Peter J. de Vries

Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis

Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.

Clinical Pharmacology and Therapeutic Potential of Artemisinin and its Derivatives in the Treatment of Malaria

SummaryArtemisinin and its derivatives are renowned for their potent antimalarial activity. They have found their way into clinical use in many areas where malaria is endemic. The in vitro concentration at which artemisinin can inhibit 50% of the growth of Plasmodium falciparum ranges from 3 to 30 μg/L. The fat-soluble derivatives artemether and arteether are approximately twice as active. The water-soluble dihydro-artemisinin and artesunate are 4 to 5 times more active in vitro. Artemisinin is available only for oral and rectal administration. Absorption is incomplete and elimination is fast, with an elimination half-life of 2 to 5 hours. Plasma concentrations after a single 500mg oral dose most often exceed 200 μg/L. Artesunate and artemether can be considered as prodrugs. Biotransformation into the active metabolite dihydro-artemisinin occurs rapidly — almost immediately for artesunate. The reported elimination half-life of artesunate is less than 1 hour, and for artemether the figure is 3 to 11 hours. The pharmacokinetics of dihydro-artemisinin are not yet completely clear. Elimination is probably also rapid, with an elimination half-life of a few hours. Arteether, dissolved in oil for intramuscular administration, has a much longer elimination half-life of over 20 hours.The clinical efficacy of this group of drugs is characterised by an almost immediate onset and rapid reduction of parasitaemia, with complete clearance in most cases within 48 hours. Efficacy is high even in areas with multidrug-resistant parasite strains. To prevent recrudescence with monotherapy of these compounds, treatment needs to be extended beyond the disappearance of parasites. After 5 days of therapy the rate of recrudescence is approximately 10%. Alternatively, combination with other drugs can be used. Combination with mefloquine is recommended for areas with multidrug-resistant P. falciparum.

In vivo parasitological measures of artemisinin susceptibility.

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

Travel and migration associated infectious diseases morbidity in Europe, 2008

BackgroundEuropeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks.MethodsTo investigate the morbidity of travel associated infectious diseases in European travellers, we analysed diagnoses with demographic, clinical and travel-related predictors of disease, in 6957 ill returned travellers who presented in 2008 to EuroTravNet centres with a presumed travel associated condition.ResultsGastro-intestinal (GI) diseases accounted for 33% of illnesses, followed by febrile systemic illnesses (20%), dermatological conditions (12%) and respiratory illnesses (8%). There were 3 deaths recorded; a sepsis caused by Escherichia coli pyelonephritis, a dengue shock syndrome and a Plasmodium falciparum malaria.GI conditions included bacterial acute diarrhea (6.9%), as well as giardiasis and amebasis (2.3%). Among febrile systemic illnesses with identified pathogens, malaria (5.4%) accounted for most cases followed by dengue (1.9%) and others including chikungunya, rickettsial diseases, leptospirosis, brucellosis, Epstein Barr virus infections, tick-borne encephalitis (TBE) and viral hepatitis. Dermatological conditions were dominated by bacterial infections, arthropod bites, cutaneous larva migrans and animal bites requiring rabies post-exposure prophylaxis and also leishmaniasis, myasis, tungiasis and one case of leprosy. Respiratory illness included 112 cases of tuberculosis including cases of multi-drug resistant or extensively drug resistant tuberculosis, 104 cases of influenza like illness, and 5 cases of Legionnaires disease. Sexually transmitted infections (STI) accounted for 0.6% of total diagnoses and included HIV infection and syphilis. A total of 165 cases of potentially vaccine preventable diseases were reported. Purpose of travel and destination specific risk factors was identified for several diagnoses such as Chagas disease in immigrant travellers from South America and P. falciparum malaria in immigrants from sub-Saharan Africa. Travel within Europe was also associated with health risks with distinctive profiles for Eastern and Western Europe.ConclusionsIn 2008, a broad spectrum of travel associated diseases were diagnosed at EuroTravNet core sites. Diagnoses varied according to regions visited by ill travellers. The spectrum of travel associated morbidity also shows that there is a need to dispel the misconception that travel, close to home, in Europe, is without significant health risk.

Pharmacokinetic Interactions of Antimalarial Agents

Combination of antimalarial agents has been introduced as a response to widespread drug resistance. The higher number of mutations required to express complete resistance against combinations may retard the further development of resistance. Combination of drugs, especially with the artemisinin drugs, may also offer complete and rapid eradication of the parasite load in symptomatic patients and thus reduce the chance of survival of resistant strains.The advantages of combination therapy should be balanced against the increased chance of drug interactions. During the last decade, much of the pharmacokinetics and metabolic pathways of antimalarial drugs have been elucidated, including the role of the cytochrome P450 (CYP) enzyme complex. Change in protein binding is not a significant cause of interactions between antimalarial agents. CYP3A4 and CYP2C19 are frequently involved in the metabolism of antimalarial agents. Quinidine is a potent inhibitor of CYP2D6, but it appears that this enzyme does not mediate the metabolism of any other antimalarial agent. The new combinations proguanil-atovaquone and chlorproguanil-dapsone do not show significant interactions.CYP2B6 and CYP3A4 are involved in the metabolism of artemisinin and derivatives, but further studies may reveal involvement of more enzymes. Artemisinin may induce CYP2C19. Several artemisinin drugs suffer from autoinduction of the first-pass effect, resulting in a decline of bioavailability after repeated doses. The mechanism of this effect is not yet clear, but induction by other agents cannot be excluded. The combination of artemisinin drugs with mefloquine and the fixed combination artemether-lumefantrine have been studied widely, and no significant drug interactions have been found. The artemisinin drugs will be used at an increasing rate, particularly in combination with other agents. Although clinical studies have so far not shown any significant interactions, drug interactions should be given appropriate attention when other combinations are used.

Pharmacokinetics of Miltefosine in Old World Cutaneous Leishmaniasis Patients

ABSTRACT The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the last week of treatment (days 22 to 28) was 30,800 ng/ml. The maximum duration of follow-up was 202 days after the start of treatment. All analyzed samples contained a concentration above the LLOQ. Miltefosine is eliminated from the body much slower than previously thought and is therefore still detectable in human plasma samples taken 5 to 6 months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond 5 months after treatment might contribute to the selection of resistant parasites, and moreover, the measures for preventing the teratogenic risks of miltefosine treatment should be reconsidered.

Seroprevalence of dengue antibodies, annual incidence and risk factors among children in southern Vietnam

Dengue is highly endemic in southern Vietnam and all four serotypes of dengue virus have already been identified. To determine the age‐specific prevalence of dengue and associated risk factors, we conducted a serological study at two primary schools and assessed risk factors by analysing childrens questionnaires and household surveys. Sera were collected from 961 primary schoolchildren in Binh Thuan Province and tested for the presence of dengue virus serum antibodies using an indirect immunoglobulin G (IgG) enzyme‐linked immunosorbent assay (ELISA). The antibody prevalence of the total population was 65.7% (n = 631) which increased from 53.0 to 88.2% with age. The annual incidence of a first dengue infection, estimated by binary regression of the seroprevalence by age, was 11.7%. Interestingly, the prevalence of dengue IgG antibodies was significantly higher in children who confirmed using a pit latrine (RR 1.467, 95% CI: 1.245–1.730) and whose domestic environment contained discarded cans (RR 1.238, 95% CI: 1.042–1.470) and pigs (RR 1.228, 95% CI: 1.002–1.504). The epidemiology of dengue in southern Vietnam is stable with a constantly high annual incidence of first infections. Transmission occurs mainly peri‐domestically, which has important public health implications.

Dengue as a cause of acute undifferentiated fever in Vietnam

BackgroundDengue is a common cause of fever in the tropics but its contribution to the total burden of febrile illnesses that is presented to primary health facilities in endemic regions such as Vietnam, is largely unknown. We aimed to report the frequency of dengue as a cause of fever in Binh Thuan Province, to describe the characteristics of dengue patients, and analyze the diagnostic accuracy of the health care workers and the determinants of the diagnostic process.MethodsAll patients presenting with acute undifferentiated fever at twelve community health posts and one clinic at the provincial malaria station, Binh Thuan Province, a dengue endemic province in southern Vietnam, were included. Record forms were used to fill in patient and diseases characteristics, pre-referral treatment, signs and symptoms, provisional diagnosis and prescribed treatment, referral and final outcome. Serum samples were collected at first presentation and after 3 weeks for serologic diagnosis.Results2096 patients were included from April 2001 to March 2002. All 697 patients with paired serum samples were tested for dengue virus IgM and IgG. Acute dengue was found in 33.6% cases and past dengue virus infections were found in 57.1% cases. Acute primary infections were more common among children under 15 years old than among adults (7.7% vs. 3.5%, p value < 0.001). Younger age significantly predicted acute dengue (RR per increasing year of age (95 % CI): 0.986 (0.975–0.997, p value = 0.014). 48.9% of cases with clinical diagnosis of acute dengue were serologically confirmed and 32.5% of cases without clinical diagnosis of acute dengue were positive by serology after all (OR = 1.981, p value 0.025, 95% CI: 1.079 – 3.635). Tourniquet test was not a predictor for dengue diagnosis.ConclusionDengue is responsible for one third of the fevers presented to the public primary health services in Binh Thuan, southern Vietnam. It presents as a highly unspecific illness and is hardly recognized as a clinical entity by primary physicians.

Dengue Dynamics in Binh Thuan Province, Southern Vietnam: Periodicity, Synchronicity and Climate Variability

Background Dengue is a major global public health problem with increasing incidence and geographic spread. The epidemiology is complex with long inter-epidemic intervals and endemic with seasonal fluctuations. This study was initiated to investigate dengue transmission dynamics in Binh Thuan province, southern Vietnam. Methodology Wavelet analyses were performed on time series of monthly notified dengue cases from January 1994 to June 2009 (i) to detect and quantify dengue periodicity, (ii) to describe synchrony patterns in both time and space, (iii) to investigate the spatio-temporal waves and (iv) to associate the relationship between dengue incidence and El Niño-Southern Oscillation (ENSO) indices in Binh Thuan province, southern Vietnam. Principal Findings We demonstrate a continuous annual mode of oscillation and a multi-annual cycle of around 2–3-years was solely observed from 1996–2001. Synchrony in time and between districts was detected for both the annual and 2–3-year cycle. Phase differences used to describe the spatio-temporal patterns suggested that the seasonal wave of infection was either synchronous among all districts or moving away from Phan Thiet district. The 2–3-year periodic wave was moving towards, rather than away from Phan Thiet district. A strong non-stationary association between ENSO indices and climate variables with dengue incidence in the 2–3-year periodic band was found. Conclusions A multi-annual mode of oscillation was observed and these 2–3-year waves of infection probably started outside Binh Thuan province. Associations with climatic variables were observed with dengue incidence. Here, we have provided insight in dengue population transmission dynamics over the past 14.5 years. Further studies on an extensive time series dataset are needed to test the hypothesis that epidemics emanate from larger cities in southern Vietnam.

Artemisinin or chloroquine for blood stage Plasmodium vivax malaria in Vietnam.

Chloroquine‐resistant Plasmodium vivax has not yet occurred in Vietnam. The efficacy of artemisinin for P. vivax was not established. We conducted a double‐blind randomized study involving 240 inpatients with P. vivax malaria who received artemisinin (40 mg/kg over 3 days) plus placebo chloroquine (Art) or chloroquine (25 mg/kg over 3 days) plus placebo artemisinin (Chl). Patients were followed up with weekly blood smears for 28 days. In each group 113 cases were analysed. All patients recovered rapidly. The median (range) parasite clearance time of regimen Art was 24 h (8–72) and of Chl 24 h (8–64; P = 0.3). Parasites reappeared in two cases in each group on day 14, in eight cases in each group (7%) on day 16 and in 25 (23%) and 18 (16%) cases, respectively, at the end of 4‐week follow‐up (P = 0.3). The population parasite clearance curve followed a mono‐exponential decline. The parasite reduction ratio per 48 h reproduction cycle was 2.3 × 104 for both regimens. We conclude that artemisinin and chloroquine are equally effective in the treatment of P. vivax infections in Vietnam. Reappearance of parasites before day 16 (7%) suggests the emergence of chloroquine resistance. Three days of artemisinin monotherapy does not prevent recrudescence.