiction out of Benzos

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Advances in technology allowed us to gather new information about the GABA-a receptor. We had known that the receptor was made of 5 subunits but we could now classify those subunits and determined that there are three main subunits: alpha, beta, and gamma. Further studies revealed that there were multiple subtypes of the subunits allowing for even more variability in the receptor! Likewise we determined that drugs bind between specific subunits—barbiturates bind between a1 and b1, the most common combination while benzodiazepines bind between the a1 and gamma. Due to this new information and the realization of the risk of benzodiazepines (and the fact they were handed out like candy), the 90s saw developments to try to make new drugs that decreased the disadvantages of BZDs like next day sleepiness, dependence, and withdrawal.
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New Lunesta Ad is 70% less moth!

• The first drug, Zopiclone (Imovane) was released in 1989 in the United Kingdom as a new class of drug that still binded to the same benzodiazepine spot. As such it was called a nonbenzodiazepine benzodiazepine-receptor agonist or less confusingly, Z-drugs. Unlike Benzodiazepines, the Z-drugs dose-response curve barely reached into dangerous toxicity territory when taken (but could with alcohol) making them more safe than their counterparts. As such, by the mid 1990s the use of benzodiazepines fell by almost 300% in the treatment of insomnia. For Americans you’ll be more familiar with the enantiomer of Zopiclone, Eszopiclone (Lunesta). For an explanation of the ‘handedness’ of drugs and how methamphetamine is in Vicks vapor rub, read here! In 1992 the second Z-drug was synthesized, Zolpidem (Ambien) followed by Zaleplon (Sonata) in 1999. All four drugs bind with less affinity than benzodiazepines allowing for the initiation of sleep with less next sleepiness. There is still a risk for dependence but it's much less.

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Insomnia by u/wee_froggy

Stepping away from GABA and looking at Melatonin

I know, I know—the only reason why you are reading this is to find out if melatonin is worth taking. The answer is yes! And also no! Okay thanks for reading, good bye…Alright fine : Melatonin as we read earlier is the endogenous chemical involved in promoting sleep when the eyes do not detect light and when the body is ready to sleep. There are two melatonin receptors, MT1 and MT2 (birds have a third) and are found all throughout the body: the retina, the heart and blood vessels, the liver and gallbladder, colon, skin, and many many other places. There is still so much about melatonin we don’t know and many potential uses of using it. Lets take a look at what we do know for sleep!
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Melatonin vs Ramelteon

• MT1 and MT2 are closely involved in the initiation of sleep. MT2 regulates and adjusts the circadian rhythm while MT1 works on inducing sleep. Studies have shown that when melatonin interacts with these receptors, the receptors are internalized inside the cell and sleep is promoted. This is why people who chronically use melatonin supplements may feel like it works less over time—higher levels of melatonin for longer may internalize the MT receptors more decreasing effectiveness. So what should we do then?
  • Setting up the ideal conditions for sleep is the best thing to do. Good sleep hygiene is less about taking the melatonin supplement and more about working with your body to promote sleep. Melatonin levels start to rise 2 hours before bed and are their maximal level at the time your body wants to sleep. What interrupts that rise is blue and green light which is produced in large quantities by screens, so yes, turn off your phone and computer 1-2 hours before bed. Melatonin also takes 30 minutes to be absorbed once taken so don’t expect to fall asleep immediately after swallowing the pill. Use that 30 minutes to relax, meditate, or read. Below the post ill put other tips for building good sleep hygiene.
  • Thankfully, melatonin isn’t the only substance that activates the MT receptors although data is pretty limited on its efficacy. Ramelteon (Rozerem) was released in 2005 while its brother Tasimelteon (Hetlioz) hit the market in 2014.

Honorable mention: Trazodone

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It wouldn’t be right to talk about insomnia without at least mentioning the black sheep of the family: Trazodone (Desyrel). Trazodone is an antidepressant and it’s primary action is through antagonism of serotonin receptors to benefit against anxiety and depression. It also is an Histamine-1 receptor antagonist which includes other over the counter medications like Diphenhydramine (Benadryl), Dimenhydrinate (Dramamine) or prescription only Hydroxyzine. Unlike those three medications, Trazodone does not have nearly as much cognitive impact while still promoting a restful night’s sleep. There is some data to suggest that Trazodone also allows for more REM time which is beneficial in having a good night's rest. All around a good choice in patients who have sleep difficulties as well as depression or anxiety at bed time.
And that’s our story! Hopefully this provides some insight into another class of drugs and you learned something new. If you have any questions, please let me know! Want to read more? Go to the table of contents!
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Likewise, check out our subreddit: SAR_Med_Chem Come check us out and ask questions about the creation of drugs, their chemistry, and their function in the body! Have a drug you’d like to see? Curious about a disease state? Let me know!
https://www.news-medical.net/health/History-of-Sleep.aspx
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918987/
https://sci-hubtw.hkvisa.net/http://dx.doi.org/10.1007/978-1-4939-2089-1_3
https://mphdegree.usc.edu/blog/the-next-u-s-drug-epidemic-as-of-2019/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1372025
https://www.benzoinfo.com/a-brief-history-of-benzodiazepines/
https://www.fda.gov/consumers/consumer-updates/taking-z-drugs-insomnia-know-risks#:~:text=He%20or%20she%20may%20prescribe,get%20a%20good%20night's%20sleep.
https://www.cpn.or.kjournal/view.html?volume=19&number=2&spage=367
Chapter 46 Pharmacotherapy for insomnia STEPHEN FEREN1 , PAULA K. SCHWEITZER1 , AND JAMES K. WALSH
Chapter 1 History of sleep medicine MICHAEL J. THORPY*

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When traditional Chinese medicine meets Western medicine and the In silico screening with the help of AI are revolutionising medicine for everyone
There is an urgent need to discover novel antivirals
Viruses are responsible for a number of human pathologies, while complex syndromes like Alzheimer’s disease, type 1 diabetes and hepatocellular carcinoma have been also associated with viral infections.
Moreover, due to increased global traveling and rapid urbanization, epidemic outbreaks caused by emerging and re‐emerging viruses represent a critical threat to public health. To date, many viruses remain without effective immunisation and only few antiviral drugs are licensed for clinical practice.
Here I summarise the antiviral activities from several natural products and Chinese herbal medicines against coronavirus (CoV). These Chinese herbal medicines and purified natural products provide a rich resource for novel antiviral drug development, while in silico screening and AI will enable more chemical combinations to be tested with fewer human trials, making drug development faster, cheaper and safer.
Coronavirus
CoV is an enveloped positive‐sense single‐stranded RNA (ss‐RNA) virus, that belongs to the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales and realm Riboviria.
The genome size of CoV ranges from approximately 27 to 34 kilobases, the largest among known RNA viruses. The name coronavirus is derived from the Latin corona, meaning “crown” or “halo”, which refers to the characteristic appearance reminiscent of a crown or a solar corona around the virus, due to the surface being covered in club-shaped protein spikes. The CoV family consists of several species and causes upper respiratory tract and gastrointestinal infections in mammals and birds, but some CoV such as SARS, MERS and COVID-19 can be lethal for humans.
The coronavirus encodes more than a dozen of proteins, some of which are essential to viral entry and replication. Among these proteins, the most well-studied are papain-like protease (PLpro), 3C-like protease (3CLpro) and spike protein. All of these three proteins make attractive targets for drug development.
So far, through in silico and biological processing, a series of small molecules from natural compounds, have been screened and confirmed to directly inhibit the three more important proteins in SARS or MERS coronavirus.
Since, the gene sequence of COVID-19 has been released — and suggests high similarities between the main proteins in COVID-19 and in SARS or MERS — probably previously reported anti-SARS or anti-MERS natural compounds may become a valuable guide to finding anti-COVID-19 herbal plants among the traditional Chinese herbs used to treat viral pneumonia.
So, let’s talk about herbal plants and CoV.
Chinese Herbal Plants
Chinese medicine (CM) approaches including oral administration of preventive herbal formulae, have always been recommended for prevention and treatment of infectious diseases.
This study has reviewed the historical and human research evidence on CM in preventing and controlling infections in order to provide guidance for the prevention of COVID-19, SARS and H1N1 influenza, by health authorities in China.
For this study the use of CM to prevent epidemics of infectious diseases was traced back to ancient Chinese practice cited in Huangdi’s Internal Classic (an ancient Chinese medical text) where preventive effects were recorded.
Based on the results, 3 studies followed using CM for prevention of SARS and 4 studies for H1N1 influenza. In these studies, none of the participants who took CM contracted SARS, while the infection rate of H1N1 influenza in the CM group was significantly lower than the non-CM group (relative risk 0.36, 95% confidence interval 0.24–0.52; n=4). Based on that information, 23 provinces in China issued CM programs for prevention of COVID-19 using the following herbs:
· Radix astragali (Huangqi), is a popular traditional Chinese medicine and its active compounds may help strengthen the immune system and reduce inflammation. Astragalus is sometimes also given as an injection or by IV in a hospital setting,
· Radix glycyrrhizae (Gancao) or liquorice root, is one of the 50 fundamental herbs used in traditional Chinese medicine,
· Radix saposhnikoviae (Fangfeng), Saposhnikovia divaricata — known as fángfēng meaning “protect against the wind” in Chinese and siler in English — is the sole species in the genus Saposhnikovia (family Apiaceae), still frequently referenced under the obsolete genus name Ledebouriella in many online sources devoted to traditional Chinese medicine,
· Rhizoma Atractylodis Macrocephalae (Baizhu), it is praised as “the most important herb of qi tonifying and invigorating the spleen”,
· Lonicerae Japonicae Flos (Jinyinhua), is one of the most commonly used traditional Chinese medicines, contains biologically active compounds such as caffeic acid derivatives, essential oil, flavonoids, iridoid glycosides and terpenoids, and has anti-inflammatory, antitumor, antioxidant, antiallergy, immunomodulating and antibacterial activity biological activities, and
· Fructus forsythia (or called Lian qiao in mandarin) has long been known as the panacea for people who are particularly susceptible to skin infections and it has a broad-spectrum antimicrobial activity (Staphylococcus aureus and Shigella) and a certain inhibition on influenza virus, leptospira, and other pathogens. It has also anti-inflammatory and antipyretic effects.
The conclusions were that based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population, but prospective and rigorous population studies are warranted to confirm the potential preventive effect of CM.
Moreover, it has been reported that saikosaponins (A, B2, C, and D) — which are naturally occurring triterpene glycosides — isolated from medicinal plants such as:
· Bupleurum spp. (Bupleurum is a large genus of annual or perennial herbs or woody shrubs, with about 190 species, belonging to the family) Apiaceae, for uses and sides effects of the plant look here)
· Heteromorpha spp. (Heteromorpha is a genus of plants within the family Apiaceae: commonly known as the celery, carrot or parsley family, or simply as umbellifers), and
· Scrophularia scorodonia (the genus Scrophularia of the family Scrophulariaceae comprises about 200 species of herbaceous flowering plants commonly known as figworts),
all exert antiviral activity against HCoV‐22E9 — a species of CoV which infects humans and bats, and along with human coronavirus OC43 it is one of the viruses responsible for the common cold).
Conclusion: Saikosaponins (A, B2, C, and D) effectively prevented the early stage of HCoV‐22E9 infection, including viral attachment and penetration. You can find the original study here.
It has also been reported that extracts from:
· Lycoris radiate (known as the red spider lily, hell flower, red magic lily, or equinox flower, is a plant in the amaryllis family Amaryllidaceae, commonly known as the amaryllis family),
· Artemisia annual (or Sweet wormwood belongs to the plant family of Asteraceae),
· Pyrrosia lingua (is an epiphyticfern in the family Polypodiaceae), and
· Lindera aggregata (is a plant species belonging to the genus Lindera, and common names include spicewood, spicebush, and Benjamin bush)
all display anti–SARS activity after a screening analysis using hundreds of Chinese medicinal herbs. You can find the original study here.
Moreover, natural inhibitors against the SARS enzymes, such as the nsP13 helicase and 3CL protease, have been identified and include:
· myricetin (flavonoid polyphenolic compound with antioxidant properties found in vegetables, fruits, nuts, berries, tea and red wine). You can find the original study here,
· scutellarein (a flavone that can be found in Scutellaria lateriflora, a hardy perennial herb of the mint family and other members of the genus Scutellaria, as well as Asplenium belangeri). You can find the original study here, and
· phenolic compounds from: Isatis indigotica and Torreya nucifera. You can find the original study here.
Other anti‐CoV natural medicines include the water extract from Houttuynia cordata (also known as fish mint, fish leaf, rainbow plant, chameleon plant, heart leaf, fish wort, Chinese lizard tail, or bishop’s weed, and is one of two species in the genus Houttuynia), which has been observed to exhibit several antiviral mechanisms against SARS, such as inhibiting the viral 3CL protease and blocking the viral RNA‐dependent RNA polymerase activity. You can find the original study here.
In silico screening
In the following study through in silico and biological processing, a series of small molecules from natural compounds have been screened searching for antiviral drugs.
For that reason, in the first step of the process a literature search was conducted for natural compounds that had been biologically confirmed acting against SARS and MERS. The resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database, and compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion (ADME) evaluation to verify that oral administration would be effective.
Next, a docking analysis was used to test whether the compound had the potential for direct COVID-2019 protein interaction. In the second step the Chinese herbal database was searched to identify plants containing the selected compounds, and the plants containing 2 or more of these compounds identified in the screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb.
In the end, 13 natural compounds (betulinic acid, coumaroyltyramine, cryptotanshinone, desmethoxyreserpine, dihomo-γ-linolenic acid, dihydrotanshinone, kaempferol, lignan, moupinamide, N-cis-feruloyltyramine, quercetin, sugiol, tanshinone IIa) that exist in traditional CM were found to have potential anti-COVID-2019 activity.
Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds and of these 125 herbs, 26 were catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these 26 herbal plants were related to regulating viral infection, immune/inflammation reactions and hypoxia response. You can find the original here.
East-meets-West: Combined Chinese and Western medicine treatment
In another interesting study, from Shanghai Public Health Clinical Center, it has been reported that four patients with mild or severe COVID-19 pneumonia have been cured or have significant improvement in their respiratory symptoms after treatment with combined
·lopinaviritonavir (Kaletra®: the two antiretroviral components lopinavir and ritonavir, are protease inhibitors designed to block HIV viral replication),
·arbidol (a broad-spectrum antiviral compound that blocks viral fusion),
·and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine: resveratrol, emodin, rhein, quercetin, rutin, kaempferol, iquiritigenin and liquiritin) on the base of supportive care.
SFJDC is a traditional Chinese medicine for treatment of influenza in China. The duration of the antiviral treatment was 6–15 days and in addition, all patients were given antibiotic treatment and started on supplemental oxygen after admission to the hospital. All four patients in this study were recruited from January 21 to January 24, 2020 at Shanghai Public Health Clinical Centre, which is a designated hospital for COVID-19 pneumonia.
So, two mild and two severe COVID-19 pneumonia patients were given combined Chinese and Western medicine treatment, and by February 4, 2020 three of them gained significant improvement in pneumonia associated symptoms, while the fourth patient with severe pneumonia was still using ventilators by the cutoff date for data collection. The efficacy of antiviral treatment including lopinaviritonavir, arbidol, and SFJDC warrants further verification in future studies.
In this clinical study 135 COVID-19 patients were all received antiviral therapy (135 received both Kaletra and interferon), while 59 received antibacterial therapy, and 36 received corticosteroids. In addition, many patients (124) received traditional CM. The Chinese herbals used to treat COVID-19 primarily included glycyrrhiza, ephedra, bitter almond, gypsum, reed root, amomum, and trichosanthes, and their primarily function was to clear heat, to relieve cough and to increase immunity.
This study suggested that patients should receive Kaletra very early and should also be treated by a combination of western and CM, since Kaletra and traditional CM played an important role in the treatment of the viral pneumonia. Of course, further studies are required to explore the role of Kaletra and traditional CM in the treatment of COVID-19.
Artificial Intelligence
Chinese patchouli, sun-dried tangerine peels, betel nuts, as well as the Peaceful Palace Bovine Bezoar Pill — a mixture of cattle gallstone, buffalo horn, and pearl and ruby sulfur, among other ingredients — are all prescribed under China’s plan for traditional CM.
As traditional CM is being promoted to fight the novel coronavirus, supporters of the age-old practice believe China’s initiative will give the long-debated CM an opportunity to prove its worth, but skeptics doubt whether this 5,000-year-old practise can actually play an important role because of lacking scientific evidence (preclinical and clinical trials).
The solution? AI drug discovery.
CODA (Context-Oriented Directed Associations) is a powerful tool, combining AI and biotechnology, that acts as a virtual human body that could help predict how people will react to new therapeutic drugs. The team (researchers at the Bio-Synergy Research Centre in Daejeon, South Korea) plans to use CODA to explore the therapeutic potential of chemical compounds found in traditional medicines, such as Samul-Tang — a combination of extracts from four Asian plants used to treat blood disorders such as anaemia.
The researchers in order to build CODA, they first developed a computer language to represent biological interactions, and then they gathered information from public databases and the scientific literature, to construct a network of potential interactions between chemicals, proteins and genes within, and between, organs.
Moreover, drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. Recent advances in AI, in the use of ‘organ-on chip’, in microfluidics technologies, in analytical and computational techniques and in predictive computational software, have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs.
In the near future (hopefully) the use of quantum computing — in modeling molecular interactions and predicting features and parameters needed for drug development among millions of drug candidates— will result in successful leads from plants for drug development. This review discusses how innovative technologies play a role in plant-based natural product drug discovery.
Although natural products have been marginalized by major pharmaceutical companies all over the world in the last 30+ years, the changing landscape of drug discovery — as pharma strives to develop innovative and highly effective new drugs — will eventually now favour a greatly enhanced role for natural products as valued sources of novel leads whose further drug development.
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#science #health #pharma #AI_drugdiscovery #drugdiscovery #AI #biotechAI #telemedicine #startup

The human body is made up of millions of cells, each cell has a wall which is called the cell membrane. The cell membrane allows certain substances to pass through it while keeping others out. Water soluble nutrients are able to pass through the cell membrane and be taken in by the body. This process is called osmosis. When fats dissolve they go into solution with water and form a substance known as an emulsion (a mixture of two or more liquids that do not normally.
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Learn more about the best way to lose weight

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1. How does fat dissolve work?

About 30% of adults in the United States are obese. Fat-soluble substances are stored in fat tissue and they can remain there for years. If you lose weight, your body will naturally dissolve these substances and excrete them through urine or stool.
Fat dissolving injections work by administering a chemical substance that breaks down fat cells. It is then excreted from the body in the form of a fatty liquid (stool or urine). The reason for this is because the fat has been dissolved into a liquid.

3. The effect of fat dissolve

As we develop old age, the fat dissolve in our body gradually slows down. So how do we speed it up? We can take the fat dissolve supplements.
There are two types of fat dissolve supplements, one is herbal fat dissolve supplement, the other is chemical fat dissolve supplement. The herbal is a safe and effective way to lose weight, while the chemical is bad for health.

4. How to use fat dissolve

The fat dissolve is a weight loss supplement that allows you to start melting away your stubborn body fat. Rather than starving yourself, you will be able to shed pounds without feeling hungry, thus getting the toned body that you always wanted without the hassle.
It is a highly effective fat burner that helps you feel full for up to four hours and can speed up your metabolism by up to 30%. What’s even better is that it doesn’t contain any stimulants such as caffeine or ephedra, so you can take it at any time of day.
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5. Where to buy fat dissolve?

You may have tried to lose weight through a variety of methods. You might have tried the diet and exercise route. Or maybe you have even tried surgical procedures. However, there are some people who are finding that they need to take a different approach to their fat loss journey.
There are many ways that you can reduce fat, but one of the most popular is through what is known as Exipure The next generation in health offers. its very easy weight loss method
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Tropical loophole dissolves fat overnight

More about Exipure

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6. To wrap things up

Thanks for reading this topic and wish you amazing health.

Fat burners and fat binders, do they work, or are they another urban legend of the internet?

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L-carnitine, glucagon, methionine, taurine, choline, inosine, lecithin, pyruvate, ephedra, nitric oxide, conjugated linoleic acid, creatinine, etc., are some of the names of the components that will supposedly allow our body to burn the surpluses of fat that we accumulate in the gut or thighs almost without having to move from the chair. Or at least some advertisements assure it ...
The fact is, only a few of this fat burners actually work (read our review of them)

Do Fat Burning Pills Work Reddit - Don't Buy Without Researching

They can be found in the form of commercial supplements in nutrition, diet or bodybuilding stores, as well as in online stores such as Amazon or eBay, many times without express reference to the fact that they can be products intended for people who practice intense exercises, so we can infer that we can all receive its benefits if we buy and take them.
On the other hand, hundreds of web pages proliferate on the internet offering natural alternatives to commercial fat burners and ensuring that they work just as well or better: algae, lemon, coffee, green tea, guarana, dairy, cold water, etc. Are there really fat burners or are they a story, a myth that moves uncontrollably on the web?

Metabolic accelerators

For this we have spoken with Mel Pescador, bio hackerbiohacker , bodybuilder and author of the book Operation Transformer. "Fat burners exist and most work, although not in all circumstances or for all profiles," says Pescador, who continues: "but their effect is very limited and undoubtedly much less than what is claimed in advertisements, which They sell it as a miracle pill, which they are not at all. "
Based on this statement, Pescador explains that most of these substances have an accelerating effect on metabolism because they are stimulants: "they are based on molecules similar to caffeine, ephedrine -the active principle of amphetamines- and other stimulants." Hence, coffee, guarana or tea are proposed as natural fat burners, although Pescador clarifies that in the case of green tea, there are other processes that make you reduce abdominal fat.
"Green tea is rich in catechins , which are antioxidant substances that act on abdominal fat, but only if the person does intense exercise," he explains. So there is no use taking pills or cups of green tea and sitting on a sofa, not even leading a normal life. Regarding ephedrine, this was the main component of the first Herbalife pills - a company of which we have already described its details in another article - and what they achieved was that the person lost weight based on being overexcited.
>>>Here are the top 4 supplements that are crushing it in 2020

They don't work eating pizza on the couch

The problem was that you didn't sleep on Herbalife pills - with the consequences that this can bring - so they ended up banning them and now Herbalife makes them based on caffeine. But the goal is the same: to have an accelerated metabolism. Not sleeping inhibits the synthesis of the satiety hormone, leptin, which in the long term ends up gaining weight.
Fisherman concludes that fat burners "help as long as one accompanies them with intense exercise and a healthy diet, that is, balanced and low in sugars; otherwise, they are useless, because if we use them and eat sugars at the same time, we will have the high insulin levels and therefore the metabolism on the one hand will burn the sugar first and on the other it will send the fats to accumulate.
In summary: fat burners do not work from the sofa at home while we eat pizza, because what fat burners consume we will replace with food if it is high in refined flours and sugars. In addition, as Pescador points out, "cortisol, which is the hormone that the body secretes when we are nervous and accelerated, lowers blood sugar levels, so the feeling that we have is that we need sugar, so we will look for it in anything sweet."

L-carnitine and other compounds

The L-carnitine is a key fatty acids long-chain fall within the mitochondria, the cell bodies use fat as energy is burned compound. Without L-carnitine or with low levels, we tend to burn less fat and therefore to accumulate it, although the normal thing in a healthy person is that this molecule is not lacking and it is the body itself that synthesizes it.
But based on the principle that L-carnitine helps to burn fat, they are sold from isotonic drinks that include it to pills with extract - since red meat is rich in this compound - and even injections applied in the belly. And the truth is that L-carnitine works as a fat burner, but only in amounts of about four grams a day, which are considered very high and would mean many liters of isotonic drink daily.
>>>Proved Fat Burners: read the review<<<
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In addition, it only works after a sustained intake of more than six months taking those four grams and L-carnitine is quite an expensive supplement. From then on, its effects begin to be noticed ... but only when doing intense exercise. Again, intense exercise and a balanced diet are necessary for fat burners to work. And in the case of L-carnitine, having enough money is also important.

Chitosan, the 'fat catcher'

Finally, there are other substances that are exploited commercially called 'fat binders' or fat carpers, which in theory prevent about 30% of the fats we eat from going into the bloodstream by blocking them. Among them is chitosan, a non-digestible linear polysaccharide that is extracted from the shells of crustaceans and that has the ability to absorb fats like a sponge.
Chitosan sequesters fats as they pass through the stomach and takes them to the large intestine, where they can be consumed by the intestinal flora, thus generating numerous and spectacular flatulence. On the other hand, it can cause loss of liquid fat through the anus if it has not been properly metabolized by the flora.
But even assuming these uncomfortable effects, the truth is that the EFSA (European Food Safety Authority) declared in 2011, after studying the product, that no relationship can be established between the consumption of chitosan and the loss of abdominal fat.

Slimming creams

Finally, there are the slimming or waist reducing creams. It is true that the waist area is the one that most resists reducing when we diet or start exercising. This is due to the fact that it is a poorly irrigated area, with little blood circulation, so that the signals sent by the body that it is necessary to start burning fat hardly reach the cells of the gut, which are isolated.
In this sense, any substance that causes an increase in circulation in this area will achieve that I get more blood loaded with hormones that make the cells start to use fat as a source of energy, as long as you are doing intense exercise and the muscles have already burned all their sugar stores. This is the objective of reducing creams: to increase circulation in this area.
To do this, volatile substances are used that, when evaporating, cause cold in the area and create a temperature difference that the blood will tend to compensate, thereby achieving better circulation. If used while exercising vigorously, they can work because there will be more signals that you need to burn fat, although it will not have the results that are advertised in your advertisements. If they are not used while exercising, they will be of no use.
If you want to know what fat burning pills actually work, read this review