Giancarlo Majori

Effects of chloroquine on viral infections: an old drug against today's diseases

Summary Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor α and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.

New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications

The clinically established gold‐based antiarthritic drug auranofin (AF) manifests a pronounced reactivity toward thiol and selenol groups of proteins. In particular, AF behaves as a potent inhibitor of mammalian thioredoxin reductases causing severe intracellular oxidative stress. Given the high sensitivity of Plasmodium falciparum to oxidative stress, we thought that auranofin might act as an effective antimalarial agent. Thus, we report here new experimental results showing that auranofin and a few related gold complexes strongly inhibit P. falciparum growth in vitro. The observed antiplasmodial effects probably arise from direct inhibition of P. falciparum thioredoxin reductase. The above findings and the safe toxicity profile of auranofin warrant rapid evaluation of AF for malaria treatment in animal models.

Genetic diversity of Plasmodium vivax isolates from Azerbaijan

BackgroundPlasmodium vivax, although causing a less serious disease than Plasmodium falciparum, is the most widespread of the four human malarial species. Further to the recent recrudescence of P. vivax cases in the Newly Independent States (NIS) of central Asia, a survey on the genetic diversity and dissemination in Azerbaijan was undertaken. Azerbaijan is at the crossroads of Asia and, as such, could see a rise in the number of cases, although an effective malaria control programme has been established in the country.MethodsThirty-six P. vivax isolates from Central Azerbaijan were characterized by analysing the genetic polymorphism of the circumsporozoite protein (CSP) and the merozoite surface protein 1 (MSP-1) genes, using PCR amplifications and amplicons sequencing.ResultsAnalysis of CSP sequences showed that all the processed isolates belong to the VK 210 type, with variations in the alternation of alanine residue (A) or aspartic acid residue (D) in the repeat motif GDRA(A/D)GQPA along the sequence. As far as MSP-1 genotyping is concerned, it was found that the majority of isolates analysed belong to Belem and Sal I types. Five recombinant isolates were also identified. Combined analysis with the two genetic markers allowed the identification of 19 plasmodial sub-types.ConclusionThe results obtained in the present study indicate that there are several P. vivax clones circulating in Azerbaijan and, consequently, a careful malaria surveillance could be of paramount importance to identify, at early stage, the occurrence of possible P. vivax malaria outbreaks.

Incidence of malaria and risk factors in Italian travelers to malaria endemic countries

BACKGROUND Imported malaria has been an increasing problem in Italy in the last three decades of the 1900s, representing the main risk for travelers visiting tropical and sub-tropical countries where malaria is endemic. Even though the total number of imported cases has been declining since 2000, malaria still represents the most frequent notifiable imported disease in Italy. The present study analyzes all the malaria cases reported in Italy in 2000-2006 in order to assess the trend of incidence over the time and reviewing the risk factors for travelers visiting malaria endemic countries. METHODS All 2000-2006 case report forms were analyzed. The incidence of malaria in Italian travelers was calculated by continent and by countries most visited, using data provided by the Ministry of Transportation. RESULTS Out of the 5219 malaria cases reported and confirmed in the study period five were autochthonous and 5214 imported, 1518 of which occurred in Italian citizen and 3696 in foreigners. Between 2000 and 2006 imported malaria cases fell from 977 to 630 respectively, with a total reduction of about 36%. Most of the cases were contracted in Africa (93%) and Plasmodium falciparum was the etiological agent in 83% of the cases, with an annual average fatality rate of about 0.5%. The average of the crude incidence rate (CIR) among Italians was calculated by continent for both global cases (gCIR) and for P. falciparum cases (pfCIR) resulting of 1.2/1000 and 0.9 for Africa, 0.08/1000 and 0.02 for Asia, 0.03/1000 and 0.003 for Central and South America, respectively. The gCIR by continent slightly but decreased constantly over the study period. DISCUSSION The different factors which may influence the risk of contracting malaria for travelers visiting endemic countries and the strategy to reduce completely the number of fatal cases were considered and discussed.

Outstanding plasmodicidal properties within a small panel of metallic compounds: hints for the development of new metal-based antimalarials

A variegate group of metallodrugs was evaluated in vitro for antimalarial activity through the pLDH test. The panel comprised one mononuclear gold(III) complex, (Aubipy), three dinuclear gold(III) compounds (Auoxo4, Auoxo5 and Auoxo6), three ruthenium(III) complexes (NAMI A, PMRU20, PMRU27), one ruthenium(II) complex (PMRU52), one bismuth(III) compound (Bismuth citrate), antimony trichloride (SbCl(3)) and arsenic trioxide (As(2)O(3)). This panel, although relatively small, was built up in such a way to include a variety of metal centers, structural motifs and metal coordination environments. In general, the tested compounds turned out to contrast effectively Plasmodium falciparum growth in vitro. In two cases, i.e. NAMI A and antimony trichloride, IC(50) values in the high nanomolar range were measured. Notably, the antiplasmodial effects appear not to be correlated to in vitro anticancer properties. The mechanistic and pharmacological implications of the obtained results are discussed.

Monitoring for multidrug‐resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola

Objectives  To assess the extent of drug resistance in Uige through molecular genetic analysis and to test whether the dhfr triple mutant alleles present in Angola are of southeast Asian origin.

Short History of Malaria and Its Eradication in Italy With Short Notes on the Fight Against the Infection in the Mediterranean Basin

In Italy at the end of 19th Century, malaria cases amounted to 2 million with 15,000–20,000 deaths per year. Malignant tertian malaria was present in Central-Southern areas and in the islands. Early in the 20th Century, the most important act of the Italian Parliament was the approval of laws regulating the production and free distribution of quinine and the promotion of measures aiming at the reduction of the larval breeding places of Anopheline vectors. The contribution from the Italian School of Malariology (Camillo Golgi, Ettore Marchiafava, Angelo Celli, Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli) to the discovery of the transmission’s mechanism of malaria was fundamental in fostering the initiatives of the Parliament of the Italian Kingdom. A program of cooperation for malaria control in Italy, supported by the Rockefeller Foundation started in 1924, with the establishment of the Experimental Station in Rome, transformed in 1934 into the National Institute of Public Health. Alberto Missiroli, Director of the Laboratory of Malariology, conducted laboratory and field research, that with the advent of DDT brought to Italy by the Allies at the end of the World War II, allowed him to plan a national campaign victorious against the secular scourge.

Frequency distribution of antimalarial drug resistance alleles among Plasmodium falciparum isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan.

In 2004, Sudan adopted artesunate + sulfadoxine/pyrimethamine (SP) combination as the first-line drug, in response to the high level of falciparum resistance to antimalarials. In 2007, a molecular study on antimalarial resistance linked genes, pfcrt, pfmdr1, pfdhfr, pfdhps, and pfATPase6, was conducted on 198 isolates from central and eastern Sudan. We observed a high frequency of point mutations at almost all loci analyzed, mainly of pfcrt 76T (72.7%), pfdhfr 51I (75.3%), and pfdhfr 108N (72.7%) alleles. The MARK III in vitro test for chloroquine sensitivity in 45 P. falciparum isolates showed that 37.8% of the isolates were low resistant and 6.7% were fully resistant. This study represents the most recent molecular investigation on antimalarial resistance in this area after the adoption of artemisinin-based combination therapy (ACT), and underlines the importance of the analysis of SP resistance evolution to monitor the efficacy of ACT therapy in endemic areas.

Genetic Confirmation of Quinine-Resistant Plasmodium falciparum Malaria Followed by Postmalaria Neurological Syndrome in a Traveler from Mozambique

ABSTRACT A case of quinine-resistant Plasmodium falciparum malaria, followed by a postmalaria neurological syndrome and a recurrence episode, is described. Genetic characterization of the P. falciparum isolate obtained by analysis of msp1 and msp2 amplicons revealed the coexistence of two genotypes causing the first malaria episode and the presence of a unique isolate responsible for the recurrence.

Prevention and morbidity of malaria in non-immune subjects; a case-control study among Italian troops in Somalia and Mozambique, 1992–1994

The impact of malaria on Italian troops taking part in 1992-1994 in the United Nations Organization humanitarian missions in Somalia and Mozambique is discussed. In Somalia, 18 cases of Plasmodium falciparum malaria occurred among 11,600 soldiers; the overall attack rate was 0.4 cases/1000/month of exposure and the risk of malaria was effectively reduced by chemoprophylaxis with chloroquine plus proguanil (C+P) (odds ratio [OR] = 0.05, 95% confidence limits [95% CL] 0.02-0.16). In Mozambique, 119 cases of P.falciparum malaria occurred among 4800 soldiers; most cases (100) occurred in the first months of deployment (late March-June 1993), with an attack rate of 17 cases/1000/month, when C+P was the recommended chemoprophylactic regimen; the remaining 19 cases occurred subsequently, with an attack rate of 1.8 cases/1000/month, after C+P was replaced by mefloquine in July 1993. Protection achieved by C+P was unsatisfactory (OR = 0.37, 95% CL 0.21-0.67), while chemoprophylaxis with mefloquine effectively reduced the risk of malaria in Mozambique (OR = 0.03; 95% CL 0.01-0.10). A significant number of malaria infections was also detected among soldiers following their return home from Somalia (147 cases) and Mozambique (40 cases); these were due mainly to P. vivax. Fifteen of 113 P. vivax primary infections imported from Somalia (13.3%) relapsed 2-13 months after the primary attack. Because of the small proportion of relapsing P. vivax tropical strains, primaquine may be limited to radical treatment of relapses or, more extensively, of all P. vivax infections, but it should not be necessarily given to all asymptomatic subjects returning from tropical endemic areas, as is generally suggested for particular groups at risk.