Diabetes

[Jhanananda]

bodhimind, you present a reasonable set of hypotheses.  I do not think any of us can say for sure why US Americans are sicker than the rest of the human population of the planet; however, one of more of your hypotheses might be the answer.  We will just have to pursue greater understanding over time.

[Jhanananda]

Here are 2 good research papers on inflammatory hyperglycemia.

Inflammation, stress, and diabetes

Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.

Diabetes, Hyperglycemia, and Inflammation in Older Individuals

The Health, Aging and Body Composition study
Abstract

OBJECTIVE—The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals.

RESEARCH DESIGN AND METHODS—Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70–79 years.

RESULTS—Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-α (>75th percentile) were, respectively, 1.95 (95% CI 1.56–2.44) and 1.88 (1.51–2.35) for diabetic participants and 1.51 (1.21–1.87) and 1.14 (0.92–1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13–3.95) and 1.45 (1.03–2.04) for diabetic women and men and 1.33 (1.07–1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-α in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA1c were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment.

CONCLUSIONS—Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT.  Aging is associated with increased inflammatory activity including proinflammatory and anti-inflammatory cytokines and acute-phase proteins (1). Previous studies suggested that low-grade systemic inflammation plays a role in the pathogenesis of some glucose disorders in adults (2). Several cross-sectional studies showed that insulin resistance and type 2 diabetes are associated with higher levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), markers of subclinical systemic inflammation (3–8). Furthermore, various longitudinal studies have shown that elevated levels of CRP and IL-6 predict the development of type 2 diabetes (9–12). Few studies to date have focused on the association between diabetes and inflammation in older individuals, and to our knowledge none of these have studied the relationship of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) with inflammation in aging.

[Jhanananda]

An article on the contaminated water of Prescott, AZ.
Arsenic-tainted discharges into county creek lead to felony charges

Owners of a Bagdad-area mine that allegedly has been discharging thousands of gallons of arsenic-contaminated water per day into Boulder Creek faces three felony counts for pollutant discharge violations.

On Tuesday, Aug. 1, Arizona Attorney General Mark Brnovich announced that a State Grand Jury had indicted Bagdad Hillside, LLC, for allegedly discharging arsenic-contaminated water into the recreational creek.

“Bagdad Hillside is facing three felony counts of Pollutant Discharge Elimination System Violations,” the news release stated.

It added that in 2013, the Arizona Department of Environmental Quality inspected the inactive Hillside Mine, located four miles north of Bagdad, and found it discharging arsenic-contaminated water directly into adjacent Boulder Creek at a rate of five gallons per minute or about 2.6 million gallons per year.

“Bagdad Hillside allegedly owns the mine and the surrounding property,” the news release stated, adding that according to tests, the water flowing from the mine contains arsenic levels that are more than 100 times the water quality standard.

“Boulder Creek is open to Arizonans for recreational swimming year-round,” the release added. “It is not believed that anyone uses Boulder Creek as a source of drinking water.”

Since 2013, ADEQ representatives reportedly have tried to work with Bagdad Hillside to stop the mine from discharging contaminated water, and the company signed three consent orders agreeing to file a plan to stop the discharge. “Those plans have not been submitted and the mine continues to discharge into Boulder Creek,” stated the news release.

Assistant Attorney General Adam J Schwartz is prosecuting the case.

[DDawson]

Hello everyone,

I was watching a health program on a Christian TV station and the host, with the last name of Becker, was excitedly promoting a cure all called black seed oil, sometimes called black cumin oil.  It's and old middle eastern medicinal that is touted to help with diabetes, auto-immune problems, and a host of many other disorders.  The next day I found and bought some and have been taking it for the past two days.  It has a strong but not terribly unpleasant taste.  Very herby, like rosemary or thyme.  We'll see how it works for me, but it looks like it may have potential.

[Anon]

I used black seed oil a few times for general health (not diabetes). It made me calmer and helped my indigestion.

[Jhanananda]

Perhaps cummin and black seed oil owe their color to a natural anti-inflammatory known as anthocynin, which we have been discussing here.  I will have to acquire a bottle of black seed oil to try it out.  Thanks for the recommendation.

[Jhanananda]

My health continues to improve with the continued use of antihistamines.  I am now taking 2 different 1/day antihistamines taken 12 hours apart, plus the occasional use of Benadryl, as needed; along with an ultra-low carb diet.  This year I have lost 37 pounds on this regimen.

[bodhimind]

Wow, this is quite interesting.

I read up more on diabetic involvement with histamine action and found the following 2011 animal study: https://www.ncbi.nlm.nih.gov/pubmed/21239440

Also interesting, from a different study:

In particular, based on its vascular actions, histamine has been suggested to be a key triggering stimulus for the functional microangiopathy in diabetes mellitus, from retinopathy to nephropathy. However, its complete functional contribution to diabetes microvascular complications is yet to be elucidated.

Happy that your health is improving

[Jhanananda]

Thanks, bodhimind, for the link.  I searched for you quote and found a published research paper with the quote in it.  It was in, Histamine in diabetes: Is it time to reconsider? in Pharmacological Research, Volume 111, September 2016, Pages 316-324

Abstract

The first studies of histamine and diabetes date back to the 1950s. Since that time the involvement of histamine in diabetes was related to its well known vasoactive properties and permeability leakage effects. In particular, the first evidence for a correlation between histamine and diabetes arose in 1989 when an increase in plasma and leucocyte histamine content was observed. Limited independent evidence followed in the subsequent two decades, focusing on both histamine glyceamic control and macro- and microvascular complications of diabetes. However, recent observations have sparked the question whether it is time to reconsider the functional contribution of histamine in diabetes. We reveal an interesting upsurge in the field which provides scope for new insights into the role of histamine in diabetes.

It looks like there is a clear connection between histamine and diabetes, and the research supporting this connection date back to the 1950s. 

More interesting data comes from your first link, Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan, Endocrinology. 2011 Mar;152(3):828-35. doi: 10.1210/en.2010-0757. Epub 2011 Jan 14.

Abstract

Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.

The conclusion is most interesting.  I will have to ask my dr about Proxyfan.

Proxyfan is a histamine H3 receptor ligand which is a "protean agonist", producing different effects ranging from full agonist, to antagonist, to inverse agonist in different tissues, depending on the level of constitutive activity of the histamine H3 receptor. This gives it a complex activity profile in vivo which has proven useful for scientific research.

And, another interesting article, The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat. Neuropharmacology, 2005 Feb;48(2):246-51.

Abstract

Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H3 receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H3 receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H3 receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H3 receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context-footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H3 receptor agonist with a low level of constitutive activity of the H3 receptor in the rat BLA.

[Jhanananda]

It seems appropriate to examine what are histamines, to understand how they effect diabetes, and other health conditions.

Histamine
Histamine is an organic nitrogenous compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus.[3][4] Histamine is involved in the inflammatory response and has a central role as a mediator of itching.[5] As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.[6]

Properties
Histamine base, obtained as a mineral oil mull, melts at 83–84 °C.[7] Hydrochloride[8] and phosphorus[9] salts form white hygroscopic crystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, histamine exists in two tautomeric forms: Nπ-H-histamine and Nτ-H-histamine. The imidazole ring has two nitrogens. The nitrogen farthest away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign. The nitrogen closest to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The position of the nitrogen with the hydrogen on it determines how the tautomer is named. If the nitrogen with the hydrogen is in the tele position, then histamine is in the tele-tautomer form. The tele-tautomer is preferred in solution.

Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5. will not be protonated.[10] Thus, histamine is normally protonated to a singly charged cation. Histamine is a monoamine neurotransmitter.

Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.

Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling.

Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish.

Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L range; wines contain it in the 2–10 mg/L range.[11]

Storage and release
Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes) called basophils. Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.

Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.

Mechanism of action

In humans, histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H1 through H4.[12] As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.[12][13]

Roles in the body

Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.[16]

Vasodilation and a fall in blood pressure
When injected intravenously, histamine causes most blood vessels to dilate, and hence causes a fall in the blood pressure.[17] This is a key mechanism in anaphylaxis, and is thought to be caused when histamine releases nitric oxide, endothelium-derived hyperpolarizing factors and other compounds from the endothelial cells.

This may explain why I observe lower blood pressure during allergies.

Effects on nasal mucous membrane

Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:[18]

    sneezing due to histamine-associated sensory neural stimulation
    hyper-secretion from glandular tissue
    nasal congestion due to vascular engorgement associated with vasodilation and increased capillary permeability

Sleep-wake regulation

Histamine is released as a neurotransmitter. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep.[19] Classically, antihistamines (H1 histamine receptor antagonists) which cross the blood-brain barrier produce drowsiness. Newer antihistamines are designed to not cross into the brain and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the sedative effect. Similar to the effect of older antihistamines, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness.

Histaminergic neurons have a wakefulness-related firing pattern. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep.
Gastric acid release

Enterochromaffin-like cells, located within the gastric glands of the stomach, release histamine that stimulates nearby parietal cells by binding to the apical H2 receptor. Stimulation of the parietal cell induces the uptake of carbon dioxide and water from the blood, which is then converted to carbonic acid by the enzyme carbonic anhydrase. Inside the cytoplasm of the parietal cell, the carbonic acid readily dissociates into hydrogen and bicarbonate ions. The bicarbonate ions diffuse back through the basilar membrane and into the bloodstream, while the hydrogen ions are pumped into the lumen of the stomach via a K+/H+ ATPase pump. Histamine release is halted when the pH of the stomach starts to decrease. Antagonist molecules, like ranitidine, block the H2 receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.
Protective effects

While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress.[20] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[21]
Erection and sexual function

Libido loss and erectile failure can occur during treatment with histamine H2 receptor antagonists such as cimetidine, ranitidine, and risperidone.[22] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[23] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake[clarification needed] of testosterone.[22]

Schizophrenia

Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H1 receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine production, because histamine levels seem to be imbalanced in people with that disorder.[24]

I have heard of several cases of people who suffer from Schizophrenia will have their symptoms lowered by simply taking an antihistamine.

Multiple sclerosis

Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4 receptors are thought to increase permeability in the blood-brain barrier, thus increasing infiltration of unwanted cells in the central nervous system. This can cause inflammation, and MS symptom worsening. The H2 and H3 receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the body's immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead attack invaders.[25]
Disorders

As an integral part of the immune system, histamine may be involved in immune system disorders[26] and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.[27]
History

The properties of histamine, then called β-iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw.[28] By 1913 the name histamine was in use, using combining forms of histo- + amine, yielding "tissue amine".

"H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.

[Jhanananda]

Histamine H3 receptor
Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release.[5] The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.

The gene sequence for H3 receptors expresses only about 22% and 20% homology with both H1 and H2 receptors respectively.

There is a lot of interest in the histamine H3 receptor as a potential therapeutic target because of its involvement in the neuronal mechanism behind many cognitive H3R-disorders and especially its location in the central nervous system.[6][7]

Tissue distribution

    Central nervous system
    Peripheral nervous system
    Heart
    Lungs
    Gastrointestinal tract
    Endothelial cells

Function

Like all histamine receptors, the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons.[8]

The diverse expression of H3 receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.

H3 receptors are thought to play a part in the control of satiety.

This may explain why some type-2 diabetics end up with an eating disorder.

Isoforms

There are at least six H3 receptor isoforms in the human, and more than 20 discovered so far.[10] In rats there have been six H3receptor subtypes identified so far. Mice also have three reported isoforms.[11] These subtypes all have subtle difference in their pharmacology (and presumably distribution, based on studies in rats) but the exact physiological role of these isoforms is still unclear.

Pharmacology
Agonists

There are currently no therapeutic products acting as selective agonists for H3 receptors, although there are several compounds used as research tools which are reasonably selective agonists. Some examples are:

    (R)-α-methylhistamine
    Cipralisant (initially assessed as H3 antagonist, later found to be an agonist, shows functional selectivity, activating some G-protein coupled pathways but not others)[12]
    Imbutamine (also H4 agonist)
    Immepip
    Imetit
    Immethridine
    Methimepip
    Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release)

Antagonists

These include:[13]

    A-349,821[14]
    ABT-239
    Betahistine (also weak H1 agonist)
    Burimamide (also weak H2 antagonist)
    Ciproxifan
    Clobenpropit (also H4 antagonist)
    Conessine
    Failproxifan (no tolerance formation, like with Ciproxifan)
    Impentamine
    Iodophenpropit
    Irdabisant
    Pitolisant
    Thioperamide (also H4 antagonist)
    VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine)

Therapeutic potential

The H3-receptor is a promising potential therapeutical target for many (cognitive) disorders that are caused by a histaminergic H3R disfunction, because it is linked to the central nervous system and its regulation of other neurotransmitters.[6][15][16] Examples of such disorders are: sleep disorders (including narcolepsy), Tourette syndrome, Parkinson, OCD, ADHD, ASS and (drug)addictions.[6][16]

This receptor has been proposed as a target for treating sleep disorders.[17] The receptor has also been proposed as a target for treating neuropathic pain.[18]

Because of its ability to modulate other neurotransmitters, H3 receptor ligands are being investigated for the treatment of numerous neurological conditions, including obesity (because of the histamine/orexinergic system interaction), movement disorders (because of H3 receptor-modulation of dopamine and GABA in the basal ganglia), schizophrenia and ADHD (again because of dopamine modulation) and research is underway to determine whether H3 receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine).[19][7]

There is also evidence that the H3-receptor plays an important role in Tourette syndrome.[20] Mouse-models and other research demonstrated that reducing histamine concentration in the H3R causes tics, but adding histamine in the striatum decreases the symptoms.[21][22][23] The interaction between histamine (H3-receptor) and dopamine as well as other neurotransmitters is an important underlying mechanism behind the disorder.[24]
History

    1983 The H3 receptor is pharmacologically identified.[25]
    1988 H3 receptor found to mediate inhibition of serotonin release in rat brain cortex.[26]
    1997 H3 receptors shown to modulate ischemic norepinephrine release in animals.[27]
    1999 H3 receptor cloned[28]
    2000 H3 receptors called "new frontier in myocardial ischemia"[29]
    2002 H3(-/-) mice (mice that do not have this receptor)[30]

See also

    Histamine antagonist#H3-receptor antagonists

[Jhanananda]

Antihistamine
Antihistamines are drugs which treat allergic rhinitis and other allergies.[1] Antihistamines can give relief when a person has nasal congestion, sneezing, or hives because of pollen, dust mites, or animal allergy.[1] Typically people take antihistamines as an inexpensive, generic, over-the-counter drug with few side effects.[1] As an alternative to taking an antihistamine, people who suffer from allergies can instead avoid the substance which irritates them.[1] Antihistamines are usually for short-term treatment.[1] Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection.[1] Doctors recommend that people talk to them before any longer term use of antihistamines.[1]

Although typical people use the word “antihistamine” to describe drugs for treating allergies, doctors and scientists use the term to describe a class of drug that opposes the activity of histamine receptors in the body.[2] In this sense of the word, antihistamines are subclassified according to the histamine receptor that they act upon. The two largest classes of antihistamines are H1-antihistamines and H2-antihistamines. Antihistamines that target the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) as well as for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antihistamines that target the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). H1-antihistamines work by binding to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body as well as in the tuberomammillary nucleus in the brain; H2-antihistamines bind to histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach.

Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptor.[3][2][4][5] Only a few currently marketed H1-antihistamines are known to function as inverse agonists.[2][5]

Medical uses

Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction — a runny nose and watery eyes. Histamine also promotes angiogenesis.[6]

Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells.

Itching, sneezing, and inflammatory responses are suppressed by antihistamines that act on H1-receptors.[2][7] In 2014 antihistamines such as desloratadine were found to be effective as adjuvants to standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production.[8][9]
Types
H1-antihistamines
Main article: H1-antihistamine

H1-antihistamines refer to compounds that inhibit the activity of the H1 receptor.[4][5] Since the H1 receptor exhibits constitutive activity, H1-antihistamines can be either neutral receptor antagonists or inverse agonists.[4][5] Normally, histamine binds to the H1 receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison, the inverse agonists bind to the receptor and reduce its activity, an effect which is opposite to histamine's.[4]

The vast majority of marketed H1-antihistamines are receptor antagonists and only a minority of marketed compounds are inverse agonists at the receptor.[2][5] Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross the blood–brain barrier; some of these drugs, such as diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-antihistamines can also reduce inflammation, since the expression of NF-κB, the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine) binding at the H1 receptor.[2]

Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating. However, high doses can still induce drowsiness through acting on the central nervous system. Some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as bupropion and benzodiazepines.[10]
H1 antagonists

Examples of H1 antagonists include:

    Acrivastine (see Benadryl entry in this section)
    Azelastine
    Benadryl is a brand name for different H1 antagonist anitihistamine preparations in different regions: acrivastine is the active component of Benadryl Allergy Relief and cetirizine of Benadryl One a Day Relief in the UK; Benadryl is diphenhydramine in the US and Canada.(see http://www.benadryl.ca/adult-allergy-medicine/benadryl-caplets)
    Bilastine
    Bromodiphenhydramine
    Brompheniramine
    Buclizine
    Carbinoxamine
    Cetirizine (Zyrtec)
    Chlorodiphenhydramine
    Chlorphenamine
    Clemastine
    Cyclizine
    Cyproheptadine
    Dexbrompheniramine
    Dexchlorpheniramine
    Dimenhydrinate (most commonly used as an antiemetic)
    Dimetindene
    Diphenhydramine (see Benadryl entry in this section)
    Doxylamine (most commonly used as an over-the-counter drug sedative)
    Ebastine
    Embramine
    Fexofenadine (Allegra)
    Hydroxyzine (Vistaril)
    Loratadine (Claritin)
    Meclizine (most commonly used as an antiemetic)
    Mirtazapine (primarily used to treat depression, also has antiemetic and appetite-stimulating effects)
    Olopatadine (used locally)
    Orphenadrine (a close relative of diphenhydramine used mainly as a skeletal muscle relaxant and anti-Parkinsons agent)
    Phenindamine
    Pheniramine
    Phenyltoloxamine
    Promethazine
    Quetiapine (antipsychotic; trade name Seroquel)
    Rupatadine (Alergoliber)
    Tripelennamine
    Triprolidine

H1 inverse agonists

The H1 receptor inverse agonists include:[2][5]

    Cetirizine (does not cross the blood–brain barrier)
        Levocetirizine
    Desloratadine (does not cross the blood–brain barrier)
    Pyrilamine (crosses the blood–brain barrier; produces drowsiness)

H2-antihistamines
Main article: H2-antihistamine

H2-antihistamines, like H1-antihistamines, occur as inverse agonists and neutral antagonists. They act on H2 histamine receptors found mainly in the parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H2 to stimulate acid secretion; drugs that inhibit H2 signaling thus reduce the secretion of gastric acid.

H2-antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease. Some formulations are available over the counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses.

Examples include:

    Cimetidine
    Famotidine
    Lafutidine
    Nizatidine
    Ranitidine
    Roxatidine
    Tiotidine

Research

These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H3-antihistamines have a stimulant and nootropic effect, whereas H4-antihistamines appear to have an immunomodulatory role.
H3-antihistamines
Main article: H3-antihistamine

An H3-antihistamine is a classification of drugs used to inhibit the action of histamine at the H3 receptor. H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3-antihistamines have stimulant and cognition-modulating effects.

Examples of selective H3-antihistamines include:

    Clobenpropit,[11]
    ABT-239[12]
    Ciproxifan,[13]
    Conessine
    A-349,821.[14]
    Thioperamide

H4-antihistamines

Examples:

    Thioperamide
    JNJ 7777120
    VUF-6002

Related agents
Histidine decarboxylase inhibitors

Inhibit the action of histidine decarboxylase:

    Tritoqualine
    Catechin

Mast cell stabilizers
Main article: Mast cell stabilizer

Mast cell stabilizers are drugs which prevent mast cell degranulation.

    cromolyn sodium
    Nedocromil
    β-agonists

History

Currently most people who use an antihistamine to treat allergies use a second generation drug.[1]

The first generation of antihistamine drugs became available in the 1930s.[15] This marked the beginning of medical treatment of nasal allergies.[15] Research into these drugs led to the discovery that they were H1 antagonists and also to the development of H2 antagonists, where H1 antihistamines affected the nose and the H2 antihistamines affected the stomach.[16] This history has led to contemporary research into drugs which are H3 receptor antagonist and which affect the Histamine H4 receptor.[16]
Society and culture

Antihistamines can vary greatly in cost.[1] Some patients consult with their doctor about drug prices to make a decision about which antihistamine to choose.[1] Many antihistamines are older and available in generic form.[1] Others are newer, still under patent, and generally expensive.[1] The newer drugs are not necessarily safer or more effective.[1] Because so many antihistamines are available, patients can have conversations with their health care provider to choose the right drug for them.[1]

The United States government removed two second generation antihistamines, terfenadine and astemizole, from the market based on evidence that they could cause heart problems.[1]
Research

Not much published research exists which compares the efficacy and safety of the various antihistamines available.[1] The research which does exist are mostly short term studies or studies which look at too few people to make general assumptions.[1] Another gap in the research is in information reporting the health effects for individuals with long term allergies to take antihistamines for a long period of time.[1] Newer antihistamines have been demonstrated to be effective in treating hives.[1] However, there is not research comparing the relative efficacy of these drugs.[1]
Special populations

Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood.[1] Older people are more likely to experience drowsiness from antihistamine use than younger people.[1] Also, most of the research has been on white people and other ethnicities are not as represented in the research.[1] The evidence does not report how antihistamines affect women differently than men.[1] Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children.[1]

[Jhanananda]

H3 receptor antagonist

An H3 receptor antagonist is a classification of drugs used to block the action of histamine at the H3 receptor.

Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.

Examples of selective H3 antagonists include clobenpropit,[1] ABT-239,[2] ciproxifan,[3] conessine, A-349,821,[4] and pitolisant.[5]

History

The histamine H3 receptor (H3R) was discovered in 1983 and was one of the last receptors that were discovered using conventional pharmacological methods.[6] Its structure was discovered later as a part of an effort to identify a commonly expressed G-protein-coupled receptor (GPCR) in the central nervous system (CNS).[7] The pharmacology of H3R is very complicated which has made drug development difficult. Many different functional isoforms of the H3R exist which means it could theoretically be possible to target a single isoform specifically. That may, however, be difficult due to genetic variability of the isoforms as well as differing functionality of each one.[8]

H3R ligands have now been classified as agonists, antagonists or inverse agonists, depending on the signaling assay used.[9][10]
Mechanism of Action

The H3R is a GPCR and it has been described as a presynaptic autoreceptor, regulating the release of histamine and also as a heteroreceptor, regulating neurotransmitters such as acetylcholine, dopamine, serotonin, norepinephrine and GABA.[11] The receptor has a high constitutive activity which means that it can signal without being activated by an agonist.[10] H3R regulates the release of neurotransmitters by influencing the amount of intracellular calcium. When activated, it blocks the influx of calcium which leads to inhibition of the release of neurotransmitters.[7] Antagonists of the receptors cause synthesis and release of these neurotransmitters which promotes waking.[12] H3Rs are mostly expressed on the histaminergic neurons of the CNS but can also be found in various areas of the peripheral nervous system.[10] The H3R has been found in high densities in the basal ganglia, hippocampus and cortical areas which are all regions of the brain associated with cognition.[11] The histaminergic system has been described as having a role in the pathophysiology of cognitive symptoms of diseases such as Alzheimer’s, schizophrenia and narcolepsy.[7]
Development
Early Pharmacophore

In the beginning of development for H3R ligands the focus was on the agonist histamine which contains an imidazole ring in its structure. The structural diversity among H3R is limited and all known H3R agonists today contain an imidazole ring.[10][9] The problem with the imidazole containing compounds was the inhibition of cytochrome P450 isoenzymes which resulted in severe drug interactions.[11][10] They also had difficulty in crossing the blood-brain-barrier. Many compounds were tested but they were too toxic to be useful.[6]

Off target function on H4R and other receptors was also a problem with imidazole-based antagonists. The wide variety of potential pathophysiology of H3R in brain disorders makes H3R antagonists interesting for drug development.[7]
Thioperamide

The first imidazole-based antagonist that was developed was thioperamide which was very potent and selective but was not useable as a drug due to hepatotoxicity. It was originally designed to improve wakefulness and cognition deficit.[6] A recent study showed potential thioperamide treatment of the circadian rhythm of patients with parkinson’s disease.[13]

New Pharmacophore

The focus turned to non-imidazole H3R antagonists.They do not seem to interact with the CYP family on the same level as imidazole-based H3R antagonists and can reach the CNS more easily. Unfortunately other problems have come up such as strong binding to hERG K+ channel, phospholipidosis as well as problems with P-gp substrate. Strong binding to hERG K+ channel can lead to QT prolongation.[11]
Pitolisant

Pitolisant was the first antagonist /inverse agonist to proceed to clinical trials and is the only drug that has been approved by regulatory authorities in the US and Europe. It is highly selective for the H3 receptor. Pitolisant has high oral bioavailability and easily accesses the brain. It undergoes extensive first-pass effects through the CYP4A4 enzyme in the gut. The whole metabolic pathway has not yet been established but involves a few CYP enzymes[14]. It has been proved to be useful for maintaining waking-state in the daytime for people with narcolepsy.[6] Side effects encountered in clinical trials were found to be dose-dependent. As expected, some of the adverse effects were neuropsychiatric in character most common of which were insomnia, headache and anxiety. Pitolisant can also potentially cause a prolonged QT interval so caution is advised in cardiac patients. Keeping doses as low as possible can minimize risk for adverse events.[14]

It can be found under the tradename Wakix and is considered an orphan drug. It was approved by the European Commission on 31 March 2016. It is available in 4.5 mg and 18 mg tablets.[15]

Structure Activity Relationship

A general structural pattern that is necessary for the antagonist affinity for H3R has been described. An H3R antagonist needs to have a basic amine group which is linked to an aromatic/lipophilic region that is connected to either a polar group or another basic group or a lipophilic region.[7]

Clinical Significance

H3R antagonists/inverse agonists demonstrate a possible way to treat diseases of the CNS for example Alzheimer's disease (AD), attention deficit hyperactivity syndrome (ADHD) , schizophrenia (SCH), pain, and narcolepsy.[16]
Narcolepsy

Narcolepsy is a sleeping disorder which is characterised by chronic sleepiness. Cataplexy, hypnagogic hallucinations and sleep paralysis can also be present in narcolepsy.[17] H3R antagonism leads to histamine release into the cerebrospinal fluid which promotes wakefulness. Therefore H3R antagonists have been studied in the hope of treating narcolepsy. Pitosilant has been approved for treatment of narcolepsy[7] and other H3R antagonists are in clinical trials.[8]
Alzheimer's disease (AD)

Alzheimer’s disease is a progressive neurodegenerative disease of the brain. Histamine plays a well documented role in AD, however the varying levels of histamine in different areas of the brain make it hard to demonstrate a direct link between histaminergic neurotransmission and AD pathology.[16] In vivo studies have shown that a number of H3R antagonists facilitate learning and memory.[7] Thioperamide blocks H3R and causes an increase in neuronal histamine release which then modifies cognition processes through H1R and H2R and other receptors (e.g. cholinergic and GABA). Degeneration of histaminergic neurons in AD doesn’t correlate to H3R expressions since a large portion of H3R in the brain are located elsewhere deep in cortical and thalamocortical neurons among others.[16]
Attention deficit hyperactivity disorder (ADHD)

ADHD is a neurodevelopmental disorder which is most pronounced in children. Current pharmacological treatments consist of stimulant medications (e.g. methylphenidate), non-stimulant medication (e.g. atomoxetin) and α2 agonists. These medications have a great deal of adverse effects as well as being potentially addictive. Developing alternative treatments is therefore desirable. In vivo studies show potential of using H3R antagonists in ADHD to aid in attention and cognitive activity by elevating release of neurotransmitters such as acetylcholine and dopamine.[16]
Schizophrenia (SCH)

SCH is a serious neurological syndrome which is characterised by shifting of thinking, behavior and emotion. Disruption of dopamine and other neurotransmitter systems plays a significant role in the development of the disease.[7][16] Current treatments are based on first and second generation antipsychotics which are dopamine antagonists. These drugs have many undesirable side-effects. Histaminergic neurons seem to play a role in schizophrenia and H3R are co-localized with dopamine receptors in GABAergic neurons. Even if H3R antagonist don’t seem to be effective against positive symptoms of SCH studies have shown that H3R antagonists may be useful in treating negative and cognitive symptoms of schizophrenia as an adjunct.[7]

ABT-239
ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia.[1][2][3][4] ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation,[5] but is still widely used in animal research into H3 antagonists / inverse agonists.

Clobenpropit
Clobenpropit is a histamine H3 receptor antagonist.[1] It has neuroprotective effects via stimulation of GABA release in the brain.[2]

Ciproxifan
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.

The histamine H3 receptor is an inhibitory autoreceptor located on histaminergic nerve terminals, and is believed to be involved in modulating the release of histamine in the brain. Histamine has an excitatory effect in the brain via H1 receptors in the cerebral cortex, and so drugs such as ciproxifan which block the H3 receptor and consequently allow more histamine to be released have an alertness-promoting effect.[1][2][3]

Ciproxifan produces wakefulness and attentiveness in animal studies, and produced cognitive enhancing effects without prominent stimulant effects at relatively low levels of receptor occupancy, and pronounced wakefulness at higher doses.[4] It has therefore been proposed as a potential treatment for sleep disorders such as narcolepsy and to improve vigilance in old age, particularly in the treatment of conditions such as Alzheimer's disease.[5][6] It also potentiated the effects of antipsychotic drugs, and has been suggested as an adjuvant treatment for schizophrenia.[7]

Conessine
Conessine is a steroid alkaloid found in a number of plant species from the Apocynaceae family, including Holarrhena floribunda,[1] Holarrhena antidysenterica[2] and Funtumia elastica.[3] It acts as a histamine antagonist, selective for the H3 subtype (with an affinity of pKi = 8.27; Ki = ~5 nM).[4] It was also found to have long CNS clearance times, high blood-brain barrier penetration and high affinity for the adrenergic receptors.[5]

A-349,821
A-349,821 is a potent and selective histamine H3 receptor antagonist[1] (or possibly an inverse agonist).[2] It has nootropic effects in animal studies,[3] although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research.

Pitolisant
Pitolisant (INN), also known as tiprolisant (USAN), and sold under the brand name Wakix, is a potent and selective inverse agonist of the histamine H3 receptor (Ki = 0.16 nM) which was approved for the treatment of narcolepsy in 2016.[1][2][3][4] It is also currently in phase III clinical trials for the treatment of hypersomnia.[1]

Pitolisant was developed by Jean-Charles Schwartz, Walter Schunack, and colleagues after the former discovered the H3 receptor.[5] It was the first H3 receptor inverse agonist to be tested in humans or introduced for clinical use.[5]

[Jhanananda]

Regular Mouthwash Use Linked to Prediabetes and Diabetes

research now links regular mouthwash use to an increased risk of diabetes.

New research published in the medical journal Nitric Oxide found that regular mouthwash use destroys beneficial bacteria in the mouth that are needed for our health, which may increase our diabetes risk.

[Jhanananda]

Apocynaceae

Apocynaceae is a family of flowering plants that includes trees, shrubs, herbs, stem succulents, and vines, commonly called the dogbane family,[1] after the American plant known as dogbane, Apocynum cannabinum.[2] Members of the family are native to European, Asian, African, Australian, and American tropics or subtropics, with some temperate members.[1] The family Asclepiadaceae (now known as Asclepiadoideae) is considered a subfamily of Apocynaceae and contains 348 genera.

Many species are tall trees found in tropical rainforests, but some grow in tropical dry (xeric) environments. Also perennial herbs from temperate zones occur. Many of these plants have milky latex, and many species are poisonous if ingested. Some genera of Apocynaceae, such as Adenium, have milky latex apart from their sap, and others, such as Pachypodium, have clear sap and no latex.

Description
The dogbane family includes annual plants, perrenial herbs, stem succulents, woody shrubs, trees, or vines.[1][3] Most[citation needed] exude a milky sap with latex[citation needed], if injured.
Leaves and stems

Leaves are (simple). Leaves may appear one at a time (singly) with each occurrence on alternating sides of the stem (alternate),[3] but usually[citation needed] occur in pairs or in whorls. When paired, they occur on opposite sides of the stem (opposite), with each pair occurring at an angle rotated 90° to the pair below it (decussate).

There is no stipule (a small leaf-like structure at the base of the leaf stem), or stipules are small and sometimes fingerlike.[3]
Inflorescence and fruit

Flowers are usually showy,[citation needed] have radial symmetry (actinomorphic), and are born in head that are cymes or racemes, but can rarely be fasciculate or solitary. They are perfect (bisexual), with a synsepalous, five-lobed calyx united into a tube at the base. Inflorescences are terminal or axillary. Five petals are united into a tube with four or five epipetalous stamens. The style is expanded at the apex into a massive clavuncle just below the stigma. The ovary is usually superior, bicarpellary, and apocarpous, with a common fused style and stigma.

The fruit is a drupe, a berry, a capsule, or a follicle.

Toxicity

All plant-derived (i.e., phytochemical) natural products have some inherent toxicity on ingestion, and many are very toxic, even lethal. This is true of many contained in species of plants from the Apocynaceae family, which include several that are extremely poisonous if parts are ingested, or if they are not handled properly. Members containing cardiac glycosides—genera Acokanthera, Apocynum, Cerbera, Nerium, Thevetia, Strophanthus, etc.[citation needed]—have therapeutic ranges, but often are associated with accidental poisonings, in many cases lethal (see below). Alkaloid-producing species like Rauvolfia, Catharanthus, and Tabernathe are likewise the source of compounds with possible therapeutic ranges, but which have significant associated toxicities if not taken in appropriate doses and in controlled fashion.[citation needed]

Uses
Several plants of the Apocynaceae family members have had economic uses in the past. Several are sources of important natural products—pharmacologic tool compounds and drug research candidates, and in some cases actual prescription drugs.[citation needed] Cardiac glycosides, which affect heart function, are a ready example.[citation needed] Members studied and known to have such glycosides include the Acokanthera, Apocynum, Cerbera, Nerium, Thevetia and Strophanthus.[citation needed] Rauvolfia serpentina (Indian snakeroot) synthesizes the alkaloids reserpine and rescinnamine, which are of interest in studies of the treatment of high blood pressure,[citation needed] as well as some forms of psychosis.[citation needed] Catharanthus roseus yields alkaloids studied with regard to the treatment of cancer.[citation needed] Certain species of the genus Tabernanthe, most notably Tabernanthe Iboga contain tryptamine alkaloids such as ibogaine in the roots.[citation needed]

Several genera are grown as ornamental plants, including Amsonia (bluestar), Nerium (oleander), Vinca (periwinkle), Carissa (Natal plum), Allamanda (golden trumpet), Plumeria (frangipani), Thevetia (lucky nut), Mandevilla (Savannah flower), and Adenium (desert-rose).[citation needed]

In addition, the genera Landolphia, Hancornia, Funtumia and Mascarenhasia were used as a commercial source of inferior rubber (see Congo rubber, made mostly from various Landolphia species harvested in the wild).[citation needed]

There may be reports of limited dietary uses of plants from this family,[clarification needed]—see however the section on toxicity above. The edible flower of Fernaldia pandurata (common name: loroco) is a popular part of El Salvadorian and Guatemalan cooking.[citation needed] Carissa (Natal plum) produces an edible fruit.[citation needed] The genus Apocynum was reportedly used as a source of fiber by Native Americans.[citation needed] The aromatic fruit juice from Saba comorensis (syn. Landolphia comorensis, the Bungo or Mbungo fruit) is a popular drink,[verification needed][citation needed] on Pemba Island and other parts of coastal Tanzania.[8]

Finally, ethnopharmacologic and ethnotoxicologic uses are also known. Ibogaine-type alkaloids from the roots of genus Tabernathe have been used in traditional African tribal ceremonies as a source of hallucinogens,[citation needed] and have been studied with regard to the treatment of drug addiction.[citation needed] The juice of Acokanthera species such as A. venenata and the milky juice of the Namibian Pachypodium have reportedly been used as venom for arrow tips by the San people,[citation needed] though others have reported that Pachypodium do not produce such milk.[9]