Quinapyramine Synthesis Essay

Animal African trypanosomiasis (AAT, nagana)

AAT [also called nagana, from the Zulu word ‘N'gana’ which means ‘powerless/useless’ (Steverding, 2008)], is caused by trypanosome species T. congolense, T. vivax and, to a lesser extent, T. brucei spp. (Fig. 1). The disease is widespread in sub-Saharan Africa (Fig. 2), where it is cyclically transmitted by the tsetse fly (Glossina spp.), the same vector responsible for the transmission of human-infective trypanosomes (T. brucei gambiense and T. b. rhodesiense, the aetiological agents of human African trypanosomiasis, HAT, or sleeping sickness) (Barrett et al.2003). In animals, tsetse flies can also transmit trypanosomes mechanically when they begin a blood meal on an infected host and end it on another one, provided that the time between the two meals is short enough to ensure survival of parasites in the insect mouthparts, as shown in experimental infections in goats (Moloo et al.2000). Unlike other trypanosomes, T. vivax does not multiply in the tsetse midgut, but remains confined to the insect proboscis, where it completes its short life cycle (Gardiner, 1989). This is the reason why this species can also be transmitted mechanically by other haematophagous flies, in particular horseflies (Tabanus spp.) and stable flies (Stomoxys spp.). Mechanical transmission has allowed T. vivax to spread far beyond the limits of the African tsetse belt: this parasite is now established in Mauritius and in 13 South American countries (Fig. 2), where it probably arrived in the 18th or 19th century via infected Zebu cattle exported from West Africa (Jones and Davila, 2001; Osorio et al.2008), an origin corroborated by phylogenetic studies (Cortez et al.2006). Although T. vivax remains enzootic in South America primarily due to mechanical transmission, other potential modes of transmission include perinatal and iatrogenic routes or via alternative, as yet unidentified vectors (Osorio et al.2008). This lack of definitive knowledge greatly hampers the implementation of surveillance and control strategies (Jones and Davila, 2001). Non-tsetse transmitted T. vivax infection in cattle is also recognized in parts of Africa, for example in regions of Ethiopia, Chad and Sudan (Ahmed et al.2016). Mechanical transmission of T. congolense has been shown under experimental conditions (Desquesnes and Dia, 2003) and can therefore not be excluded from contributing to its spread in Africa (Desquesnes et al.2009).

Fig. 2. Countries where the most important livestock trypanosomes are present. Modified from (Auty et al.2015), based on PubMed search and including countries where data were not available and parasite presence is inferred. To note that the real geographical distribution in some countries is limited (as, for example, for T. congolense in South Africa, Namibia and Botswana and for T. b. evansi in Russia). Cases of eradicated outbreaks of T. b. evansi in Europe (i.e. in France) are not indicated.

The host range is wide (Uilenberg, 1998). Trypanosoma congolense is considered the most pathogenic trypanosome in cattle (followed by T. vivax), but it also causes infections in horses, sheep, goats, pigs and dogs. Apart from bovines, T. vivax can affect sheep, goats, horses and camels (Osorio et al.2008). Trypanosoma b. brucei is found in various domestic ungulates but it is particularly virulent in dogs, camels and horses, the latter often succumbing to infection within a few months in the absence of treatment. In areas where more than one trypanosome species is present, mixed infections in domestic animals are often encountered (Kihurani et al.1994; Auty et al.2008; Biryomumaisho et al.2013; Takeet et al.2013; Moti et al.2015) and modern molecular techniques (Desquesnes and Davila, 2002) facilitate speciation. Many wild animal species in Africa also host one or more trypanosome species and can serve as reservoirs for both human and domestic animal infective trypanosomes (Mulla and Rickman, 1988; Auty et al.2012). Similarly, wild South American fauna can harbour T. vivax and act as reservoir of infection (Osorio et al.2008).

Belonging to the same Nannomonas subgenus as T. congolense, T. simiae is the only trypanosome species to be extremely pathogenic to pigs, which represent the main host, although other domestic species can harbour the parasite (Joshua and Kayit, 1984; Salim et al.2014). In pigs, T. simiae causes a hyperacute, often fatal infection, with death often occurring within 48 h of the appearance of symptoms (Leach and Roberts, 1981). For this reason, chemoprophylaxis is preferred to curative treatment.

The pathogenicity of trypanosomal infections varies considerably depending on several factors, including parasite-related aspects (species and virulence), host (species, breed, age, immunological status, nutritional status, presence of co-infection and physical condition), vector (species, density, infection rate and host preference), epidemiological situation (endemic or epidemic) and the environment (e.g. the availability of food and water and the season) (Leach and Roberts, 1981; Van den Bossche and Delespaux, 2011). Anaemia is the most prominent pathological feature of AAT (Taylor and Authié, 2004) and, in conjunction with other systemic lesions, can contribute to death through eventual congestive heart failure. Other symptoms include pyrexia, lymph node and spleen enlargement, ataxia, lethargy, weight loss, oedema, immunosuppression, abortion and decrease in milk production. The immunosuppression caused by trypanosomes can affect animal health by interfering with vaccination against other diseases (Singla et al.2010), or by increasing susceptibility of the host to other infections. Inflammatory, degenerative lesions are also observed, and can damage various organs such as heart, central nervous system (CNS), eyes, testes, ovary and pituitary gland. Death may occur within weeks from onset of the acute disease. Otherwise the animal enters a chronic phase (spontaneous recovery is rare but not unknown), characterized by intermittent or sub-patent parasitaemia, general malaise and infertility, and may last months or years prior to death (Taylor and Authié, 2004).

While mortality due to the disease is clearly important, the impact upon overall cultivation and crop production due to reduced draught power is the most significant contributor to the economic impact of AAT (Swallow, 2000). This is considered the livestock disease with the highest impact on agricultural production and animal husbandry in Africa, causing annual losses which run to billions of US$ (Shaw et al.2014). Across the tsetse belt as many as 55 million cattle are at risk of infection (Cecchi and Mattioli, 2009), plus 30 million sheep and 40 million goats. Of these cattle, 3 million die every year from AAT. The disease has devastating effects on the livelihoods of local farmers, for whom cattle represent not only a source of food (meat and milk), manure, and draught power, but have also fundamental social roles as ‘living banks’ and are used for social obligations (e.g. dowry and ritual use) (Swallow, 2000; Grace et al.2009; Mungube et al.2012).

Infection with T. vivax is considered an emerging disease in South America where it has a significant impact on cattle farming, but where it also affects horses and other ruminants (Batista et al.2007, 2009, 2012; Da Silva et al.2011). In a region including the Brazilian Pantanal and the Bolivian lowlands, where cattle ranching is the single most important economic activity (11 million head of cattle are reared in the region), the losses caused to the industry by a single outbreak of T. vivax in 1995 were calculated at more than US$ 160 million (Seidl et al.1999). The gross financial burden of T. vivax in South America, however, is not known with any degree of certainty.

Surra

Surra (from the Hindi word for ‘rotten’) is the most widely used of a plethora of names given to T. b. evansi infection in animals (Desquesnes et al.2013b). As seen for T. vivax, T. b. evansi (a T. brucei subspecies) has also evolved a mechanical mechanism of transmission that has allowed this species to spread beyond Africa by export of infected animals (Lun et al.2010). Trypanosoma b. evansi is today the pathogenic animal trypanosome with the broadest geographical distribution (Fig. 2), which stretches from North-East Africa to much of Asia in the east (Luckins, 1988; Payne et al.1991; Lun et al.1993) and to Latin America in the west (Desquesnes et al.2013b), and it is spreading steadily. In Europe, recent imported cases of surra have been documented and vigilance remains necessary after outbreaks in the Canary Islands, mainland Spain, France and Germany (Desquesnes et al.2008; Gutierrez et al.2010; Tamarit et al.2011; Defontis et al.2012).

Several probable or suggested methods of surra transmission exist: by biting insects including horseflies and stable flies (the major credited route), by vampire bats, by iatrogenic (e.g. as a result of a vaccination intervention), sexual, horizontal or vertical transmission, or by per-oral contamination in the case of carnivores eating infected meat (Desquesnes et al.2013a).

Trypanosoma b. evansi can parasitize a wide range of wild and domestic animal hosts, but the infection is particularly pathogenic in horses, camels and Asian water buffaloes (Desquesnes et al.2013b). There is increasing evidence that common rodents are an important reservoir host for T. b. evansi and other trypanosomes (Jittapalapong et al.2008; Maia da Silva et al.2010; Kocher et al.2015; Pumhom et al.2015), such as T. lewisi, a parasite of rats also found in atypical human infections (Howie et al.2006; Sarataphan et al.2007). These findings revive the important question of rodents as reservoirs of other T. brucei species. Rare cases of human infection with T. b. evansi (Joshi et al.2005; Haridy et al.2011; Van Vinh et al.2016), where individuals were infected through trypanosome-carrying animal blood, have been reported and, in at least one case, infection was associated with a null mutation in the trypanosome lytic factor blood component Apolipoprotein L1 (APOL1), which normally protects humans from animal trypanosome infections (Vanhollebeke et al.2006; Truc et al.2013). In a more recent case, no mutations in APOL1 were found to explain the unusual infection (Van Vinh et al.2016).

Symptoms of surra overlap those previously described for AAT and their intensity can vary greatly between and within host species and depend on the geographical area and epidemiological situation (Desquesnes et al.2013b).

In the Philippines, outbreaks of surra cause high morbidity and mortality in water buffaloes and other large ruminants, greatly affecting the livelihood of local small-scale farmers (Dargantes et al.2009; Desquesnes et al.2013a). In the Brazilian Pantanal T. b. evansi affects over 6000 horses per year (of the 50 000 present), with serious consequences to the local economy, horses being essential for herding livestock. The total impact of T. b. evansi infection in horses in this region was estimated at US$ 2·4 million per year (Seidl et al.1998). Surra is also one of the most frequent diseases affecting camels in North Africa, causing severe economic damage.

Dourine

Dourine is a disease caused by the subspecies T. brucei equiperdum, the only Salivarian trypanosome whose transmission cycle avoids invertebrate vectors completely. Instead, this parasite is transmitted among horses and other equids during mating (Claes et al.2005). Of note, vertical or perinatal transmission of trypanosomes other than T. b. equiperdum in the reproductive tissues has been reported (Griffin, 1983; Melendez et al.1993; Lindner and Priotto, 2010; Biteau et al.2016), although the role and relative importance of this mode of transmission in the field is not clear.

Trypanosoma b. equiperdum is an important veterinary trypanosome endemic in Africa and Asia, and is also found in the Middle-East, South-East Europe and South America. Strict control policies have eradicated T. b. equiperdum from Western Europe in the past century (Claes et al.2005), but the risk of reintroduction remains, as shown by a recent outbreak in Italy (Pascucci et al.2013).

The infection presents with typical oedema of the genital organs as well as weakness, emaciation, urethral discharge, characteristic plaques in the skin and neurological symptoms such as lack of coordination of the hind legs (Hagos et al.2010). Dourine in horses is generally fatal without treatment but it is usually subclinical in donkeys and mules (Brun et al.1998).

Considering the transmission mechanism and the absence of a reservoir in other species, the control strategies for the disease follow a different approach as compared with other insect-borne forms of trypanosomiasis (Claes et al.2005). The World Health Organization for Animal Health (OIE) recommends breeding and movement restrictions, compulsory notification and slaughter of infected animals to block new infection outbreaks or achieve eradication. Additionally, pharmacological therapy is not advised as this may result in clinical improvement but not in complete cure, leaving the animal as a potential carrier of the parasite. However, the feasibility or effectiveness of this strict policy in developing countries, where horses have a significant role in transport and agriculture, is questionable. Here, chemotherapy may help to sustain animal health and productivity. Although no official cure for dourine is available, studies have indicated the efficacy of melarsomine in the treatment of acute and chronic T. b. equiperdum infection in horses (Hagos et al.2010).

Introduction

"Have a chew of dulie," said Crubog . . . "What is it?" asked Potter, half-suspiciously. "Seaweed. " "Is it good for the virility? . . . " "And what is the virility?" asked the old man. "Does it make you more attractive to women?" Potier shouted in his ear. "No. " "What is it good for then?" "WortnS. " "Worms?" "Intestinal worms. You'll never again pass a worm if you eat a fistful of dulse first thing in the morning and last thing at night. " "If it's an anthelmintic, I'll try a spot of it," said Potter. - From Bogmail, a novel by Patrick McGinley (1981) With modern techniques of chemical isolation and structure determination, the old distinction between herbal and chemical remedies has largely been broken down. By chemotherapy we now mean simply the treatment of disease by drugs (the word medicines has unhappily been eclipsed). The distinction made between chemotherapy and non­ chemical therapy (e. g. , radiation, physiotherapy, surgical intervention, immu­ nomodulation) remains useful despite some minor overlapping. The present work thus deals with drugs and their use in parasitic disease. (Since we are dealing with the treatment of incipient as well as established infection, chemotherapy subsumes chem­ oprophylaxis as well as chemotherapeusis per se. ) Definition of parasitism as a biological modus vivendi, although important in itself, need not concern us here. We need simply delimit the scope of the book, and that is easily done.

Keywords

Malaria Schistosomiasis antibiotics chemotherapy clinical trial infection infections intestinal infections metabolism pesticide pharmacology prevention protozoan infection toxicity toxicology

Editors and affiliations

  • William C. Campbell
  • Robert S. Rew
  1. 1.Merck Institute for Therapeutic ResearchRahwayUSA
  2. 2.Merck Sharp & Dohme Research LaboratoriesRahwayUSA

Bibliographic information

  • DOIhttps://doi.org/10.1007/978-1-4684-1233-8
  • Copyright InformationSpringer-Verlag US 1986
  • Publisher NameSpringer, Boston, MA
  • eBook PackagesSpringer Book Archive
  • Print ISBN978-1-4684-1235-2
  • Online ISBN978-1-4684-1233-8
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