Mosquito Repellent, Prevention is better than cure

 

Supriya Aldar*1, Dr. Ganesh Deshmukh*2

1Master of Pharmacy Student, Department of Pharmaceutics,

Oriental College of Pharmacy, Sanpada, Navi Mumbai, 400705

2Assistant Professor, Department of Pharmaceutics, Oriental College of Pharmacy,

Sanpada, Navi Mumbai, 400705

*Corresponding Author E-mail: supriyaaldar17@gmail.com

 

ABSTRACT:

Mosquito being the major medically important arthropod vector requires utmost attention to reduce the sufferings and economic consequences of those population living in the endemic regions. This is possible only, by minimising the human-mosquito contact by an absolute preventing measure. However, such absolute measures are yet to be developed despite enormous efforts and huge investments world-wide. In the absence of vaccines for number of mosquito-borne diseases, repellents could be an attractive option for both military personal and civilians to minimise the risk of different mosquito-borne diseases. However, to achieve this golden goal, the detailed knowledge of a particular repellent is must, including its mode of repellency and other relevant informations. Here, in the present article, an effort has been made to convey the best and latest information on repellents to enhance the knowledge of scientific community. The review offers an overview on mosquito repellents, the novel discoveries, and areas in need of attention such as novel repellent formulations and their future prospective.

 

KEYWORDS: N, N-diethyl-meta-toluamide (DEET), Nepetalactone (NPL), mosquito repellent, mosquito control

 

 


1. INTRODUCTION:

Mosquitoes are the most disturbing blood sucking insects afflicting human beings. Mosquito species belonging to Anopheles, Culex and Aedes genera are vectors for the pathogens of various diseases like Dengue fever, Malaria, Yellow fever, etc. The mosquitoes eject their saliva into the blood of the host that creates an immune response due to the binding of the antibodies IgG and IgE to the antigens.

 

 

The reactions result in irritations, itching, redness and sometime it develops into the bumps. [1] It is the saliva of the mosquito that often causes an irritating rash that is a serious nuisance. In addition, mosquito bites can cause severe skin irritation through an allergic reaction to the mosquito's saliva by human mosquito contact. Only female mosquitoes bite, because they need to drink blood to develop and lay eggs. (The males drink flower nectar.) [2]

 

Mosquitoes bear set of sensors that have the capability to track their prey’s presence, these include:

 

A. Chemical Sensors: The studies have proved that the mosquitoes sense the lactic acid, carbon dioxide, and the propen-3-ol upto many yards away. Humans and the animals release these compounds, on breathing or perspiration. This is the reason that a person who sweats more becomes the target of the species.

 

B. Heat Sensors: The mosquitoes also have the ability to detect heat and can target the warm blooded animals very fast once they get close enough.

 

C. Visual Sensors: It’s been recorded that the mosquitoes are the intelligent insects as they can easily detect humans by looking at their clothing if it contrasts with the background.

 

Humans are easily detected by mosqitoes as anything that moves is alive and hence full of blood. Control of Mosquito Borne Diseases Mosquito control and personal protection from mosquito bites are currently the most important measure to control this disease. Prevention of this type of disease involves protecting yourself against mosquito bites. [3] .Mosquito control methods are habitat change, biological control, physical control and chemical control including individual safeguards from the mosquitoes. For control of these mosquito borne diseases is by killing or preventing mosquitoes from biting a human being. This can be achieved by use of mosquito repellents. [4]

 

Anatomy of mosquito:

Mosquitoes are relatively small insects which compose the family Culicidae, mosquito anatomy is divided into three basic parts, namely, head, thorax and abdomen. Mosquito’s head is consisting of sensors that help the mosquito to find and feed on people and animals. Mosquitoes have two large compound eyes covered with tiny lenses that are capable of detecting even slight movements. Simple photo-sensitive eyes are located on top of their heads to detect variations in light. Mosquito-antennae are ong feathery organs which are positioned in front of their heads and those antennae contain sensitive receptors that detect carbon dioxide in human breath from distances of more than 100 feet. The maxillary palp between the antennae picks up the odour of ocentol and other chemicals released in human sweat. Right in the middle, also between the antennae, is the proboscis, a long serrated mouth-part used to pierce the skin and suck out blood. The thorax is connected to the head and it has a pair of wings. The legs also come out of the thorax, six in all, with tiny claws at the end of each to help the mosquitoes stay attached to surfaces. The abdomen hangs from the thorax and serves as the mosquito’s stomach and lungs. [2]

 

What is a mosquito repellent? 

A mosquito repellent is a substance applied to skin, clothing, or other surfaces which discourages mosquitoes from landing on that surface. It makes the surface unpleasant and unattractive to mosquitoes so as to reduce the human mosquito contact. Mosquito repellents repel insects but do not kill them. Therefore, they are not technically insecticides nor pesticides. They help prevent and control the mosquito borne diseases such as Dengue fever, Malaria, Yellow fever, Japanese Encephalitis, etc. They contain active ingredient which is the only reason to repel mosquitoes by blocking their olfactory senses which detects the carbon dioxide and lactic acid that gets released when the human perspires. These products also contain some more ingredients which aids them with cosmetic finishing. [4]

 

2. MATERIAL AND METHODS:

It is believed that DEET blocks electrophysiological responses of olfactory sensory neurons to attractive odors in Anopheles gambiae and Drosophila melanogaster via the highly conserved olfactory co-receptor OR83b. It may imply that DEET could mask the host odor by inhibiting subsets of heteromeric odorant receptors that require the OR83b co-receptor. The dual role of mosquito repellent implies that the repelling mechanism is much more complicated than what we expect and, therefore, previous structure–activity relationship studies, even quantitative ones, may not be enough because the role of characteristic compounds from the skin secretions or exhaled gas from human host and its role in the repelling mechanism were ignored completely[5]. The subsequent QSAR study shows that not only the structure of repellents but also the repellent–lactic acid complexes may play an important role. [6]

 

Mosquito repellent’s mode of action Most repellent chemicals work by interfering with the mosquito's homing system. This homing system, located on the antennae and is made up of a number of chemical receptors. Research has shown that these chemical receptors are activated by lactic acid. Lactic acid naturally evaporates from the skin of warm-blooded animals [7]. The mosquitoes have the innate ability to follow the lactic acid emissions to their source. However, when a repellent ingredient such as DEET is applied to the skin, it also evaporates. It is thought that the chemical inhibits the binding of the lactic acid to the mosquito's chemical receptors. This essentially "hides" the protected person from the mosquito. Since the active ingredient must evaporate from the surface to work, the repellent activity lasts for a limited time [8][7]

 

A series of experiments showed that without the Orco protein, the mosquitoes struggled to distinguish the smell of honey from that of glycerol (an odourless liquid of similar consistency), and humans from other animals. “[9][10][11]

 

Protein - Odorant receptor coreceptor [7]

 

Gene - Orco Synonyms: GPRor7

 

ORF Names: AGAP002560

 

Alternative name(s): AgOr7 Gustatory and odorant receptor 7

 

Organism - Anopheles gambiae (African malaria mosquito)[12]

Function:

Odorant coreceptor which complexes with conventional odorant receptors (ORs) to form odorant-sensing units, providing sensitive and prolonged odorant signaling and calcium permeability. Orco is a universal and integral part of the functional odorant receptor, involved in the dendritic localization of other olfactory receptors. Can form functional ion channels in the absence of an odor-binding or. Plays a key role in preferred attraction of females for humans over non-human hosts for blood feeding. [9][10] Human attraction plays a crucial role in the transmission of Plasmodium protozoans by the mosquito leading to infection diseases like malaria. Also required for the response to N,N-Diethyl-meta-toluamide (DEET), the most widely used insect repellent worldwide. [2][13][5]

 

mosquito repellnt is in need today…. because Malaria is a leading cause of human death. In 2015, the World Health Organization (WHO) estimated that 212 million cases of malaria occurred, leading to 419 000 deaths – 82% of casualties are in sub-Saharan Africa. Children under the age of 5 account for 64% of victims. [14][15]

 

Malaria’s mortality rate dropped by 31% between 2010 and 2015 in Africa and the life expectancy of children under 5 increased by 1.2 years. However, in 80% of malaria endemic countries, mosquitos developed resistance to at least one insecticide. [14]

 

Furthermore, in Burundi, mortality have increased by 13% in the last year, stunting economic growth where the annual per capita income is lower than 400 USD and farmers hire labour at 1 USD a day. [14]

 

As with the mass drug administration of chloroquine, which contributed to the resurgence of malaria in Peru after 30 years of low incidence, Plasmodium falciparum protozoa may develop resistance to artemisinin monotherapy. Mutations of the K13 gene are markers of artemisinin resistance but tetraoxane-based compounds have inhibitory characteristics against various strains of the protozoa. [14]

 

Artesunate is more effective than quinine with fewer side effects but a child administered a high dose rectally died due to its toxicity. Moreover, Burke et al. reported that Anopheles vaneedeni became a new malaria vector complicating the fight against the disease. [14]

 

Cutaneous mosquito repellents are one means to reduce the frequency of mosquito bites. N, N-diethyl-meta-toluamide (DEET) is an effective mosquito repellant  but is cost prohibitive for rural sub-Saharan populations [16]. Targeting indigenous plants as a source of mosquito repellents will stimulate local economies and at the same time protect the population. [2][14]

 

Odalo et al. extracted and tested the topical repellency of essential oils indigenous to Kenya from Conyza newii (Compositae), Plectranthus marrubioides (Lamiaceae),  Lippia javanica (Verbenaceae), Tetradenia riparia (Lamiaceae), as well as Tarchonanthus camphoratus (Asteraceae). The oils, under their experimental conditions (3 min, forearm exposure), repelle N. cataria, commonly known as catnip or catmint, is a species of the Lamiaceae family. It is native to temperate and tropical zones in Asia and in Europe and is widely cultivated. Nepeta cataria (N. cataria) has many uses in traditional medicine including treatment of chills, colds, constipation, headaches, infections, inflammations, rheumatism, sore throats, spasms, and stomaches [14][16].

 

N. cataria’s essential oil possesses antibacterial and antimicrobial properties. Nepetalactone (NPL) is the major constituent of this oil, DEET, applied to the forearm, repelled Aedes aegypti, Anopheles quadrimaculatus, and Anopheles albimanus for 426 min, 96 min, and 87 min, respectively [14]. A 25% volume fraction of DEET in ethanol repelled Aedes aegypti for 8 h. Whereas, Bernier found that a dose of 0.5 mg cm−2 of DEET applied to a muslin cloth patch was active for 24 h. Catnip’s oil is a better spatial repellent than DEET and demonstrated effective topical repellency properties. [14] Nepetalactone  (NPL )is as active as DEET and its hydrogenated form dihydronepetalactone  is two times more active than DEET when formulated with isopropyl alcohol (1% w/v). Among 41 different essential oils applied to skin, Catnip’s offered protection for 480 min. Moreover, N. cataria exhibits a more favorable safety profile than DEET. Local communities widely accept essential oil based MR [13]. In Ghana, 97% of the studied population desired to continue applying the MR after the 3-month trial. Mng’ong’o et al. found that six repellent plants essential oil were widely accepted by the population studied due to their efficacy. [14]

 

Plant essential oils showed more mosquito repellent activities compared to plant extracts. When 10% (V/V%) extracts and essential oils were compared, the mosquito repellent activities occurred in the following order: Citronella essential oil and Eucalyptus essential oil (100%) > Tulsi essential oil (97.94%) > Clove bud essential oil (95.81%) > Sweet Orange essential oil (93.75%) > Turmeric essential oil (89.56%) > Nika extract (85.44%) > Neem extract (81.25%) [16].

 

When 20% (V/V%) extracts and essential oils were compared, the mosquito repellent activity was found to be in the following order: Turmeric essential oil (100%) > Nika extract and Neem extract (97.94%). The mosquito repellent gel and the mosquito repellent spray which contained 16% (V/V %) total active ingredients each, showed 100% mosquito repellency for outdoor and indoor field trials which were carried out for six hours each day for two days. [2]

 

Novel discoveries:

1) Anthranilate based insect repellents (ABIRs)

The repellency of ABIRs  has been detected recently after the identification of potential receptor for DEET by a group of scientists led by Prof. Anandasankar Ray A.The discovery was possible after the in  silico screening of a large virtual chemical library consisting of more than 440,000 volatile-like chemicals to find out chemicals that worked on the DEET receptor. [17]

 

The compounds that worked, were then narrowed down to 3000 (approx.) chemicals originating from plants, insects or vertebrate species that worked well specifically on mosquitoes and compounds already approved for human use as fragrances, cosmetics or flavours. Ultimately, the screening was left with three ABIRs  they are, ethyl anthranilate, butyl anthranilate, and methyl N,N-dimethylanthranilate. The screening also identified 2,3-Dimethyl-5-isobutyl-pyrazine as a potential insect repellent.The repellency of ABIRs is due to the expression of green  fluorescent protein (GFP) of column glumerulus, innervated by axons of an ionotropic receptor Ir40a expressing neurons of sacculus, a pit like structure in the antenna of fruit fly Drosophila.One of the most interesting fact about Ir40a receptor proteins is that they are also highly conserved across several agricultural pests and insects as well, such as mosquitoes, head lice.Tribolium etc. ABIRs also activated the DEET-sensitive gustatory neurons that project to the areas of the sub-oesophageal ganglion (SOG) region similar to those of   taste neurons Originating in the labellum and the pharynx.

 

ABIRs were recently revealed to elicit avoidance behaviour with host seeking Aedes aegypti mosquitoes in\a caged landing assay. [13] In that assay, a non-contact version of the assay was used by inserting a human hand protected by a net in a mosquito cage, while an intermediate net Treated with 10% ABIRs in acetone was used for the test. Thus, mosquitoes had a choice between landing and not landing on the net surface.

 

In another investigation, ethyl Anthranilate was found to interfere with both the oviposition and host seeking behaviour of Aedes aegypti Mosquitoes and the results were comparable to DEET. Butyl anthranilate strongly inhibited the Oviposition behaviour of Aedes aegypti mosquitoes [13], but  Butyl anthranilate did not influence the host seeking behaviour of aedes aegypti mosquitoes. On the other hand, methyl N, N-dimethyl anthranilate is a repellent only in host seeking con-text which does not have influence on oviposition activity of Aedes aegypti mosquitoes. Thus, ethyl anthranilate is a true repellent, while methyl N,N-dimethyl anthranilate is repellent only in a host-seeking context, and butyl anthranilate is deterrent only in an  oviposition context.

 

 

However, unlike other odors that convey an ecologically relevant message for example odors of known mosquito predators that deter oviposition, the association of these Compounds with natural habitats in mosquito evolution are largely unknown. Therefore, explicit investigation for mosquito avoidance of these compounds remains to be elucidated. However, owing to the above facts, ABIRs fulfil the requirementsof an ideal repellent and,In comparison with other common repellents available in market, ABIRs have the advantage of being approved by Food and Drug Administration (FDA), WorldHealth Organization (WHO) and European Food Safety Authority (EFSA), and have been listed in the ‘generally recognized as safe’ (GRAS) list by the Flavourand Extract Manufacturer’s Association (FEMA) (Apietal., 2015; Flavors And Fragrances, 2007, Kain etal.,2013). Moreover, unlike DEET, ABIRs do not damage syntheticfabrics, plastics and Painted and varnished surfaces which further widen the applicationof ABIRs In bed nets, uniforms, and in many urban settings (Kain etal., 2013). ABIRs Are generally Used in chewing gums and beverages as grape  and flavouring and odor and fragrance as soaps detergents, creams, lotions and perfumes [18]

 

2) 2,3-Dimethyl-5-isobutyl-pyrazine (DIP)

It is a volatile ant trail pheromone which is now emerged as an insect repellant it act by targeting ir40a receptor proteins of fruit Fly Drosophila melanogaster. It shows repellency against Aegypti mosquitoes, although is not approved for human use. At present suitability of it on human and for agriculture use has to be evaluated [18]

 

3) Ortho hydroxy-substituted molecules might be of importance for the prevention of bloodsucking by mosquitoes

 

Studies performed on an ethanolic extract of Achillea millefolium L. (Asteraceae) showed a high antifeedant effect on the mosquito, Aedes aegypti L. This effect was supposedly higher than the sum of its single active components. Amongst the active compounds caffeic acid, mandelonitrile glucoside, pyrocatechol, and salicylic acid, were found to have free hydroxy groups in ortho position [19]

 

The importance of ortho substituents, especially free hydroxy groups, seems evident in the test series pyrocatechol, resorcinol and hydroquinone, where pyrocatechol showed the highest activity. Furthermore, the importance of the free ortho hydroxy groups in the molecule was indicated by a decreased activity by methylation of pyrocatechol,i.e. the compounds guaiacol and veratrol [19]

 

Testing the mosquito repellent activity of extracts and essential oils using arm-in-cage method The mosquitoes used in this experiment were caught using a net. Mosquitoes were starved for 24 hours and 20 mosquitoes were placed in the cage (45 × 15 × 30 cm). Host-seeking behaviour of the mosquitoes was tested prior to the experiment. This was done by placing a pre-cleaned hand in the cage and counting the number of mosquitoes that aligned within 10 seconds. If at least 5 mosquitoes aligned on the hand, the mosquitoes inside the cage were regarded as host-seeking and the repellency experiment was continued. Volunteer’s forearm which had been rubbed with 1 ml of the test solution was exposed to the cage and the number of mosquitoes that aligned or biting the arm was recorded in each minute for 5 minutes. Mosquitoes were given an over one hour interval and the above procedure was followed for each of the other extracts and essential oils. Each test was repeated thrice to get a mean value of mosquito repellent activity. [2][13]

 

Repellency (%) 100    =   A- B   ÷ A ×100

 

A – Number of bites on control arm, B –Number of bites on treated arm [16]

 

Acute toxicity studies (Dermal irritation test): For the Primary irritation test, the back hairs of albino rats were shaved using a shaving stick to expose a skin area ofabout 5 cm. The albino rats were grouped in replicates of three for each extract. The exposed area of the albino rat was treated with 0.5 g of the extracted oil and covered with a gauze pad (bandage). The groups were labelled A, B and C respectively for the different oil extracts. After 24 h the tape and gauze were removed and the treated area evaluated for erythematous lesions (Redness of the skin produced by congestion of the capillaries) and edematous lesions (accumulation of excess fluid in skin and tissue). The results were expressed on a numerical scale. After additional 24 to 48 h, the treated areas were further evaluated.[2][20]

 

3. RESULTS AND DISCUSSION:

Common synthetic insect repellents

·       Methyl anthranilate and other anthranilate-based insect repellents

·       Benzaldehyde, for bees

·       DEET (N,N-diethyl-m-toluamide) [16]

·       Dimethyl carbate

·       Dimethyl phthalate, not as common as it once was but still occasionally an active ingredient in commercial insect repellents

·       Ethylhexanediol, also known as Rutgers 612 or "6-12 repellent," discontinued in the US in 1991 due to evidence of causing developmental defects in animals

·       Icaridin, also known as picaridin, Bayrepel, and KBR 3023

·       Indalone. Widely used in a "6-2-2" mixture (60% Dimethyl phthalate, 20% Indalone, 20% Ethylhexanediol) during the 1940s and 1950s before the commercial introduction of DEET

·       IR3535 (3-[N-Butyl-N-acetyl]-aminopropionic acid, ethyl ester)

·       Metofluthrin

·       Permethrin is different in that it is actually a contact insecticide [16]

·       A more recent repellent being currently researched is SS220, which has been shown to provide significantly better protection than DEET

·       Tricyclodecenyl allyl ether, a compound often found in synthetic perfumes [21][22]

 

Natural repellant:

nardus (Citronella), Cymbopogon citratus (Lemongrass), Cymbopogon winterianus (Citronella), Ocimum basilicum (Sweet Basil), Ocimum sanctum (Tulsi), Ocimum americanum (Hairy Basil), Eucalyptus citriodora (Eucalyptus), Eucalyptus globulus (Eucalyptus), Rosmarinus officinalis,  Melissa officinalis,  Curcuma longa (Turmeric rhizomes), Citrus sinensis (Sweet Orange) peels, Citrus hystrix (Kaffir Lime) peels, Citrus limonum (Lemon) peels, Syzygium aromaticum (Clove) buds1 and Pinus roxburghii resins have shown very high mosquito repellent activity [16]. Moreover, the extracts of Azadirachta indica (Neem) seeds, leaves of Alpinia galangal (Greater Galangale), Vitex negundo (S. Nika) and Tribulus terrestris (S. Gokatu) also have been studied as possible mosquito repellents. The selection of these plants was based on their availability as raw materials, scientific evidence and folkloric use as mosquito repellents [23][21][24].

 

CONCLUSION:

A lot of progress has been made in the field of repellent researchand the repellents have a proven history of success. Many potential repellents are available today, however unfortunately their useis still limited due to unknown chemical ecology of insect andenigmatic mechanism of insect repellents. Therefore, better understanding of the chemical ecology of pests and basic knowledgeof the mechanism of repellency would be helpful for identifying candidate semiochemicals that could then be used in attractantand repellent formulations.For example, insect repellents exert their effects through interactions witholfactory (antennae and maxillary palps) and gustatory (maxil-lary palps, mouthparts, tarsi and wind) receptors. With greater knowledge on neural mechanisms, the new candidate in repellent research could be explored. Therefore, much more work needs tobe done such as screening of chemical libraries, bioassay of different biological products from plants and animals, development of structure-activity relationships, etc. to develop new generations ofrepellents for personal protection from the nuisance and vector-borne pathogens.

 

Preventing rather than treating the disease is a better approach….

Sleeping under nets impregnated with insecticides has reduced the world mortality rate from 2 million a year; they save 5.5 per 1000 children yearly. Insecticides are losing their efficacy due to increasing mosquito resistance. Furthermore, weather patterns like La Niña can cause unexpected peaks in mosquito populations.

 

Furthermore, the mosquitos are changing their feeding patterns to adapt to the mosquito nets. Mosquitos have adapted to insecticide treated nets by changing their biting habits. Proportion of outdoor biting increased from 45% to 68%. Thus, nets will be less effective for young children and pregnant women, who are the most vulnerable to the disease.[14]


 

Table 1: Newly Discovered Mosquito Repellant 


Chemical name

Vapour pressure mm (hg 25c)

Repellency spectrum

Methyl jasmonate

0.001

Culex quinquefasciatus

4-methylpiperidine

10.0

Aedes aegypti, drosophila, melangustor

2,3-dimethyl-5isobutyl pyrazine

0.13

Aedes aegypti, drosophila, melangustor

Ethyl-2-aminobenzoate

(ethyl anthranilate)

0.01

Aedes aegypti, drosophila, melangustor

Ethyl-2-aminobenzoate

(Butyl anthranilate)

1.29

Aedes aegypti, drosophila, melangustor

 

Table 2: safety properties of repellent compound

Compound

Oral toxicity

Dermal toxicity

Organoleptic

Dissolves plastics

DEET

4280mg/kg (rabbit)

3180mg/kg

(rabbit)

Unpleasant odour

Yes

Ethyl-2-aminobenzoate

3750mg/kg (rat)

0.0012mg/kg/day

Sweet floral grape orange bloosom wintergreen

No

Butyl aminobenzoate

>5000 mg/kg(rat)

>5000 mg/kg

Sweet grape like, fruity with wine floral berry

No

Methyl-2-(dimethylamino)benzoate

Not determined

Not determined

Green leafy, nutty

No

2,3-dimethyl-5-isobutyl pyrazine

Not determined

Not determined

Unpleasant odour floral fruity green waxy seedy melon

No

 


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Received on 30.06.2019            Modified on 14.07.2019

Accepted on 05.08.2019            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2019; 9(3):193-198.

DOI: 10.5958/2231-5659.2019.00030.4