A Short History of Pills

An old Cadmach rotary tablet press

Photo credit: Slashme at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21895660

 

 

Pills date back to roughly 1500 BCE. They were presumably invented so that measured amounts of a medicinal substance could be delivered to a patient. A long time ago, around 4,000 years or so, medicines were generally liquid preparations. An inscription on an Assyrian clay tablet instructs the user to pulverize various seeds, plant resins and leaves together–then dissolve them in beer. Pills are first referenced in ancient Egyptian. One famous set of papyruses is filled with medical remedies, including pills made from bread dough, honey or grease. Medicinal plants would be reduced to powders, and other active ingredients, and would then be mixed with these substances–then little balls, or pills, would be formed with the fingers. Early ingredients of pills included saffron, myrrh, cinnamon, tree resins and many other botanicals. Pills came in various sizes as well as flat and round, and other assorted shapes. As far back as 500 BCE, some were even trademarked with special indentations in the pills.

 

Hippocrates, knew about the curative powers of willow bark. And in ancient Greece, the round balls or other shapes were called katapotia (meaning “something to be swallowed“). It was the Roman scholar Pliny (23-79 CE–who first coined the word “pilula.“

 

Some early pills still exist in museums, such as a famous one dating from 500 BCE. that was known as Terra Sigillata–consisting of clay from a particular island that was mixed with goat’s blood then shaped into pills. Terra Sigillata was supposedly good for practically every ailment, including dysentery, ulcers and gonorrhea. A pill was originally defined as a small, round, solid pharmaceutical oral dosage form of medication. The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes, and were found aboard a Roman ship Relitto del Pozzino which wrecked in 140 BCE. Today, pills include tablets, capsules, and variants thereof like caplets ? essentially any solid form of medication, colloquially falls into the pill category. There are pieces of ancient Roman pill-making equipment, such as a carved stone in the British Museum. The stone has long flat grooves into which the pill maker would press clay or other substances to make long, snaky strings. Then the pill maker would pry the strings out and cut them into discs to form pills–much the way one cuts dough for cookies.

 

During the Middle medieval times, people would coat their pills with slimy plant substances and other materials so they were easier to swallow and tasted less bitter. Some pills were rolled in spices, and later pills began to be coated with gold and silver. Silver, unfortunately, rendered the pills pretty inert, since they’d pass right through the digestive tract without releasing any of their medicinal compounds. Gilding of pills, continued well into the 19th century. Medicines in pill form were popular in 17th century England and thereafter. Pill manufacturers were granted special patent rights from the king for their top-secret formulas. One famous patented product from the 18th century: “Hooper’s Female Pills,“ which were guaranteed to contain “the best purging and anti-hysterik ingredients.“ And pills, of course, made their way over to the still-new United States–which had its own set of patent-protected preparations, courtesy of the U.S. Patent office–including Chase’s Kidney-Liver Pills, Cheeseman’s Female Regulating Pills and Williams’ Pink Pills for Pale People.

 

The old-fashioned, roll-and-cut kinds of pills had a drawback: Their preparation required moisture. Early researchers, (doctors) were learning that this moisture could de-activate the drugs contained. In the 1800s, innovators began sugar-coating and gelatin-coating pills. At this time gelatin capsules were invented, as well as the ability to compress tablets. In 1843, English scientist, William Brockedon invented a different pill form. Powder was placed in a tube and then compressed with a mallet, until it solidified. Eventually, this invention became popular. Holloway’s Pills were perhaps the most famous of the patent medicines, and were popular enough to make Thomas Holloway a wealthy man. Testimonials to the value of the pills can be found at this time, in newspapers all over the British Empire, including Indian, Australia and the North American colonies. The range of diseases the pills claimed to cure is astonishing. Along with Holloway’s Ointment, Holloway’s Pills could treat almost anything. Analysis of the pills showed that they contained aloe, myrrh, and saffron. While probably not harmful, these pills would be unlikely to have the claimed affects. The Holloway advertising changed from time to time, listing a variety of dangers that the pills could prevent. An example, for “Children’s Complaints“:

 

“It is not generally known, but such is the fact that children require medicine oftener than their parents. Three-fourths of the children die before they attain the age of eight years. Let their

mothers, then, be wise, and give to their children small doses of these invaluable pills once or twice every week… The gross humors that are constantly floating about in the blood of children, the forerunners of so many complaints, will thus be expelled, and the lives of thousands saved and preserved to their parents.“

 

Pills have always been difficult to swallow and efforts long have been made to make them go down easier. In medieval times, people coated pills with slippery plant substances. Another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. In the 1800s sugar-coating and gelatin-coating was invented, as were gelatin capsules. In 1843, the British painter and inventor William Brockedon was granted a patent for a machine capable of “Shaping Pills, Lozenges and Black Lead by Pressure in Dies“. The device was capable of compressing powder into a tablet without use of an adhesive. In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet. Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).

 

Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants. Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets with special properties, for example, sustained release or fast dissolving formulations. Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the “first pass effect“), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosa, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example, salbutamol, used to treat problems in the respiratory system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action. A proportion of the population have difficulties swallowing tablets either because they just don’t like taking them or because their medical condition makes it difficult for them (dysphagia, vomiting). In such instances it may be better to consider alternative dosage form or administration route.

 

Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems. Tablet diameter and shape are determined by the machine tooling used to produce them – a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don’t break up in the bottle, yet friable enough that they disintegrate in the gastric tract. Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (i) simple failure and erosion tests, and (ii) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.). The hardness of tablets is the principle measure of mechanical strength. Hardness is tested using a tablet hardness tester. The units for hardness have evolved since the 1930s, but are commonly measured in kilograms per square centimeter. Models of tester include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.

 

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.

 

Combined oral contraceptive pills were nicknamed “the pill“ in the 1960s

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https://www.pinterest.com/nanherriman/19th-century-medicine/

 

ONCOLOGY

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Study Identifies Essential Genes for Cancer Immunotherapy

 

According to a study published online in Nature (7 August 2017), genes have been identified that are necessary in cancer cells for immunotherapy to work. These results address the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.

 

Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. The authors have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients, and that T cells can directly recognize and kill tumor cells. However, some tumor cells are resistant to the destruction unleashed by T cells.

 

To investigate the basis for this resistance, the authors sought to identify the genes in cancer cells that are necessary for them to be killed by T cells. Working with a melanoma tumor cell line, the authors used a gene editing technology called CRISPR that “knocks out,“ or stops the expression, of individual genes in cancer cells. By knocking out every known protein-encoding gene in the human genome and then testing the ability of the gene-modified melanoma cells to respond to T cells, the authors identified more than 100 genes that may play a role in facilitating tumor destruction by T cells. Once the authors identified these “candidate“ genes, they sought additional evidence that these genes play a role in susceptibility to T cell-mediated killing. To this end, they examined data on “cytolytic activity,“ or a genetic profile that shows cancer cells are responding to T cells, in more than 11,000 patient tumors from The Cancer Genome Atlas, a collaboration between NCI and the National Human Genome Research Institute, also part of NIH. Results showed that a number of the genes identified in the CRISPR screen as being necessary for tumor cells to respond to T cells were indeed associated with tumor cytolytic activity in patient samples. One such gene is called APLNR. The product of this gene is a protein called the apelin receptor. Although it had been suspected to contribute to the development of some cancers, this was the first indication of a role in the response to T cells. Further investigation of tumors from patients resistant to immunotherapies showed that the apelin receptor protein was nonfunctional in some of them, indicating that the loss of this protein may limit the response to immunotherapy treatment.

 

According to the authors, the results show that many more genes than were originally expected play a vital role in dictating the success of cancer immunotherapies. The authors also noted that this gene list could serve as a blueprint to study the emergence of tumor resistance to T cell-based cancer therapies, and that if this set of genes is validated in clinical trials, then this data could eventually lead to more effective treatments for patients.

 

Obesity During Pregnancy May Lead to Fetal Overgrowth

 

Macrosomia, or large body size at birth, is common among children born to obese women, particularly those who have gestational diabetes (high blood sugar during pregnancy). Macrosomia also increases the risk that an infant will experience bone fracture during delivery, as well as the likelihood that the infant will need to be delivered by cesarean section. Having a large infant also increases a mother’s risk for postpartum hemorrhage, or excessive bleeding at birth.

 

According to an article published in JAMA Pediatrics (13 November 2017), obesity during pregnancy — independent of its health consequences such as diabetes — may account for the higher risk of giving birth to an atypically large infant.

 

In the current study, researchers analyzed ultrasound scans taken throughout pregnancy of more than 2,800 pregnant women: 443 obese women with no accompanying health conditions, such as diabetes, and more than 2300 non-obese women. The researchers categorized the women’s weight according to their body mass index (BMI) score. Women with a BMI ranging from 30 to 44.9 were classified as obese, while those with a BMI of <29.9 were considered non-obese.

 

Results showed that beginning in the 21st week of pregnancy, ultrasound scans revealed that for fetuses of obese women, the femur (thigh bone) and humerus (upper arm bone) were longer than those of the fetuses of non-obese women. The differences between fetuses of obese and non-obese women continued through the 38th week of pregnancy. For fetuses in the obese group, the average femur length was 0.8 millimeters longer (about 0.03 inches), compared to the non-obese group, and humerus length was about 1.1 millimeters longer (about 0.04 inches), compared to the non-obese group. Average birth weight was about 100 grams (about 0.2 pounds) heavier in the obese group. Moreover, infants born to obese women were more likely to be classified as large for gestational age (birth weight above the 90th percentile), compared to infants born to non-obese women.

 

The study could not determine exactly why the fetuses of obese women were larger and heavier than fetuses in the non-obese group. The authors theorized that because obese women are more likely to have insulin resistance (difficulty using insulin to lower blood sugar), higher blood sugar levels could have promoted overgrowth in their fetuses. The authors also pointed out that earlier studies have indicated that the higher risk of overgrowth seen in newborns of obese women may predispose these infants to obesity and cardiovascular disease later in life. They called for additional studies to follow the children born to obese women to determine what health issues they may face.

 

FDA Launches Comprehensive Regenerative Medicine Policy Framework

 

The FDA has announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. The framework, which is outlined in a suite of four guidance documents, builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products. Further, two of the guidance documents propose an efficient, science-based process for helping to ensure the safety and effectiveness of these therapies, while supporting development in this area. The suite of guidance documents also defines a risk-based framework for how the FDA intends to focus its enforcement actions against those products that raise potential significant safety concerns. This proposed framework is intended to balance the agency’s commitment to safety with mechanisms to drive further advances in regenerative medicine so innovators can bring new, effective therapies to patients as quickly and safely as possible. The policy also delivers on important provisions of the 21st Century Cures Act.

 

The framework includes two final guidance documents and two draft guidance documents.

 

New Final Guidance Documents

 

The two final guidance documents clarify the FDA’s interpretation of the risk-based criteria manufacturers use to determine whether a product is subject to the FDA’s premarket review. The first guidance provides greater clarity around when cell and tissue-based products would be excepted from the established regulations if they are removed from and implanted into the same individual within the same surgical procedure and remain in their original form. The second final guidance helps stakeholders better understand how existing regulatory criteria apply to their products by clarifying how the agency interprets the existing regulatory definitions “minimal manipulation“ and “homologous use.“

 

As this field advances, the FDA has noted that there are a growing number of regenerative medicine products subject to FDA premarket authorization. These guidance documents will help explain how the FDA will provide a risk-based framework for its oversight. The policy framework defines how we intend to take action against unsafe products while facilitating continued innovation of promising technologies. To accomplish this goal, the guidance document has clarified the FDA’s view of “minimal manipulation“ and “homologous use.“ These are two concepts that are defined in current regulation to establish the legal threshold for when a product is subject to the FDA’s premarket approval requirements. By further clarifying these terms in the final guidance, the FDA is applying a modern framework for its oversight. Under the new policy, in order to allow manufacturers of products time to comply with the requirements, for the first 36 months following issuance of the final guidance document the FDA intends to exercise enforcement discretion for certain products that are subject to the FDA’s premarket review under the existing regulations, but are not currently meeting these requirements. The FDA does not intend to exercise such enforcement discretion for those products that pose a potential significant safety concern. Going forward, the FDA will apply a risk-based approach to enforcement, taking into account how products are being administered as well as the diseases and conditions for which they are being used. This risk-based approach allows product manufacturers time to engage with the FDA, as to determine if they need to submit a marketing authorization application and, if so, submit their application to the FDA for approval.

 

New Draft Guidance Documents

 

The two draft guidances provide important information to help spur development and access to innovative regenerative therapies. The first draft guidance, which builds off the regenerative medicine provisions in the 21st Century Cures Act, addresses how the FDA intends to simplify and streamline its application of the regulatory requirements for devices used in the recovery, isolation, and delivery of regenerative medicine advanced therapies (RMATs), including combination products. The guidance specifies that devices intended for use with a specific RMAT may, together with the RMAT, be considered to comprise a combination product.

 

The second draft guidance describes the expedited programs that may be available to sponsors of regenerative medicine therapies, including the new Regenerative Medicine Advanced Therapy (RMAT) designation created by the 21st Century Cures Act, Priority Review, and Accelerated Approval. In addition, the guidance describes the regenerative medicine therapies that may be eligible for RMAT designation – including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, as well as gene therapies that lead to a durable modification of cells or tissues (including genetically modified cells).

 

Both draft guidance documents will have 90-day comment periods.

 

Adaptation of Lebanese Fattoush Salad with Grilled Haloumi

After adapting this Lebanese salad to available produce, and adjusted to our taste, I have come up with one of the most delicious and refreshing salads, we have had in a long time. Easy to make and beautiful to serve. ©Joyce Hays, Target Health Inc.

 

Most of these ingredients are easy to find, if not, I’ve given substitutes. The haloumi cheese is available at Amazon and Zabar’s. ©Joyce Hays, Target Health Inc. 

 

Fattoush (also fattush, fatush, fattoosh, and fattouche) is a Levantine bread salad made from toasted or fried pieces of Arabic flat bread combined with mixed greens and other vegetables, such as radishes and tomatoes. Fattush belongs to the family of dishes known as fattat (plural of fatteh), which use stale flatbread as a base.

 

Fattoush includes vegetables and herbs according to season and taste. The vegetables are cut into relatively large pieces compared to tabbouleh which requires ingredients to be finely chopped. Staghorn sumac is usually used to give fattoush its sour taste.

 

I decided not to make croutons out of the pita or flat bread. Instead, I served warm pita at the table, with garlic hummus. Although I like to use ground sumac in other dishes, I didn’t want a sour taste in this salad, so omitted the sumac.

 

Ingredients

1 large green capsicum (pepper) or avocado, cut in cubes

1 Lebanese, or long English cucumber, finely chopped

2 ripe truss or vine tomatoes, finely chopped

1/2 red onion, finely chopped

1/2 bunch fresh parsley, leaves chopped

1/2 bunch fresh coriander, leaves chopped

2 pita bread toasted, then make small croutons in food processor

1/4 to 1/2 pound haloumi cheese, cubed (or muenster)

Zest of 1/2 lemon

Juice of 1/2 lemon

 

Dressing 

1/4 cup extra virgin olive oil

1 pinch chili flakes

2 Tablespoons lemon juice

3 small garlic cloves, crushed or squeezed

1/2 teaspoon caster sugar

 

Using a garlic press, you can squeeze the garlic right into a small bowl with the other dressing ingredients. ©Joyce Hays, Target Health Inc.

  

Directions

1. Rinse all of your raw veggies well. You don’t know where they’ve come from or who has handled them. Also, there could be residue from pesticides, even though the claim is organic. Why take a chance, when it only takes a few minutes.

2. Do all of your chopping, cutting slicing, squeezing, peeling etc.

3. Make the dressing first. Simply combine all the ingredients into a small bowl, as you see above.

 

Something so-o refreshing about the smell of chopped cucumbers. ©Joyce Hays, Target Health Inc.

 

Do all of your chopping first. ©Joyce Hays, Target Health Inc.

 

4. If you plan to toast pita or flat bread, do that now. Then, either cut the toasted bread into cubes, or put into food processor and pulse, until you get the size of crouton you want to put into the salad. I have no photos to show re: bread, because decided not to have bread in this kind of salad.

5. In a large salad bowl, that you plan to use for serving, add all of the salad (veggies plus herbs) ingredients, in no special order, and toss them.

 

Making this salad made me feel really healthy; eating it was even better and such a pleasure. You’re going to love this salad. ©Joyce Hays, Target Health Inc.

 

Not a chore; rather, time well spent! ©Joyce Hays, Target Health Inc.

 

You decide if you want to fry the cheese or simply add the cheese cubes to the salad. Do this step last, add the cheese cubes to the salad and give one last toss. I didn’t fry the cheese. ©Joyce Hays, Target Health Inc.

 

I added the dressing last, after adding the cheese cubes. Then several good tosses. ©Joyce Hays, Target Health Inc.

 

6. After tossing the fresh ingredients, add the toasted pita to the salad, if you want to.

7. If you decide to fry the cheese, heat a non-stick frying pan over medium-high heat. Cook the haloumi or muenster, turning, for 2 minutes or until golden. Arrange over the salad. Serve drizzled with a little extra lemon juice.

 

©Joyce Hays, Target Health Inc.

 

We had this salad with warm pita, hummus and well chilled white wine. Then a new recipe I’m working on, curried quinoa with chicken thighs, toasted pistachios, golden raisins. Just about ready to share with you

For dessert, a simple fresh berry combo, photo below.

 

Fresh berry combo for dessert. ©Joyce Hays, Target Health Inc.

 

Varieties of Arab salad: Arab salad, Fattoush, Palestinian salad, Matbucha, Tabbouleh and Raheb. Source: Wikipedia Commons.

 

Pouilly-Fuisse has become our default white wine, taking the place of sauvignon blanc and pinot grigio.

 

We have been following the work of Rajiv Joseph for many years. This weekend we saw his latest play, Describe the Night, produced by one of the theaters we are proud to be patrons of, The Atlantic Theater Company on West 20th Street, here in Manhattan. YOU CANNOT MISS THIS WONDERFUL PRODUCTION WHICH IS RAJIV JOSEPH’S BEST! This is an epic drama based on the life and writings of the great Russian-Jewish, playwright and author, Isaak Babel (1894-1940), who was executed by Stalin’s secret police in 1940. His work was not published in its original versions again, until the 1990s. Babel’s diary becomes a focal point, around which this drama unfolds and weaves around, going, very affectively, back and forth in time. This play is so well acted and directed, that it catches the audience’s attention, immediately, and doesn’t let it go until the final scene. During the two intermissions, we all said agreed (members of audience) that we couldn’t wait to see what would happen next. Certain years of Soviet and Russian history are well integrated into this amazing play.

The sets are excellent and so is the sound design. Be prepared for one of the best theatrical experiences of the year, as Rajiv Joseph expertly traces the stories of seven men and women connected by history, myth and conspiracy theories.

 

Playwright, Rajiv Joseph

Photo credit: Jessica Johnston – Nefariouschafe, CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=17945095

 

Isaak Babel

More about Isaak Babel

Hope you had a great week!

 

From Our Table to Yours

Bon Appetit!

 

Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as ‘Lou Gehrig’s disease’

Date:
November 16, 2017

Source:
University of Montreal Hospital Research Centre (CRCHUM)

Summary:
A drug used to treat schizophrenia has the potential to slow the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which there is currently no effective cure. After six years of research on several animal models and a few patients, researchers discovered that pimozide stabilizes the disease in the short term. A clinical trial must confirm the efficacy and safety of the drug before it is offered to patients.

 

Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as “Lou Gehrig’s disease.”
Credit: Alex Parker and Pierre Drapeau

 

 

Researchers from the University of Montréal Hospital Research Centre (CRCHUM) and the Cumming School of Medicine (CSM) at the University of Calgary have discovered a medication that could make it possible to treat individuals with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

An article published today in JCI Insight concludes that pimozide was found to be safe and over the short term, preliminary data shows that it could stabilize the progression of ALS. This neurodegenerative disease normally leads to a progressive paralysis of the skeletal muscles and, on average, three years after the onset of symptoms, to death.

“This medication alleviates the symptoms of ALS in animal models,” said Alex Parker, a CRCHUM researcher and professor at Université de Montréal. “Riluzole and edaravone, the drugs currently used, have modest effects. Other studies must be conducted to confirm our results, but we believe that we’ve found a medication that may prove to be more effective in improving patients’ quality of life.”

From worm to man

The story behind the discovery began six years ago with a little millimeter-long nematode worm called C. elegans. In his laboratory, Parker genetically modified the worms so that they would exhibit aspects of the human form of ALS. Simultaneously, his colleague Pierre Drapeau did the same thing to another animal, the zebrafish, a tiny tropical fish only 5 centimetres long.

The two scientists obtained funding from the U.S. Department of Defense to test medications on these worms and fish born with ALS. “We sifted through a library of 3,850 molecules approved for the treatment of other diseases, and found a class of antipsychotic drugs that stabilize mobility in worms and fish,” said Drapeau, a CRCHUM researcher, professor at Université de Montréal and principal investigator on the study. “Pimozide works especially well in preventing paralysis in fish by preserving the neuromuscular junction.”

Subsequently, Université de Montréal Professor Richard Robitaille performed electrophysiological tests on mice in his laboratory and reached the same conclusion. Thus, pimozide was shown to maintain neuromuscular function in three different animal models: worms, fish and mice.

At the annual ALS Canada Research Forum in 2012, the researchers met Dr. Lawrence Korngut, an Associate Professor at the CSM, member of the Hotchkiss Brain Institute (HBI) and Director of the Calgary ALS/Motor Neuron Disease Clinic. “Pimozide is a drug that has been well-known for 50 years,” the neurologist said. “It was approved for treating certain types of psychiatric conditions, like schizophrenia, and costs only 9 cents per pill. Other recent studies have shown genetic links between schizophrenia and ALS. The next logical step was to test it on human volunteers with ALS.”

In 2015, the first preclinical trial for ALS was launched in Canada with a small group of 25 patients who had ALS. Funding was provided by the Quirk family of Calgary, by the HBI, and the Clinical Research Unit at UCalgary.

“We found the highest dose most likely to be tolerated in individuals with ALS — a lower dose than that used in other conditions — and we have preliminary proof showing that pimozide may be useful,” said Korngut.

The initial clinical trial was modest in scope. But after only six weeks, the researchers had a first indication of the drug’s efficacy. Loss of control of the thenar muscles, located in the palm of the hand between thumb and index finger, is usually one of the first signs of ALS. For patients who took pimozide, this function remained stable. This observation is tempered by the very limited size and length of the clinical trial.

“For us, this is an indication that we found the right therapeutic target,” said Drapeau. “Pimozide acts directly on the neuromuscular junction, as shown in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it only preserves normal neuromuscular function to at least stabilize the disease. This is also the first time that a potential drug for human patients was discovered based on basic research on small organisms such as worms and fish.”

Now comes the next step: a phase II clinical trial on 100 volunteers, funded by the “The Ice Bucket Challenge” through a partnership between ALS Canada and Brain Canada to begin in the next few weeks. Headed by Korngut in Calgary and conducted in nine hospital centres across Canada, the study aims to confirm that pimozide is safe and to measure, over a six-month period, its effect on the progression of the disease and its symptoms and on patients’ quality of life.

Daniel Rompré, 47, father of two teenage girls, hopes to participate in the new study. He was diagnosed with ALS in March 2016. The muscles of his upper body are getting weaker, he is beginning to have trouble speaking, and he can no longer use his left arm. “It is hard to maintain a positive outlook,” Rompré said. “You ask yourself: ‘Why me?’ But at least it’s encouraging to see that research is advancing. There has been more progress in the last five years than in 100 years of research on the disease.”

It is too soon to draw firm conclusions about the safety and efficacy of pimozide. “At this stage, people with ALS should not use this medication,” Korngut emphasized. “We must first confirm that it is really useful and safe in the longer term. It is also important to be aware that pimozide is associated with significant side effects. Therefore, it should only be prescribed in the context of a research study.”

Story Source:

Materials provided by University of Montreal Hospital Research Centre (CRCHUM)Note: Content may be edited for style and length.


Journal Reference:

  1. Shunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, Pierre Drapeau. Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosisJCI Insight, 2017; 2 (22) DOI: 10.1172/jci.insight.97152

 

Source: University of Montreal Hospital Research Centre (CRCHUM). “Discovery of a promising medication for amyotrophic lateral sclerosis (ALS): Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as ‘Lou Gehrig’s disease’.” ScienceDaily. ScienceDaily, 16 November 2017. <www.sciencedaily.com/releases/2017/11/171116104804.htm>.

So much snow that researchers needed the help of tractor-mounted snowblowers

Date:
November 15, 2017

Source:
National Science Foundation

Summary:
A 6-foot-wide snow blower mounted on a tractor makes a lot of sense when you live on the Tug Hill Plateau. Tug Hill, in upstate New York, is one of the snowiest places in the Eastern US and experiences some of the most intense snowstorms in the world. This largely rural region, just east of Lake Ontario, gets an average of 20 feet of snow a year, and a new report explains why.

 

Why does New York’s Tug Hill Plateau get so much snow? Scientists faced blizzards to find out.
Credit: University of Utah

 

 

A 6-foot-wide snow blower mounted on a tractor makes a lot of sense when you live on the Tug Hill Plateau. Tug Hill, in upstate New York, is one of the snowiest places in the Eastern U.S. and experiences some of the most intense snowstorms in the world. This largely rural region, just east of Lake Ontario, gets an average of 20 feet of snow a year.

Hence the tractor-mounted snow blower.

The region’s massive snow totals are due to lake-effect snowstorms and, it turns out, to the shape of Lake Ontario.

Lake-effect storms begin when a cold mass of air moves over relatively warm water. The heat and moisture from the water destabilize the air mass and cause intense, long-lasting storms. Lake-effect snow is common in the Great Lakes region and in areas downwind of large bodies of water, including the Great Salt Lake.

Researchers, including the University of Utah’s Jim Steenburgh and University of Wyoming’s Bart Geerts, now report that these intense snowstorms are fueled by air circulation driven by the heat released by the lake, and that the shoreline geography of Lake Ontario affects the formation and location of this circulation. The result? Very heavy snowfall.

The findings, published in three papers, show how the shorelines of lakes may help forecasters determine the impacts of lake-effect storms.

“Lake Ontario’s east-west orientation allows intense bands of snow to form,” said Ed Bensman, a program director in the National Science Foundation’s (NSF) Division of Atmospheric and Geospace Sciences, which funded the research. “This study found that the shape of the lake’s shoreline can have an important influence on the low-level winds that lead to bands of snow for long periods of time — and to heavy snow totals. The research team analyzed the strength of these snow bands, and their formation and persistence. Snow bands were often active for several days.”

Lake-effect

When land breezes move offshore from places where the coastline bulges out into a lake, unstable air masses form and drive a narrow band of moisture that dumps its moisture as snow on a strip of land downwind of the lake.

Steenburgh said it’s long been known that breezes coming from the shore onto a lake help initiate and direct the formation of snow bands. Steenburgh and Geerts, and colleagues from universities in Illinois, Pennsylvania and upstate New York, traveled to Lake Ontario as part of an NSF-funded project called Ontario Winter Lake-effect Systems (OWLeS). The scientists investigated several questions about lake-effect systems:

  • What environmental factors have the greatest influence on the amount of snowfall and location of snowbands over and near Lake Ontario?
  • How does the interplay between wind and clouds produce long-lived snowbands far downstream of open water?
  • How does the local terrain influence the strength and longevity of these systems?

To find out, Geerts’ team flew a Wyoming King Air research plane through winter storms, and Steenburgh’s group set up weather monitoring equipment, including profiling radars and snow-measurement stations, to monitor the arrival of lake-effect storms near Tug Hill.

The researchers witnessed the region’s intense snowfall, including one storm that dropped 40 inches in 24 hours. Snowfall rates often exceeded 4 inches per hour. “That’s an amazing rate,” Steenburgh said. “It’s just an explosion of snow.”

The role of the bulge

Wyoming Cloud Radar aboard the King Air plane detected an intense secondary air circulation across the main snow band. “This circulation had a narrow updraft, creating and lifting snow like a fountain in a narrow strip that dumped heavy snow where it made landfall,” Geerts said. Using a weather model, Steenburgh’s team found that this circulation’s origin was a land breeze generated by the lake’s uneven shoreline geography.

In some cases, another land breeze generated a second snow band that merged with the first. “The intense secondary circulation, with updrafts up to 20 miles per hour, had never been observed before,” Geerts said.

One particular shoreline feature played a large role: a gentle, broad bulge along Lake Ontario’s southern shore that extends from about Niagara Falls in the west to Rochester, New York, in the east.

“This bulge was important in determining where the lake-effect snow bands developed,” Steenburgh said. “A bulge near Oswego, New York, on the southeast shore, also contributed to an increase in the precipitation downstream of Lake Ontario over Tug Hill.”

Steenburgh says the residents of the region take the heavy snowfall in stride. Roads are kept plowed, and the team found that on many days, the biggest challenge was just getting out of the driveway of the house they stayed in. Once the tractor-snow blower was fired up, however, the researchers had a clear shot.

“We’re a bunch of snow geeks,” Steenburgh said. “We love to see it snowing like that. It’s really pretty incredible. And our friends on Tug Hill made sure we could do our research.”

Better forecasts

Incorporating considerations of shoreline geography into weather forecast models can help predict which communities might be most affected by snowstorms, Steenburgh said. Understanding the effect of breezes that arise from the shore’s shape is the key.

“If we want to pinpoint where the lake-effect is going to be, we’re going to have to do a very good job of simulating what’s happening along these coastal areas,” he said.

Story Source:

Materials provided by National Science FoundationNote: Content may be edited for style and length.


Journal References:

  1. Philip T. Bergmaier, Bart Geerts, Leah S. Campbell, W. James Steenburgh. The OWLeS IOP2b Lake-Effect Snowstorm: Dynamics of the Secondary CirculationMonthly Weather Review, 2017; 145 (7): 2437 DOI: 10.1175/MWR-D-16-0462.1
  2. Leah S. Campbell, W. James Steenburgh. The OWLeS IOP2b Lake-Effect Snowstorm: Mechanisms Contributing to the Tug Hill Precipitation MaximumMonthly Weather Review, 2017; 145 (7): 2461 DOI: 10.1175/MWR-D-16-0461.1
  3. W. James Steenburgh, Leah S. Campbell. The OWLeS IOP2b Lake-Effect Snowstorm: Shoreline Geometry and the Mesoscale Forcing of PrecipitationMonthly Weather Review, 2017; 145 (7): 2421 DOI: 10.1175/MWR-D-16-0460.1

 

Source: National Science Foundation. “Shape of Lake Ontario generates white-out blizzards, study shows: So much snow that researchers needed the help of tractor-mounted snowblowers.” ScienceDaily. ScienceDaily, 15 November 2017. <www.sciencedaily.com/releases/2017/11/171115175313.htm>.

Spanish researchers have discovered this effect in granular media, opening the door to the theoretical understanding of the Mpemba effect

Date:
November 14, 2017

Source:
Universidad Carlos III de Madrid

Summary:
A team of researchers has defined a theoretical framework that could explain the Mpemba effect, a counterintuitive physical phenomenon revealed when hot water freezes faster than cold water.

 

Icicles (stock image).
Credit: © Lela Kieler / Fotolia

 

 

A team of researchers from Universidad Carlos III de Madrid, the Universidad de Extremadura and the Universidad de Sevilla have defined a theoretical framework that could explain the Mpemba effect, a counterintuitive physical phenomenon revealed when hot water freezes faster than cold water.

The researchers, who have recently published the findings in Physical Review Letters, have confirmed how this phenomenon occurs in granular fluids, that is, those composed of particles that are very small and interact among those that lose part of their kinetic energy. Thanks to this theoretical characterization, “we can simulate on a computer and make analytical calculations to know how and when the Mpemba effect will occur,” said Antonio Lasanta. Lasanta is from the UC3M Gregorio Millán Barbany University Institute for Modeling and Simulation on Fluid Dynamics, Nanoscience and Industrial Mathematics. “In fact,” he said, “we find not only that the hottest can cool faster but also the opposite effect: the coldest can heat faster, which would be called the inverse Mpemba effect.”

The fact that preheated liquids freeze faster than those that are already cold was observed for the first time by Aristotle in the 4th century AD. Francis Bacon, the father of scientific empiricism, and René Descartes, the French philosopher, were also interested in the phenomenon, which became a theory when, in 1960, a Tanzanian student named Erasto Mpemba explained to his teacher in a class that the hottest mixture of ice cream froze faster than the cold one. This anecdote inspired a technical document about the subject, and the effect began to be analyzed in educational and science magazines. However, its causes and effects have hardly been studied until now.

“It is an effect that, historically, has not been addressed in a rigorous manner but merely as an anomaly and a didactic curiosity,” said Antonio Prados, one of the researchers from the Universidad de Sevilla Department of Theoretical Physics. “From our perspective, it was important to study it in a system with the minimum ingredients to be able to control and understand its behavior,” he said. This has enabled them to understand what scenarios it is easier to occur in, which is one of the main contributions of this scientific study. “Thanks to this, we have identified some of the ingredients so that the effect occurs in some physical systems that we can describe well theoretically,” stated researcher Francisco Vega Reyes and Andrés Santos, from the Universidad de Extremadura Instituto de Computación Científica Avanzada (Institute of Advanced Scientific Computation).

“The scenario that the effect will most easily occur in is when the velocities of the particles before heating or cooling have a specific disposition — for example, with a high dispersion around the mean value,” he said. This way, the evolution of the temperature of the fluid can be significantly affected if the state of the particles is prepared before the cooling.

This research of “basic science,” in addition to contributing to improving fundamental knowledge, might have other applications in the mid or long term. In fact, this group of researchers is planning to carry out an experiment that verifies the theory. Learning to emulate and use this effect might have applications in our daily life, according to scientists. For example, it could be used to make electronic devices which we want to cool faster.

Video (Spanish with English subtitles): https://youtu.be/esHynYASgeY

Story Source:

Materials provided by Universidad Carlos III de MadridNote: Content may be edited for style and length.


Journal Reference:

  1. Antonio Lasanta, Francisco Vega Reyes, Antonio Prados, Andrés Santos. When the Hotter Cools More Quickly: Mpemba Effect in Granular FluidsPhysical Review Letters, 2017; 119 (14) DOI: 10.1103/PhysRevLett.119.148001

 

Source: Universidad Carlos III de Madrid. “Why hot water freezes faster than cold water: Spanish researchers have discovered this effect in granular media, opening the door to the theoretical understanding of the Mpemba effect.” ScienceDaily. ScienceDaily, 14 November 2017. <www.sciencedaily.com/releases/2017/11/171114104825.htm>.

Date:
November 14, 2017

Source:
Scripps Research Institute

Summary:
NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

 

Researchers are hopeful that a new drug may be able to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).
Credit: © Lori Werhane / Fotolia

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children — roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice — it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have — like human children with MHS — just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests — in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome — and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

Story Source:

Materials provided by Scripps Research InstituteNote: Content may be edited for style and length.


Journal Reference:

  1. Shichun Tu, Mohd Waseem Akhtar, Rosa Maria Escorihuela, Alejandro Amador-Arjona, Vivek Swarup, James Parker, Jeffrey D. Zaremba, Timothy Holland, Neha Bansal, Daniel R. Holohan, Kevin Lopez, Scott D. Ryan, Shing Fai Chan, Li Yan, Xiaofei Zhang, Xiayu Huang, Abdullah Sultan, Scott R. McKercher, Rajesh Ambasudhan, Huaxi Xu, Yuqiang Wang, Daniel H. Geschwind, Amanda J. Roberts, Alexey V. Terskikh, Robert A. Rissman, Eliezer Masliah, Stuart A. Lipton, Nobuki Nakanishi. NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autismNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01563-8

George Washington was Inaugurated in New York City

 

On Thursday, April 30, 1789, on the balcony of Federal Hall in New York City, New York George Washington was inaugurated as the first President of the United States. Thus ends the final chapter of a fascinating book entitled, “A Brilliant Solution: Inventing the American Constitution,“ by Carol Berkin. This is a must read for anyone fascinated by the foundations of the American experience in governing. But most important to note is the profound insight our founders had into human behavior and the human psyche, and the intelligent and prescient controls they put in place to avoid concentration of power. Our goal is to share a copy of the book on your next visit to our offices.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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