Adverse Health Effects Of Recreational Cannabis Use

Background: Cannabis plants produce a unique family of terpeno-phenolic compounds called cannabinoids, which produce the "high" one experiences from consuming marijuana. Cannabis is usually smoked in a ‘joint’ or with a water pipe (sometimes with tobacco added) because smoking is the most efficient way to achieve the desired psychoactive effects.

Two Major Constituents of Cannabis. THC is psychoactive.

A quick summary for all:

1. There are 483 identifiable chemical constituents known to exist in the cannabis plant, and at least 85 different cannabinoids have been isolated from the plant.

2. The two cannabinoids usually produced in greatest abundance are cannabidiol (CBD) and/or delta-9-tetrahydrocannabinol (THC), but only THC is psychoactive or gives “high”.

3. Since the early 1970s, Cannabis plants have been categorized by their chemical phenotype or "chemotype", based on the overall amount of THC produced, and on the ratio of THC to CBD. Although overall cannabinoid production is influenced by environmental factors, the THC/CBD ratio is genetically determined and remains fixed throughout the life of a plant.

4. Non-drug plants produce relatively low levels of THC and high levels of CBD, while drug plants produce high levels of THC and low levels of CBD. When plants of these two chemotypes cross-pollinate, the plants in the first filial (F1) generation have an intermediate chemotype and produce similar amounts of CBD and THC. Female plants of this chemotype may produce enough THC to be utilized for drug production.

Recreational Use:

Cannabis is used for a wide variety of purposes including recreational use, medical use and as hemp fibre. Many human culture including Chinese, Indian and Greek, etc., have records of cannabis use in various social and religious activities. Cannabis is a popular recreational drug around the world, only behind alcohol, caffeine and tobacco, and it is also available as baked product and as a tea!!!

Summary: The article reports analysis of various “side-effects” that have been associated with ‘heavy’ or ‘regular’ cannabis, which for the study purpose is defined as daily or near-daily use. Starting from year 1993 till year 2013, a comparison of the evidence in 1993 with the evidence and interpretation of the same health outcomes in 2013 is attempted. Various fallouts including health, social behaviors, education, etc. are evaluated for regular user vis-à-vis a non-regular/non-user.

Results: The key conclusions are:

Adverse Effects of Acute Cannabis Use

1. Cannabis does not produce fatal overdoses.

2. Driving while cannabis-intoxicated doubles the risk of a car crash; this risk increases substantially if users are also alcohol-intoxicated.

3. Cannabis use during pregnancy slightly reduces birth weight of the baby.

Adverse Effects of Chronic Cannabis Use

1. Regular cannabis users can develop a dependence syndrome, the risks of which are around 1 in 10 of all cannabis users and 1 in 6 among those who start in adolescence.

2. Regular cannabis users double their risks of experiencing psychotic symptoms and disorders, especially if they have a personal or family history of psychotic disorders, and if they start using cannabis in their mid-teens.

3. Regular adolescent cannabis users have lower educational attainment than non-using peers but researchers don't know whether the link is causal.

4. Regular adolescent cannabis users are more likely to use other illicit drugs, but researchers don't know whether the link is causal.

5. Regular cannabis use that begins in adolescence and continues throughout young adulthood appears to produce intellectual impairment, but the mechanism and reversibility of the impairment is unclear.

6. Regular cannabis use in adolescence approximately doubles the risk of being diagnosed with schizophrenia or reporting psychotic symptoms in adulthood.

7. Regular cannabis smokers have a higher risk of developing chronic bronchitis.

8. Cannabis smoking by middle aged adults probably increases the risk of myocardial infarction.

Article Citation: Hall, W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction 2015, 110(1), 19-35. (free copy)

Cannabis Addicts Have Reduced Dopamine Release in Brain

Summary: Various reported studies have shown that addiction to drugs of abuse such as cocaine and heroin, have serious effects on dopamine release in human brain, but such evidence for cannabis was missing until now. A latest publication in the journal Molecular Psychiatry provides evidence of a compromised dopamine system in heavy users of marijuana. Lower dopamine release was found in the striatum - a region of the brain that is involved in working memory, impulsive behavior, and attention.

Whether Dark or Light: It Doesnt Make You BRIGHT!!!!!!!

Study: The study was carried involving 11 adults between the ages of 21 and 40 who were severely dependent on cannabis (CD) and 12 matched healthy controls (HC). On average, the cannabis group started using at age 16, became dependent on cannabis by age 20, and have been dependent for the past 7 years. In the month prior to the study, nearly all users in this study smoked marijuana daily. Moreover, during the study period the heavy marijuana users stayed in the hospital for a week, during which they abstained from using it. This was to ensure that the experiments (scans) were not measuring the drug's effects.

Experimental Details: The researchers used positron emission tomography (PET) scans to track a radio-tracing molecule that binds to the brain's dopamine receptors. In scientific terminology, 11 CD and 12 HC completed two positron emission tomography scans with [¹¹C]-(+)-PHNO, before and after oral administration of d-amphetamine. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [¹¹C]-(+)-PHNO-binding potential (delta-BP_ND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined.

From this, they were able to measure the release of dopamine in the striatum, which is a brain region involved in memory, impulsive behavior and attention. Additionally, the team was able to track dopamine release in other brain regions, including the thalamus, midbrain and globus pallidus.

Participants were scanned before and after being given oral amphetamine to elicit dopamine release. The percent change in the binding of the radiotracer was taken as an indicator of capacity for dopamine release.

Results: Compared with the controls, the cannabis users had significantly lower dopamine release in the striatum, including subregions involved in associative and sensorimotor learning, and in the globus pallidus.

On further investigating the link between dopamine release in the striatum and cognitive performance on learning and working memory tasks, the researchers did not observe a difference in performance between the two groups. However, they do note that among all participants, those who had lower dopamine release performed worse on both tasks.

Conclusions: The researchers conclude their study by noting that the lower dopamine release is linked with inattention and negative symptoms in marijuana users, and with "poorer working memory and probabilistic category learning performance" in both groups. 

Article citation: Abi-Dargham, A.; et. al. Deficits in striatal dopamine release in cannabis dependence. Molecular Psychiatry 2016 | doi:10.1038/mp.2016.21

How Blood Group O Protects Against Malaria

It was the pioneer work by Oliver Gonzalez (1944) where it was postulated that plasmodia possess antigens equivalent to the blood-group antigens A and B of man. The work referred showed that the anti-A titre of Group O subjects, who had often had attacks of Plasmodium vivax and Plasmodium falciparum malaria, was far greater than in control Group O subjects; and also that the anti-B titre of the infected subjects was raised, though not to the same extent as for anti-A [1]. His theory was not totally accepted nor was it denied [2]. Since, that time till early 2000, the same dilemma persisted, whether to accept this theory or totally reject it.

Though it was well documented that people with blood type O are protected against severe malaria [3], while those with other types, such as A, often fall into a coma and die. Then there were reports that suggest otherwise, such as where blood group A, B and O were equally susceptible to malaria infection, AB blood group had less number of persons with malaria parasites. A significantly lower frequency of Plasmodium falciparum was observed among individuals with blood groups A and O. In other two blood groups B and AB, no difference in P. vivax and P. falciparum proportions were observed. A two-year study showed that the frequency of repeated attacks between all blood groups was similar [4].

Understanding the mechanisms behind this has been one of the main goals of malaria research. Although it has been known for two decades that human red cell ABO blood group affects the ability of malaria parasites to form rosettes [5], the precise details of the interaction remained obscure. Rosettes are clusters of infected red blood cells binding to uninfected red blood cells. 

Rosetting is characterized by the binding of P. falciparum-infected red blood cells (RBCs) to uninfected RBCs to form clusters of cells that are thought to contribute to the pathology of falciparum malaria by obstructing blood flow in small blood vessels.

Many previous work had shown that rosetting parasites form larger, stronger rosettes in non-O blood groups (A, B or AB) than in group O RBCs. Furthermore, the percentage of infected RBCs forming rosettes is significantly lower in fresh clinical isolates derived from group O than in non-O patients. It appears that this is because the A and B antigens are receptors for rosetting on uninfected RBCs, being bound by a parasite protein called PfEMP1 which is expressed on the surface of infected RBCs. Rosettes still form in group O RBCs (albeit smaller and weaker than in non-O RBC) through the involvement of other RBC molecules which act as alternative receptors for rosetting. Thus, it was reasoned that if rosetting contributes directly to the pathogenesis of severe malaria and is reduced in blood group O RBCs, then group O individuals should be protected against life-threatening malaria [6].

The life-saving effect of group O is thought to occur due to the impaired ability of Plasmodium falciparum parasites to form rosettes in group O blood. Rosetting occurs due to specific members of the P. falciparum Erythrocyte Membrane Protein one (PfEMP1) family of variant antigens, on the surface of infected red cells, binding to receptors, including the A and B blood group trisaccharides, on uninfected red cells. Rosetting contributes to microvascular obstruction in severe malaria, leading to hypoxia, acidosis, organ dysfunction and death [7].

In 2012, Vigan-Womas et. al. provided an insight to the mechanism explaining how rosetting malaria parasites bind to the blood group A sugars. The team used a comination of in vitro functional studies, insights from crystallography and computational docking studies to examine the binding site for interaction between the malaria parasite rosetting ligand, PfEMP1 and the group A-trisaccharide (GalNAc-α1,3(Fuc-α1,2)Gal). They expressed the extracellular domains from a rosette-mediating PfEMP1 variant (Palo Alto VarO) as recombinant proteins, and found that the N-terminal head-structure region (known as NTS-DBLα-CIDR), bound the group A-trisaccharide. Furthermore, they crystallized the PfEMP1 N-terminal region to analyze its structure, and used computer docking to identify potential binding sites for the A-trisaccharide [8].

The salient findings were:

1. VarO rosetting shares with other rosetting lines three generic characteristics, namely an extreme sensitivity to sulphated glycosaminoglycans, the need for human serum and a marked ABO blood group preference characterised by reduced binding to group O RBCs. 

2. The experimental data indicate that the major determinant affecting VarO rosetting efficiency is indeed the ABO blood group. 

3. On exploring VarO-infected RBCs (iRBCs) binding characteristics using a monovariant culture of the Palo Alto 89F5 clone, in which greater than 90% of the iRBCs were positively selected to express PfEMP1-VarO, it was observed that VarO-iRBCs preferentially bind to blood group A compared to blood group B, which itself is preferred to blood group O.

4. More detailed RBC subgroup analysis showed preferred binding to group A1, weaker binding to groups A2 and B, and least binding to groups Ax and O.

Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα1. The authors hypothesized that RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins. This opens novel opportunities for intervention against severe malaria.

In 2015, another aspect was explored to this ever expanding mechanism, the RIFINs [9]. Their presence has been reported as members of rif (repetitive interspersed family), clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Their high copy number, sequence variability, and red cell surface location indicated an important role for RIFINs in malaria host–parasite interaction but the mechanism was still missing [10]. The researchers now have attempted the same.

Though sequestration and rosetting in individuals with severe Plasmodium falciparum malaria has been attributed to P. falciparum erythrocyte membrane protein 1 (PfEMP1) still few questions remained:

a: Antibodies to PfEMP1 disrupt rosettes of parasites grown only in blood group O RBCs, not group A RBCs. 

b: The majority of P. falciparum strains and fresh clinical isolates prefer group A RBCs for rosetting. 

Researchers found that enzymatic removal of PfEMP1 from the iRBC surface reduced rosetting in blood group O but not blood group A, indicating that PfEMP1 may not be the only molecule responsible for RBC binding and rosette formation. A second family of antigens found at the iRBC surface is RIFINs. These polypeptides are encoded by 150 rif genes and comprise the largest family of antigenically variable molecules in P. falciparum. Given that the function of RIFINs is unknown and that they are resistant to enzyme degradation and upregulated in rosetting parasites, researchers speculated that RIFINs contribute to the rosetting and sequestration of P. falciparum mediated by blood group A antigen.

To study the function of the RIFINs, researchers investigated primary structures of RIFINs and found that the majority (~70%) belong to subgroup A (A-RIFIN) and possess an insertion of 25 amino acids at the N terminus (indel) that the B-RIFINs lack. Researchers analyzed the ability of rif gene–transfected CHO cells to bind RBCs. A-RIFIN CHO cells bound large numbers of group A RBCs (up to ~25 RBCs per CHO cell), whereas the binding of group O RBCs was less pronounced and similar to that of CHO cells expressing the N-terminal domain of PfEMP1 (DBL1α). This suggests that the group A antigen is a major receptor for A-RIFINs. RBC binding was negligible with B-RIFIN CHO cells or CHO cells expressing PfEMP1 (DBL1α of PfEMP1-FCR3S1.2var1) (control) [10]. Moreover, group A1 RBCs bound significantly better than group A2 RBCs. The researchers through various models examplified the role of RIFINs in microvascular binding of P. falciparum iRBCs. Their results hint that RIFINs may contribute to the varying global distribution of ABO blood groups in favor of blood group O.

References:

1. Oliver-Gonzalez, J.; et. al. A substance in animal parasites related to the human isoagglutinogens. J Infect Dis 1944, 74, 173-177.

2. Raper, A. B. ABO blood groups and malaria. 1967.

3. Gupta, M.; et. al. Relationship between ABO blood groups and malaria. Bull World Health Organ 1980, 58(6), 913-915.

4. Singh, N.; et. al. ABO blood groups among malaria cases from district Mandla, Madhya Pradesh. Indian J Malariol 1995, 32(2), 59-63.
5. Carlson, J.; et. al. Plasmodium falciparum erythrocyte rosetting is mediated by promiscuous lectin-like interactions. J Exp Med 1992, 176(5), 1311-1317.
6. Rowe, J. A.; et. al. Blood groups and malaria: fresh insights into pathogenesis and identification of targets for intervention. Curr Opin Hematol 2009, 16(6), 480-487.
7. Alexandra, R. J. Revealing the secrets of malaria parasite interaction with blood group A sugars. Pathog Glob Health 2013, 107(2), 45.
8. Vigan-Womas, I.; et. al. Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting. PLoS Pathog 2012, 8(7), e1002781.
9. Wahlgren, M.; et. al. RIFINs are adhesins implicated in severe Plasmodium falciparum malaria. Nat Med 2015, 21(4), 314-317.
10. Kyes, S. A.; et. al. Rifins: A second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Proc Natl Acad Sci U S A 1999, 96(16), 9333-9338.

"Oliver like Einstein knew something, that we still dont"

Malignant Melanoma Metastasize Faster with Antioxidants

Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing cells known as melanocytes. Melanomas typically occur in the skin but may rarely occur in the mouth, intestines, or eye. Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet (UV) light from the sun. Genetics also play a role. About 20-25% develop from moles where a history of affected family members, or ones with poor immune function are at greater risk.

Melanoma is the most dangerous type of skin cancer. Treatment is typically removal by surgery. In those with slightly larger cancers nearby lymph nodes may be tested for spread. Most people are cured if spread has not occurred. In those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. The likelihood that it will come back or spread depends how thick the melanoma is, how fast the cells are dividing, and whether or not the overlying skin has broken down.

Researchers at Sahlgrenska Academy, University of Gothenburg, demonstrated in January 2014 that antioxidants hastened and aggravated the progression of lung cancer. Mice that were given antioxidants developed additional and more aggressive tumors. Experiments on human lung cancer cells confirmed the results. The group now report that antioxidants in mice double the rate of metastasis in malignant melanoma. Mice that were given antioxidants developed additional and more aggressive tumors. One of the fastest expanding types of cancer in the developed world, malignant melanoma has a high mortality rate - which is one reason that researchers at Sahlgrenska Academy were so anxious to follow up on the lung cancer studies.

Their findings reveal the following:

a: As opposed to the lung cancer studies, the primary melanoma tumor was not affected.

b: Antioxidant boosted the ability of the tumor cells to metastasize.

c: Metastasis is the cause of death in the case of melanoma.

d: The primary tumor is not dangerous per se and is usually removed.

Free radicals are believed to cause cancer, and there is large volume of literature to support this theory. So it was simply assumed that antioxidants, which destroy free radicals, provide protection against the disease. Found in many nutritional supplements, antioxidants are widely marketed as a means of preventing cancer. The researchers from University of Gothenburg have added a condition apply logo to use of antioxidant which now says “antioxidants protect healthy cells from free radicals that can turn them into malignancies but may also protect a tumor once it has developed”. Moreover, experiments on cell cultures from patients with malignant melanoma confirmed the new results.

The authors conclude “Our current research combined with information from large clinical trials with antioxidants suggests that people who have been recently diagnosed with cancer should avoid such supplements.”

The next task for this group is study the roles of lotions in melanoma progression as skin and suntan lotions sometimes contain beta carotene or vitamin E, both of which could potentially affect malignant melanoma cells in the same way as antioxidants in nutritional supplements.

Article Citation: Bergo, M. O.; et. al. Antioxidants can increase melanoma metastasis in mice. Science Translational Medicine 2015, 7(308), 308re8. DOI: 10.1126/scitranslmed.aad3740

Caripill: A Pill with Papaya Leaf Extract to Fight Dengue

Micro Labs (Bengluru, India), a fully integrated generic manufacturing pharma company recently launched Caripill, which helps to increase the platelet count in patients suffering from dengue.  Approved by the scientific and regulatory authority, the pill is made from Carica Papaya leaf extract and reportedly does not have any side-effects.

Caripill: Papaya Leaf Extract in a Pill

What is Dengue?

Dengue is an acute viral infection with potential fatal complications. Dengue viruses (DV or DENV) belong to family Flaviviridae and there are four serotypes of the virus referred to as DV-1, DV-2, DV-3 and DV-4. DV is a positive stranded encapsulated RNA virus and is composed of three structural protein genes, which encode the nucleocapsid or core (C) protein, a membrane-associated (M) protein, an enveloped (E) glycoprotein and seven non-structural (NS) proteins. It is transmitted mainly by Aedes aegypti mosquito and also by Ae. Albopictus. An incubation period varying from 3 to 14 days is followed by a febrile illness consisting of sudden-onset fever, headache, myalgia, arthralgia and rash. Thrombocytopenia is a common feature of the illness. The patient develops hemorrhagic manifestations such as petechiae and bleeding through the nose, gastrointestinal tract and gums. A number of atypical manifestations have also been reported in the literature, which include encephalitis, encephalopathy, myocarditis, hepatitis and cholecystitis [1].

All four serotypes can cause full spectrum of disease from a subclinical infection to a mild self limiting disease, the dengue fever (DF) and a severe disease that may be fatal, the dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Though, the most common virus responsible for dengue is DV- 2 (dengue virus-2). WHO currently estimates there may be 50-100 million dengue infections and half a million DHF worldwide every year, with an average case fatality rate of around 5% [2].

Four main characteristic manifestations of dengue illness are [3]: 

a:  continuous high fever lasting 2-7 days;

b:  haemorrhagic tendency as shown by a positive tourniquet test, petechiae or epistaxis;

c:   thrombocytopoenia (platelet count less than 100 x 10⁹ /L); and

d: evidence of plasma leakage manifested by haemo-concentration (an increase in haematocrit 20% above average for age, sex and population), pleural effusion and ascites, etc.

Whether papaya leaves are effective in controlling dengue or not? Whether Ayurveda, one of the oldest medicine systems from India advocate the usage of papaya leafs in curing dengue? Such questions were answered in modern perspective [4]. Carica papaya belongs to family Caricaceae. It is an erect, fast-growing and unbranched tree or shrub indigenous to Central America and cultivated in Mexico and most tropical countries for its edible fruits. The author has pointed about four trials, where papaya leaves, seeds etc where proven to be effective against dengue and toxic to Aedes aegypti mosquito, which is a vector for the etiologic agents of both yellow and dengue fever.

Carica papaya leaf has been used traditionally in the treatment of dengue. The leaf has been investigated for its potential against DF. The aqueous extract of leaves of this plant exhibited potential activity against DF by increasing the platelet (PLT) count, white blood cells (WBC) and neutrophils (NEUT) in blood samples of a 45-year-old patient bitten by carrier mosquitoes [9]. After 5 days of oral administration of 25 mL aqueous extract of Carica papaya leaves to the patient twice daily, the PLT count increased from 55 × 10³/µL to 168 × 10³/µL, WBC from 3.7 × 10³/µL to 7.7 × 10³/µL and NEUT from 46.0 to 78.3 %. Increased platelets could lead to reduced bleeding, thus avoiding progression to the severe illness of DHF.

Currently available treatment for dengue:

1. The standard treatment protocol for management of Dengue includes symptomatic treatment with fluid management. This is the best option, if detected on time.

2. Drugs like Eltrombopag and Romiplastim are available for increasing the platelet counts, but they pretty costly options. Again, very much avoidable.

3. Using corticosteroid is advised by some as it is supposed to halt further platelet destruction but generally not preferred. The side-effects are pretty bad enough. Moreover, it is an immunosuppressant, it will "hide" any other secondary infection.

4. Platelet transfusion if the platelet count goes below 20000 /µl, where such is advocated.

Caripill costs Rs 25 per tablet with the dosage of administering one pill (1100 mg) three times a day, for five days.

Phase trial that sealed the deal [3]

Concept: A multi-centric open labeled, randomized, comparative pilot study was conducted at two centres of Bengaluru metropolis. The Carica papaya leaf extract was formulated in appropriate dosage form of tablet in the strength of 1100mg. A total of 30 subjects (n=30) diagnosed as dengue cases by NS1 antigen test were enrolled and randomized in this study. Exclusion and Inclusion criteria were followed and those meeting all the inclusion criteria’s were allowed to participate. A clinical diagnosis of DF and DHF was made by the clinician based upon the patient’s presentation and blood investigations. A rapid dengue test (NS1 Ag) was used to confirm the dengue case.

Method: Of the total subjects 14 were randomized to study group where in addition to the routine standard supportive management of dengue the investigational drug Carica papaya leaf extract 1100mg tid for 5 days was administered. The remaining 16 in control group received the routine standard supportive management of dengue, only. All the subjects were followed up every day for five days and their platelet counts were monitored daily.

Results:

a: At baseline, mean Platelet Count was 64.79 among test group, which was comparable with 65.94 among control group and the difference was not statistically significant.

b: After the treatment at the end of Day 5, mean Platelet Count showed a significant increase of 61.6% in Test group and an insignificant rise of 1.0% in Control group from baseline.

c: If compared change was more in Test group than Control group and the difference was statistically significant.

Sideeffects: In the published text the authors [3] have not mentioned any adverse event (AE) reported by the participants. Subsequent self-study and information from various users have pointed cases of nausea, vomiting, abdominal pain, heartburn, dyspepsia happening with them.

Individuals with bleeding disorders or those taking blood thinning drugs such as aspirin or warfarin, should avoid Caripill. Monitor blood glucose levels regularly. There is no special warning found for Caripill usage in pregnancy but it is better to start this medication under medical supervision if you are pregnant.

{If you have some information to share on an adverse reaction with Caripill, please fill the same in comment field. It will be updated and shared to benefit all.}

The authors conclude as "Papaya extract no doubt offers a cheap and possibly effective treatment for dengue. Various clinical and preclinical studies conducted have demonstrated a positive effect in dengue cases with thrombocytopenia. The current pilot study also demonstrates the same positive beneficial trend in increasing the platelets significantly. However, large scale randomized clinical trials are necessary to further establish its pivotal role in the management of dengue."

Being a product of extensive research and clinical trials conducted by Micro Labs, the pill has proved its safety and efficacy in about one lakh patients across India, claims a company release.

References:

1. Cho Paknikar, S. S.; et. al. Papaya Extract to Treat Dengue: A Novel Therapeutic Option? Ann Med Health Sci Res 2014, 4(3), 320-324. (FMO only)

2. WHO. 2. Dengue: Guidelines for diagnosis, treatment, prevention, and control in sub-Saharan Africa and 13 countries in South America. Geneva: World Health Organization; 2009, 2012. (FMO only)

3. Nagabhushan, K. H.; et. al. A Pilot Study to Evaluate the Effectiveness of Carica Papaya Leaf Extract in Increasing the Platelet Count in Cases of Dengue with Thrombocytopenia. Indian Medical Gazette 2015, 109-116. (FMO only)

4. Manohar, P. R.; et. al. Papaya, dengue fever and Ayurveda. Anc Sci Life 2013, 32(3), 131-133. (FMO only)

5. Ahmad, N.; et. al. Dengue fever treatment with Carica papaya leaves extracts. Asian Pac J Trop Biomed 2011, 1(4), 330-333. (FMO only)

Soaps Sans Triclosan, Do Good As Much As They Can

“Bunty tera saboon slow hai ? {Bunty is your soap slow (in killing germs)?}......... This is a catch pharse (or selling phrase) of an anti-bacterial soap in India. It shows a chubby boy cleaning his hands with a regular soap and water for a minute to ensure germs are removed because his mother told him so. The smart girl (let’s call her Pinky) advices Bunty to use her soap, claiming its kills 99% germs in a 10 SECOND handwash.

Well, South Korean researchers have published a report that supports the advice of Bunty’s mother. Through experiments, they have reported that for a regular hand-wash, the combination of a regular soap and water gives same results as an anti-bacterial soap. The difference if any is so insignificant that the money spent over anti-bacterial soap just makes it “too costly”. I wonder what Pinky and her mother are thinking now.

Concept: To check whether anti-bacterial soaps are effective or not. All tested anti-bacterial soaps had Triclosan (the most widely used antiseptic agent in soap). The triclosan concentration of 0.3% is the maximum allowed by law.

Methods: Twenty bacterial strains (proposed by the US-FDA) were exposed to plain and antibacterial soaps (the same formulation as plain soap, but containing 0.3% triclosan) for 20 s at 22°C (room temperature) and 40°C (warm temperature). The temperature and time were selected to simulate the hand washing conditions and procedures used by consumers. The decontamination efficacy of plain soap and antibacterial soap was also examined in vivo: the hands of volunteers were artificially inoculated with Serratia marcescens.

Results:

a: There was no significant difference in bactericidal activity between plain soap and antibacterial soap at either test temperature.

b: Antibacterial soap showed significantly greater bactericidal effects after 9 h.

c: Although triclosan-containing soap does have antibacterial activity, the effects are not apparent during the short time required for hand washing.

Conclusions: Antibacterial soap containing triclosan (0.3%) was no more effective than plain soap at reducing bacterial contamination when used under ‘real-life’ conditions.

Article Citation: Rhee, M. S.; et. al. Bactericidal effects of triclosan in soap both in vitro and in vivo. J Antimicrob Chemother 2015. DOI: 10.1093/jac/dkv275

Dear Pinky, you need a soap that goes ON and ON and ON ................. 9 hour long

Teens Can Switch to Traditional Cigarette Smoking After Electronic Cigarette Usage

A new investigational research has proven an old saying “If you play with fire, you get burned”. Electronic cigarettes (e-cigarettes) manufactures have promoted their product as a tool that may help smokers reduce the use of traditional combustible cigarettes. This might not be completely true (Cigarettesare BAD - Both Normal as well as E-Cigs).

Concept: Adolescents and young adults are true-to-word experimentalist, who will just taste anything and everything that is advertised. Moreover, this unique nature of the young’s is a global phenomenon. So, it didn’t take E-cigs any time to move into the world of the young and restless. According to data collected in 2014, 13.4% of US high school students have used e-cigarettes in the past 30 days, compared with only 9.2% who smoked cigarettes. Though the percentages users of e-cigs are more than traditional cigarettes, a report published in JAMAPediatrics suggest that these E-cigs users may be at risk for subsequent progression to traditional cigarette smoking.

E-cigarettes, also called electronic nicotine delivery systems produce an aerosol mix of flavored liquids and nicotine that is inhaled by the user. E-cigarettes are available in various designs such as resembling traditional cigarettes, cigars, pipes, or even like common gadgets such as flashlights, flash drives, or pens. E-cigarette use has increased rapidly in the past decade in both adolescents and adults. National Youth Tobacco Survey done by Centers for Disease Control and Prevention’s report an increase in E-cig usage from 4.5% in 2011 to 13.4% in 2014, affecting more than 2.2 million students.

This alarming rise in E-cigs usage promoted the study to determine whether baseline use of e-cigarettes among nonsmoking and nonsusceptible adolescents and young adults is associated with subsequent progression along an established trajectory to traditional cigarette smoking.

Method: In this longitudinal cohort study, a national US sample of 694 participants aged 16 to 26 years who were never cigarette smokers and were attitudinally nonsusceptible to smoking cigarettes completed baseline surveys from October 1, 2012, to May 1, 2014, regarding smoking in 2012-2013. They were reassessed 1 year later. Analysis was conducted from July 1, 2014, to March 1, 2015.

Results:

a: Adolescents and young adults who smoke electronic cigarettes (e-cigarettes) are much more likely than those who had not smoked e-cigarettes to progress to traditional combustible cigarette use.

b: Among 694 youth who were not susceptible to cigarette use, after 1 year, 68.8% of e-cigarette users and only 18.9% of those who had not smoked e-cigarettes had smoked a traditional combustible cigarette.

The authors concluded as “Our study identified a longitudinal association between baseline e-cigarette use and progression to traditional cigarette smoking among adolescents and young adults. Especially considering the rapid increase in e-cigarette use among youth, these findings support regulations to limit sales and decrease the appeal of e-cigarettes to adolescents and young adults.”

Article Citation: Mikkelsen Primack, B. A.; et. al. Progression to Traditional Cigarette Smoking After Electronic Cigarette Use Among US Adolescents and Young Adults. JAMA Pediatr 2015. DOI:10.1001/jamapediatrics.2015.1742

Risk of Type 2 Diabetes from Antibiotics

Results from a population-based case-control study could support the possibility that antibiotics exposure increases type 2 diabetes risk. There are two types of theories which link antibiotic with type 2 diabetes:

a: patients with type 2 diabetes are more prone to develop infections many years before they become diagnosed with type 2 diabetes and therefore have increased demand for antibiotics

b: antibiotics increase the risk of type 2 diabetes

There are suitable examples in literature that support both the theories, individually.

Concept: The human gut is populated by a dense community of microbes, aptly called, the gut microbiota. As the name suggest, it provides the host body “guts” to hold a battle against many auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and perhaps some cancers. The human body contains over 10 times more microbial cells than human cells, although the entire microbiome only accounts for about for 1-3% total body mass, with some weight-estimates ranging as high as 1.5 – 2.0 Kgs. Obesity too is believed to be caused by inefficiency of gut microbes. Gut microbiota is unique to each individual, is generally non-pathogenic and they exist in harmony and symbiotically with their hosts. In rare cases even their abnormal growth can cause some alarming situations. In addition, gut bacteria are known to aid the production of certain vitamins - such as vitamins B and K.

The very fact that an infant gut is sterile, and that gut microbiota is unique to each individual makes them good study material to understand the immunity and disease pattern of a person. Antibiotics cause marked alterations in the human gut microbiota with stereotypic declines and expansions in the abundance of certain taxa and incomplete recovery to the initial composition in some individuals. In simple words, antibiotics are able to change the composition and concentration of gut microbes, weakening bodies response against certain disease set. No wonder antibiotic abuse has alarming results.

To understand the consequences of such an absue, Danish researchers conducted a nationwide case-control study to investigate whether use of antibiotics influences the risk of developing type 2 diabetes and, if so, if the effect can be attributed to individual types of antibiotics, individual groups of antibiotics, or the number of antibiotics courses.

Methods: Researchers conducted a population-based case-control study of incident type 2 diabetes cases in Denmark (population 5.6 million) between January 1, 2000, and December 31, 2012. Researchers obtained information on use of all systemic antibiotics for the cohort between January 1, 1995, and July 1, 2012. Antibiotics were classified into narrow-spectrum or broad-spectrum and bactericidal or bacteriostatic. Exposure was quantified according to number of antibiotic courses before the index date, three different categories were defined; 0-1 antibiotic courses (reference), 2-4 antibiotic courses or greater than/equal to 5 antibiotic courses. Filling a prescription on the same antibiotic within 20 days of the first use was considered as belonging to the same course. Moreover, some certain type of diabetic patients was excluded from the study such as cases with chronic pancreatitis, pancreatic cancer, or polycystic ovary syndrome etc. The analysis conformed to a conventional matched case-control study. The crude and adjusted odd ratios (ORs) for developing type 2 diabetes associated with antibiotic exposure were estimated using conditional logistic regression, controlling for potential confounders.

Results:

1. The OR for type 2 diabetes increased almost linearly with the exposure to antibiotics.

2. Patients with type 2 diabetes redeemed on average 0.8 prescriptions on antibiotics per year compared to 0.5 prescriptions per year among controls.

3. Slightly higher ORs were found for narrow-spectrum and bactericidal antibiotics compared with broad-spectrum and bacteriostatic antibiotics, respectively.

4. Researchers found increased ORs for all groups of antibiotics except for clindamycin.

4. Researchers found a steep increase in OR for type 2 diabetes with increasing exposure to narrow spectrum antibiotics when the exposure to broad-spectrum antibiotics was held fixed. In contrast, there was a relatively unchanged OR for type 2 diabetes with increasing exposure to broad-spectrum antibiotics when exposure to narrow-spectrum antibiotics was fixed.

5. The increased exposure to antibiotics was observed both 5 years before and 5 years after the type 2 diabetes index date for cases.

The authors conclude as “Patients with type 2 diabetes, compared to control subjects free of type 2 diabetes, are overexposed to antibiotics before their diagnosis with type 2 diabetes as defined by the first redemption of a prescription on an oral glucose-lowering agent. However, the possibility that antibiotics exposure increases diabetes risk cannot be excluded and deserves further investigation in interventional studies. In particular, we suggest investigation of commonly used narrow-spectrum penicillins because these drugs are frequently prescribed and showed the highest OR for type 2 diabetes risk.”

Article Citation: Mikkelsen, K. H.; et. al. Use of Antibiotics and Risk of Type 2 Diabetes: A Population-Based Case-Control Study.  J Clin Endocrinol Metab 2015. DOI: 10.1210/jc.2015-2696

To Be, or Not to Be, Well ...... Do You Have Guts to Answer ?

Incense: A Pleasant Smelling Poison

Incense sticks (or agarbattis as called in India and adjoining nations) are one of omnipresent essential entity of all religious rituals in East, both for living as well for dead. If the advertisements are to be believed, incense provides a soothing pleasant aroma that helps in concentration, meditation and even has aphrodisiac ability. 

Intelligent people don’t believe in advertisement and neither did the researchers from South China University of Technology and the China Tobacco Guangdong Industrial Company in China. This group of researchers for the first time proved that incense smoke is as harmful as cigarette smoke.

Indoor air pollution affects the health of the household because of two apparent reasons:

a: Activities like cooking, smoking, and burning incense happen on daily basis. Moreover, these activities are repeated day over, so the harmful residues from these activities get concentrated over time.

b: People spend most of their indoors. Thus, they breathe air which is highly concentrated with the residues of the flame-dependent activities.

Just like cigarette smoke, epidemiological investigations have demonstrated that the combustion of incense is correlated with lung cancer, childhood leukemia and brain tumors. Incense burning being a part of tradition (and religion) prevented in-depth analysis of its harmful effects. The raw materials used to make incenses are diverse, but two of the most common ingredients are agarwood and sandalwood tree resin. The researchers short-listed two incense types with these two components for their study. The smoke from a cigarette (3R4F reference cigarette, University of Kentucky) was measured on a smoking machine, according to ISO 3308:2000. The total particulate matter and major chemical components of two types of incense smoke were characterized using an electrical low pressure impactor and gas chromatography coupled with mass spectrometry. Their genotoxicity and cytotoxicity were compared with mainstream tobacco smoke using in vitro assays.

Four different incense sticks (sourced from Australia, Indonesia, Malaysia and southwest China) were experimentally involved in 45 min of incense burning. The observations/analysis of these experiments are reported as:

Particle size distribution: The aerodynamic diameters of particulates emitted by these four samples were all below 5 uM. Particles smaller than 0.1 uM are labeled ultrafine particles, and those between 0.1 and 2.5 uM are termed fine particles. The data obtained from this study clearly showed that the particulate number and mass measured in incense smoke were dominated by ultrafine and fine particles (99%) which is likely to cause adverse health effects such as bronchitis etc.

Chemical composition: The highly volatile compounds common to all four samples were mostly irritants and hypotoxic. A number of compounds occurred in all four samples, including monoterpenes, methoxylated phenolics, two hexose dehydration compounds, as well as other highly volatile compounds. There also were some hypertoxic compounds detected in one or two samples, for example ethyl cyanoacetate and 2-butenal.

In vitro mutagenicity: The total particulate matter from four incense smoke samples was shown to be mutagenic in Ames tests. Incense smoke contains chemical properties that could potentially change genetic material such as DNA, and therefore cause mutations.

In vitro cytotoxicity: Genotoxicity to different strains of certain incense samples was higher than for the reference cigarette sample with the same dose. The half maximal inhibitory concentration of this cigarette was much higher than for the four incense samples, indicating that incense smoke was more cytotoxic against Chinese hamster ovary cells.

Incense smoke was also more cytotoxic and genotoxic than the cigarette smoke used in the study. This means that incense smoke is potentially more toxic to a cell, and especially to its genetic contents. Mutagenics, genotoxins and cytotoxins have all been linked to the development of cancers.

The authors conclude as “Clearly, there needs to be greater awareness and management of the health risks associated with burning incense in indoor environments but one should not simply conclude that incense smoke is more toxic than cigarette smoke. The small sample size, the huge variety of incense sticks on the market and differences in how it is used compared to cigarettes must be taken into account.”

The burning of incense might need to come with a health warning.

Article Citation: Zhou, R.; et. al. Higher cytotoxicity and genotoxicity of burning incense than cigarette. Environmental Chemistry Letters. 2015. DOI:10.1007/s10311-015-0521-7.