My Scientific Blog - Research and Articles: 2018

Research Completed entitled "FACTORS LIMITING THE UTILIZATION OF PRIMAQUINE FOR RADICAL TREATMENT OF VIVAX MALARIA IN FAR WESTERN REGION OF NEPAL"

funded by

Ministry of Education, Science and Technology, Singhadurbar, Kathmandu

Research Team:

Nabaraj Adhikari, Prakash Ghimire, Megha Raj banjara, Komal Raj Rijal and Upendra Thapa Shrestha

SUMMARY

Backround: Plasmodium vivax malaria remains an important public health problem in many parts of the world. The World Health Organization (WHO) estimates that P. vivax was responsible for 8.5 million cases of malaria globally in 2015. Malaria remains a priority public health problem in Nepal, where approximately 50% of the population is at risk of malaria and the threat of an outbreak is still real primarily as a result of receptivity and vulnerability characteristics of the country. The trend of malaria during the last decade indicates that substantial progress has been made towards elimination in Nepal. All districts now have an API less than 1/1000 and the country is moving towards “vision of malaria free Nepal by 2025”. An essential element to achieving the elimination of malaria will be killing both the blood and liver stages of the parasite. Primaquine (PQ), an 8-amnoquinoline, is the only licensed drug that effectively kills P. vivax hypnozoites. While it is well tolerated in the majority of recipients, primaquine and related compounds can cause severe side effects (haemolysis) in individuals with the inherited enzymopathy glucose-6-phosphate dehydrogenase (G6PD) deficiency. Prioritization of radical cure for P. vivax malaria has become better recognized recently, along with malaria elimination. Though the national malaria treatment protocol has lucidly states the use of primaquine for the treatment of vivax malaria after screening of G6PD status of the patient, many health care personnels are reluctant to use this drug in endemic districts of the country.

Aim: This study has been designed to explore the factors limiting utilization of primaquine for the management of vivax malaria in far western region of Nepal. In addition, the patient’s perspective in the provided treatment, limitations in laboratory facilities will also be explored during the study period.

Study sites: Mahakali Zonal Hospital Kanchanpur, Malkheti and Tikapur Hospital of Kailai district.

Study Population: The study population were the malaria patients (infected with vivax malaria) and drug prescribers (physicians, health assistants and nurses).

Sample size: Altogether 125 (75 malaria patients and 50 drug prescribers) individuals were enrolled in the study.

Study tools: A semi structured questionnaire was developed for interview of the patients and the drug prescribers. In addition to individual questionnaire, a focus group discussion of drug prescribers was also conducted as part of qualitative research.

Results: during the course of study majority of the patents were Dalits (56%). Around three-fourth of the patients were male and most of the patients were in the age group of 16-45 years. Maximum patients had their job in India (37.3%) and higher number of patients had formal primary level education (42.6%). About 78.7% of the patients had heard about malaria and 56% had knowledge about the transmission of malaria. However, only 20% of the patients had knowledge regarding the signs and symptoms of malaria. About 50.7% of the patients were aware about the preventive measures of malaria. Only 33.3% of the patients had known that the diagnosis and treatment of malaria is free in the government health facilities of Nepal. Majority of the patients (50.7%) had come to the health care facilities 3 or more days after the onset of fever. In addition, 36% of the patients visited repeatedly in the health care facilities in the last 3 months. Only 33.3% of the patients were found sure that the malaria can be cured by antimalarial drugs. About 34.7% of the patients did not understand the counseling by drug prescribers on how to take the antimalarial drugs. About 36% of the patients reported that there is no need of taking the drugs after the fever subsides. About 84% of the patients reported that they were not advised by the drug prescribers for follow up. About 40% of the drug prescribers had experience in the field of malaria for 10 or more than 10 years. About 92% of the drug prescribers believed vivax malaria as the problem in their catchment area. About 84% of the drug prescribers had told that they follow the new malaria treatment guidelines 2015. However only 40% of the drug prescribers have received training on new treatment guidelines. About 80% of the drug prescribers had reported that they use to treat vivax malaria with 14 days primaquine therapy. About 82% of the drug prescribers use to review the result of G6PD test before administration of 14 days primaquine to the patient. No one of the drug prescriber had ever noticed the adverse effects after primaquine treatment.

Conclusion: The study finds some gaps between the patients and drug prescribers for the effective management of vivax malaria in the study sites.

Recommendation: The stakeholders must address and hit in those gaps for the timely elimination of malaria from Nepal.

"This article was originally published at HVMN."

Beta-hydroxybutyrate (or BHB) is topic often discussed in keto circles, but one that might seem foreign to an outsider.

Whether it’s talk of the ketogenic diet or ketosis or exogenous ketones, understanding BHB is essential to developing a well-rounded knowledge of keto. It can be a confusing topic, but we’ll demystify BHB by explaining it from several angles.

In this piece, we analyze the science behind BHB, what it does, where it comes from, and why it’s important for optimizing your keto goals (whatever they may be).

What Exactly is BHB?

It’s always good to start at the chemical description. Beta-hydroxybutyrate is also known as beta-hydroxybutyric acid or 3-hydroxybutyrate. It’s an organic compound with the formula C4H803.¹

Under the umbrella of ketones in human metabolism, BHB is considered one of the three “physiological” ketone bodies produced and burned in our cells. But opening an organic chemistry textbook, BHB won’t fit the true criteria of a “ketone.”

A ketone is defined as having carbonyl carbons (carbon joined to oxygen with a double bond) bonded to two other carbon atoms. BHB has a carbonyl carbon, but it’s only bound to one other carbon atom.

The double bond of an oxygen molecule to a carbon molecule, the chemical formula of a ketone

The chemical structure of a ketone: a carbon molecule joined to an oxygen molecule with a double bond

Chemical formulas for the different kinds of ketone bonds: BHB, AcAc and Acetone

The chemical formulas of the three main ketone bodies: AcAc, Acetone and BHB (which doesn't fall under the traditional definition of a ketone)

Despite this technicality, BHB is still considered one of the three ketone bodies because this family of metabolites are closely related and affect the body similarly. BHB levels increase in the brain, heart, muscle, liver and other tissues when restricting calories, fasting, following a ketogenic diet, or even as a result of exercise.²

Ketosis Recap

Before exploring BHB further, let’s develop a basic understanding of what ketosis is, and how it works.

Ketosis marks the presence of ketones in the body, usually at >0.5mM. Ketosis is usually achieved through endogenous ketones, meaning ketones are produced naturally by the body as a result of diet or fasting. You can read more deeply about the nuances of ketosis here.

When we eat carbohydrates, they’re converted into glucose in the blood. Glucose is then used as our brain’s fuel source–but when carb intake is restricted (like when following a low-carb, high-fat ketogenic diet) the brain requires an alternate fuel source.

While most other organs in the body can use fat as fuel, the brain can’t; however, the brain can use ketones for energy.

So the body turns fat into ketones to be used both as body and brain fuel. Ketones can provide up to 60% of the energy needed by the brain.³

Ketogenic metabolism produces three different types of ketones:

· Acetate (Acetone)

· Acetoacetate (AcAc)

· Beta-hydroxybutyrate (BHB)

Acetone is the least abundant, produced in much smaller amounts, and is usually exhaled through the lungs rather than being used as fuel.⁴ Acetoacetate is part of the metabolic pathway whereby humans make and use ketones, but it tends to be found in the blood at lower levels than BHB.

BHB is the predominant ketone body in the blood.

Did you know there are different types of ketones?

Many companies cite the benefits of ketone esters for a ketone salts, but they couldn’t be more different. Salts, esters, and the multiple kinds of esters–it can be confusing. Our team is conducting research on each compound to clarify it all for you. Subscribe to see how we set the record straight.

How is BHB Made?

It happens two different ways.

Endogenous BHB

Endogenous ketones are produced by the body naturally through a low-carb diet or fasting. The process for creating endogenous BHB is called ketogenesis.

The ketone produced in a fasted state via ketogenesis is Acetoacetate (AcAc). Fatty acids are broken down to produce acetyl CoA, which then undergoe a chain of reactions to eventually form AcAc.

In the liver, the BHB-dehydrogenase enzyme reduces AcAc to form BHB. This BHB then goes on to be used as fuel for the body as the primary circulating ketone body.

The best way to increase production of endogenous BHB is to reach a state of nutritional ketosis by reducing carbohydrate intake or fasting.

Exogenous BHB

Priming the body to trigger endogenous ketone production takes time and effort. To provide a quicker alternative to natural ketone production, there are exogenous BHB ketones which can be consumed through supplements. Exogenous ketones come from an external source since they’re not produced in the body.

There several different options when considering which exogenous ketone supplement to take.

MCT Oils: Medium chain triglycerides (MCT) don’t contain BHB, but consuming MCT oils can moderately raise BHB. They contain fat molecules that are easily converted into BHB.

MCTs require more processing inside of the body compared to other types of exogenous ketones and therefore take longer to get a body into ketosis. They’re also calorie-dense (a natural source of MCT is coconut oil), so it may be ultimately counterproductive to rack up calories just to elevate ketones.

Ketone Salts: Ketone salts are a compound consisting of a mineral ion, such as sodium (Na+), potassium (K+), and BHB. The compound is held together by ionic bonds, but when consumed, the salt dissociates into free Na+, K+, and BHB. Thus, BHB blood concentrations are raised, but only to levels of 0.5 - 1 mM.⁵

Combining sodium and potassium to bond BHB is cost-effective, but it can lead to excessive sodium consumption to attain the desired level of blood ketones. An advantage of ketone salts is that they’re high in electrolytes; so they can replenish electrolytes lost in urine while on the ketogenic diet.

Ketone Esters: Ketone esters are composed of a raw ketone molecule (BHB or AcAc) bound to a ketone precursor using an ester bond (butanediol or glycerol).

An example is HVMN Ketone–the world’s first ketone ester drink. Deeper and faster ketosis can be obtained from ketone ester drinks, with levels reaching 3 - 5 mM–several times higher than ketone salt drinks.⁵

Benefits of HVMN Ketone also include:

· Increased cognitive performance: HVMN Ketone improved maze solving time by 38% in an animal experiment⁶

· Decreased food cravings/increased satiety: HVMN Ketone decreases hunger and ghrelin⁵

· Improved athletic performance and endurance: HVMN Ketone improved athletic performance in elite cyclists⁷

· Lowered blood sugar: HVMN Ketone decrease blood sugar in response to a meal and lowered blood lipids^5,8

For athletes, in particular, using exogenous ketone bodies like HVMN Ketone allows them to receive some of the benefits of ketosis without the time spent fasting and dieting to achieve nutritional ketosis.

Benefits of BHB

Having discussed BHB, and how it gets into the body, it’s time to look at its benefits.

BHB Provides Natural, Clean Energy

As the main ketone body, BHB acts as an energy source. Through ketolysis, ketones are broken down using aerobic respiration inside the mitochondria. Ketolysis occurs throughout all tissues in the body except the liver (because the liver doesn’t contain one of the key enzymes for ketone oxidation).

When BHB enters the mitochondria of the cell, it’s converted to acetoacetate, after which it undergoes a reaction where CoA is added. The result is acetoacetyl-CoA, which is cleaved to form acetone and acetyl-CoA.

The acetyl-CoA progresses into the Krebs cycle and results in the production of ATP, which as you know, is the energy needed for the cellular functions.⁹

Ketones are clean-burning because they reduce the production of potentially harmful reactive oxygen species (ROS) inside cells. They’re also able to scavenge (clean up) ROS produced by other metabolic processes.

BHB is Powerful Brain Fuel

BHB easily crosses the blood-brain barrier (crossing from the peripheral circulation to the central nervous system).² While BHB can provide energy for the body, it’s particularly well-suited to provide energy for the brain.

BHB isn’t just an energy source for the brain–it has other effects which promote brain health. BHB can trigger the release of chemicals called neurotrophins, which support neuron function and synapse formation. One of these neurotrophins is called BDNF (brain-derived neurotrophic factor), which is a protein in the brain associated with cognitive enhancement, alleviation of depression and reduction of anxiety.¹⁰

A 2017 study that injected rats with intravenous ketones, then subjected them to stressful situations, found that BHB reduced stress-induced neuroinflammation.¹¹

This combination of energy provision, neurotrophins and anti-inflammatory benefits illustrate that BHB has broad-spectrum effects that might improve the pathology of various neurological conditions.

Increased levels of BHB in the body were found to be associated with greater cognitive performance through better performance in memory recall tests¹² on a study of 20 subjects with Alzheimer’s disease or demonstration of a mild cognitive deficit. Similarly, BHB ketone esters helped to reverse symptoms of Alzheimer's Disease in one clinical case study.¹³ More research in humans is needed, but the various hypotheses are backed up by strong animal data.

BHB is the Easiest Ketone to Measure Accurately in the Blood

Beta-hydroxybutyrate (BHB) can be measured in the blood.

For those looking to maintain ketosis, testing should be regularly undertaken to verify the presence of ketones in the blood, breath or urine.

The three ketones are measurable as follows:

· BHB: in the blood

· Acetone: in the breath

· Acetoacetate (AcAc): in the urine

In blood, BHB is the most prevalent of the ketones. It’s widely used to measure ketone levels because it is present at far higher concentrations than Acetone and Acetoacetate and it exists outside the cell, making it both easy to measure and accurate.

A handheld blood glucose monitor is the most common measuring tool, as it has the capability to also measure blood ketone levels. The test is akin to a diabetic testing blood sugar with a finger prick.

Optimizing Keto Goals with BHB

BHB plays a pivotal role in the world of ketones and ketosis. Knowledge about BHB will help further map the keto landscape, and allow anyone to plot a course to achieve their goals.

It’s your body–knowing how it works can empower you to make the best decisions for it.

We’re actively investigating BHB. Be first to know the results.

HVMN is working with several research organizations, conducting human studies on the benefits of BHB. Everything from sports performance to mental benefits to medical use cases are being explored. Subscribe to be on the cutting edge of that science.

Scientific Citations

1.	National Center for Biotechnology Information. PubChem Compound Database; CID=441, https://pubchem.ncbi.nlm.nih.gov/compound/441 (accessed Feb. 7, 2018).
2.	Sleiman SF, Henry J, Al-Haddad R, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elmquist JK, ed. eLife. 2016;5:e15092. doi:10.7554/eLife.15092.
3.	Kossoff, E.H., and Rho, J.M. (2009). Ketogenic Diets: Evidence for Short- and Long-term Efficacy. Neurotherapeutics 6, 406-414.
4.	Yue Qiao, Zhaohua Gao, Yong Liu, et al., “Breath Ketone Testing: A New Biomarker for Diagnosis and Therapeutic Monitoring of Diabetic Ketosis,” BioMed Research International, vol. 2014, Article ID 869186, 5 pages, 2014. doi:10.1155/2014/869186
5.	Stubbs, B.Cox, P.; Evans, R.; Santer, P.; Miller, J.; Faull, O.; Magor-Elliott, S.; Hiyama, S.; Stirling, M.; Clarke, K. (2017). On the metabolism of exogenous ketones in humans. Front. Physiol.
6.	Murray, A.J., Knight, N.S., Cole, M.A., Cochlin, L.E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M.K., Atherton, H.J., Schroeder, M.A., et al. (2016). Novel ketone diet enhances physical and cognitive performance. FASEB J.
7.	Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, Andrew J., Stubbs, B., West, J., McLure, Stewart W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism 24, 1-13.
8.	Myette-Cote E, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. LID - 10.1113/JP275709 [doi]. 2018(1469-7793 (Electronic)).
9.	Stojanovic V, Ihle S. Role of beta-hydroxybutyric acid in diabetic ketoacidosis: A review. The Canadian Veterinary Journal. 2011;52(4):426-430.
10.	Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends in neurosciences. 2013;36(1):32-40. doi:10.1016/j.tins.2012.11.005.
11.	Yamanashi, T., Iwata, M., Kamiya, N., Tsunetomi, K., Kajitani, N., Wada, N., Iitsuka, T., Yamauchi, T., Miura, A., Pu, S., et al. (2017). Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Sci. Rep. 7, 7677.
12.	Reger, M.A., Henderson, S.T., Hale, C., Cholerton, B., Baker, L.D., Watson, G.S., Hyde, K., Chapman, D., and Craft, S. (2003). Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 25, 311-314.
13.	Newport, M.T., VanItallie, T.B., Kashiwaya, Y., King, M.T., and Veech, R.L. (2015). A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 11, 99-103.