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N-methyl-D-aspartate (NMDA) receptors are inhibited by many medicinal drugs. The recent successful repurposing of NMDA receptor antagonists ketamine and dextromethorphan for the treatment of major depressive disorder further enhanced the interest in this field. In this work, we performed a screening for the activity against native NMDA receptors of rat CA1 hippocampal pyramidal neurons among biguanide compounds using the whole-cell patch-clamp method. Antimalarial biguanides proguanil and cycloguanil, as well as hypoglycemic biguanide phenformin, inhibited them in micromolar concentrations, while another hypoglycemic biguanide metformin and antiviral biguanide moroxydine were practically ineffective. IC50 values at −80 mV holding voltage were 3.4 ± 0.6 µM for cycloguanil, 9.0 ± 2.2 µM for proguanil and 13 ± 1 µM for phenformin. The inhibition by all three compounds was not competitive. Cycloguanil acted as an NMDA receptor voltage-dependent trapping channel blocker, while proguanil and phenformin acted as allosteric inhibitors. Our results support the potential clinical repurposing of biguanide compounds for the treatment of neurodegenerative disorders linked to glutamatergic excitotoxicity while also providing a better understanding of structural determinants of NMDA receptor antagonism by biguanides. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors are inhibited by many medicinal drugs. The recent successful repurposing of NMDA receptor antagonists ketamine and dextromethorphan for the treatment of major depressive disorder further enhanced the interest in this field. In this work, we performed a screening for the activity against native NMDA receptors of rat CA1 hippocampal pyramidal neurons among biguanide compounds using the whole-cell patch-clamp method. Antimalarial biguanides proguanil and cycloguanil, as well as hypoglycemic biguanide phenformin, inhibited them in micromolar concentrations, while another hypoglycemic biguanide metformin and antiviral biguanide moroxydine were practically ineffective. IC50 values at −80 mV holding voltage were 3.4 ± 0.6 µM for cycloguanil, 9.0 ± 2.2 µM for proguanil and 13 ± 1 µM for phenformin. The inhibition by all three compounds was not competitive. Cycloguanil acted as an NMDA receptor voltage-dependent trapping channel blocker, while proguanil and phenformin acted as allosteric inhibitors. Our results support the potential clinical repurposing of biguanide compounds for the treatment of neurodegenerative disorders linked to glutamatergic excitotoxicity while also providing a better understanding of structural determinants of NMDA receptor antagonism by biguanides.

Simple Summary: This study assessed the efficacy of treating snowy owls naturally infected by Plasmodium relictum with atovaquone (AV) and proguanil (PH). AV/PH was administered at 10/4 mg/kg/day for three days, repeated a week later. Results showed the treatment was effective in clearing the parasite from the birds' blood, with no relapses observed. Additionally, hematological improvements were noted, suggesting recovery. No significant adverse effects were observed, indicating the safety of the treatment. This study highlights the potential of AV/PH as a treatment option for avian malaria in unconventional or endangered bird species. Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus Plasmodium, mainly Plasmodium relictum. The even wider diffusion of the disease, probably because of the increase in the areas covered by their mosquito vectors, may pose new risks for avian species lacking natural resistance (especially those from artic or sub-artic environments) or those hosted in structures like zoos and wildlife rescue centers. With that premise, this study describes the efficacy and safety of a therapeutic protocol to treat avian malaria in three snowy owls (Bubo scandiacus) hosted in a wildlife rescue center in Apulia, south of Italy, and affected by avian malaria by P. relictum. The protocol consisted of administering 10/4 mg/kg atovaquone/proguanil per os once a day for three consecutive days, repeating this seven days later. Seven days after the end of the treatment, P. relictum was not detected in the birds' blood and no adverse effects were observed during the 60 days of monitoring after the end of the treatment. Therefore, a therapeutic regimen of 10/4 mg/kg/day may be considered safe and effective in a valuable and endangered species such as B. scandiacus. [ABSTRACT FROM AUTHOR]

BackgroundThe Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug-susceptibility data for P falciparum field isolates are limited.MethodsWe studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda, from 2016 to 2020, sequenced 383 isolates, and assessed associations between genotypes and drug-susceptibility phenotypes.ResultsMedian half-maximal inhibitory concentrations (IC50s) were 42 100 nM for pyrimethamine, 1200 nM for cycloguanil, 13000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, 3 PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50s of 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I/59R/108N/164L) parasites.ConclusionsResistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.

The present research study was aimed to investigate the efficiency of selected medicinal plants against Plasmodium vivax. Crude methanolic extracts from the seeds of leaves of Datura stramonium, Parthenium hysterophorus, Calotropis procera, and Dodonaea viscosa were prepared. In addition, Atropine was also isolated from alkaloid components of Eucalyptus obliqua to evaluate their in vitro anti-plasmodial effects. It was observed that proguanil (positive control) and Atropine displayed strong anti-plasmodial activity (94.04 and 68.02%, respectively) against P. vivax at 0.1 mg/mL concentration while the leaf extracts of other medicinal plants did not exhibit any notable anti-plasmodial activity. It was concluded that alkaloids of E. obliqua plant’s extracts were rich in anti-plasmodial compound Atropine, which exhibit a remarkable anti-plasmodial activity against P. vivax. Anti-plasmodial action of medicinal plants are attributed to these phytochemicals. In vitro studies using medicinal plant’s extracts and standardized methods will help to make more powerful and cost-effective anti-plasmodial compounds.

The therapeutic efficacy of herbal medicines in the treatment of human diseases or disorders has gained more attention over the years. A survey established that approximately 15 % of patients receiving orthodox medicine also take herbal products, and among these, potential adverse herbto- drug interactions were observed in 40 % of patients. Recently, there have been reports of herbdrug interactions which have impacted on wellness of users resulting in toxicity or loss of therapeutic efficacy of either the herb or the orthodox drug when co-administered. These reports make herb-drug interactions a research area of public interest. This study was embarked upon to evaluate the effect of Ciklavit® used for the management of sickle cell anaemia on the pharmacokinetic profile of proguanil tablets in healthy Nigerian volunteers. Twelve healthy participants were recruited and completed the study after signing a consent form. The study was performed using a single dose, two-way randomized crossover design. The participants were randomly grouped into control and treatment. The treatment group were administered proguanil tablets with Ciklavit® while the control group took proguanil with water only. The blood and urine samples collected at different time interval for 24 hours were analyzed using High Performance Liquid Chromatography. The results obtained, demonstrated that co-administration of Ciklavit® with proguanil altered pharmacokinetic parameters of proguanil but the difference in values were found to be statistically insignificant (p>0.05). The study demonstrated that there are no significant pharmacokinetic interactions between proguanil and Ciklavit® hence the two medicinal agents can be co-administered. [ABSTRACT FROM AUTHOR]

Abstract Background Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking. Methods By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62–0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81). Conclusions This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.

Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus Plasmodium, mainly Plasmodium relictum. The even wider diffusion of the disease, probably because of the increase in the areas covered by their mosquito vectors, may pose new risks for avian species lacking natural resistance (especially those from artic or sub-artic environments) or those hosted in structures like zoos and wildlife rescue centers. With that premise, this study describes the efficacy and safety of a therapeutic protocol to treat avian malaria in three snowy owls (Bubo scandiacus) hosted in a wildlife rescue center in Apulia, south of Italy, and affected by avian malaria by P. relictum. The protocol consisted of administering 10/4 mg/kg atovaquone/proguanil per os once a day for three consecutive days, repeating this seven days later. Seven days after the end of the treatment, P. relictum was not detected in the birds’ blood and no adverse effects were observed during the 60 days of monitoring after the end of the treatment. Therefore, a therapeutic regimen of 10/4 mg/kg/day may be considered safe and effective in a valuable and endangered species such as B. scandiacus.

With an aim to assess the pharmacokinetics of atovaquone, 10 healthy subjects were administered Malarone® alone and in combination with ketoconazole in a crossover study. The results indicated 68% higher Cmax, 74% higher AUC and 34% lower CL/F of atovaquone following co-administration with ketoconazole compared to administration of atovaquone alone. [ABSTRACT FROM AUTHOR]

Aim: In Nigeria, proguanil is the recommended drug for malaria chemoprophylaxis in persons with sickle cell anaemia (SCA); however, over the years, studies have given controversial reports on the effectiveness of proguanil as chemoprophylaxis. This paper highlights the controversies and the problems of continuous chemoprophylaxis with proguanil; and the need to explore more effective malarial chemoprevention method: Intermittent Preventive Treatment (IPT). This is a narrative review of studies on the efficacy of malaria chemoprophylaxis in persons with SCA focusing on proguanil and IPT. Method: A total of seven (7) studies on the efficacy of IPT and malaria chemoprophylaxis using proguanil in SCA were found using the following search engines: Google Scholar, Pub Med, MEDLINE, Med Scape and Cochrane review databases. Result: Malaria chemoprophylaxis seems to be more useful in young children than in adults. Proguanil is less efficacious in reducing malaria induced morbidity and mortality in SCA, compared to IPT using sulphadoxine/pyrimethamine (SP) or mefloquine/artesunate (MQAS). Conclusion: Age may bean important determinant of efficacyof malaria chemoprophylaxis in the reduction of malaria induced morbidity (parasite density, clinical malaria, severe anaemia, and vasoocclusive crises) in persons with SCA; being more useful in young children than in adults. There may be a need to set separate policies on malaria chemoprevention for adults and children. It is paramount to consider a change of the current policy on malaria chemoprophylaxis in children with SCA from proguanil to IPT using SP, MQAS or other efficacious drugs for the present and the future.

Over one billion people worldwide are expected to have Toxoplasma gondii infection with anonymous health problems. Available therapies are ineffective for persistent chronic toxoplasmosis. So, there is an imperative need for effective therapies to eliminate chronic tissue stage. In this study, we aimed to assess the effect of a drug combination of atovaquone and proguanil hydrochloride in the treatment of experimental chronic toxoplasmosis. Fifty Swiss Webster mice were used in the study. Forty mice were infected with Me49 type II cystogenic Toxoplasma gondii strain and allocated into four groups: infected untreated (vehicle-administered), infected and treated with cotrimoxazole (CTX) 370 mg/kg/day, infected and treated with atovaquone (ATV) 100 mg/kg/day, and infected and treated with atovaquone/proguanil (ATV/PROG) 50 mg/kg/day. An additional group of uninfected mice was used as an uninfected control group. Drug treatment was initiated 8 weeks post-infection and continued for two weeks. All mice were sacrificed 12 weeks post-infection. Parasitological and histopathological parameters were assessed. Toxoplasma gondii cysts recovered from brain tissue homogenates of both infected untreated and ATV/PROG-treated groups were examined by scanning electron microscopy. Combined ATV/PROG treatment demonstrated a significant reduction of Toxoplasma gondii cyst count in brain tissue (a reduction rate of 84.87%) compared to untreated group (P <.001). Brain tissues obtained from ATV/PROG treated group showed reduction of inflammatory infiltrate and marked attenuation and deformation of recovered Toxoplasma gondii cysts. We conclude that ATV/PROG drug combination could offer a potential drug therapy for Toxoplasma gondii chronic cystic stage. [ABSTRACT FROM AUTHOR]

• PRG and CHX combined with CLR or RIF are effective against A. baumannii. • Combination therapy prevents the formation of antibiotic resistance in A. baumannii. • Combination therapy improves survival and speeds wound healing in infected mouse. • PRG and CHX enhance intracellular accumulation of CLR and RIF. The emergence of Acinetobacter baumannii infections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates of A. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistant A. baumannii , exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistance in vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitoneal A. baumannii infections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption of A. baumannii cell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combat A. baumannii infections and improve treatment outcomes in clinically challenging scenarios. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model., Methods: The animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 10 4 P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge., Results: Group 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ + CD8 + , IFN-γ + CD4 + , and IFN-γ + γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ + CD8 + , IFN-γ + CD4 + , and IFN-γ + γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow., Conclusions: This research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax., (© 2024. The Author(s).)

We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms other than metabolic inhibition may be involved., Competing Interests: Declaration of competing interest The authors declare no competing interests., (© 2023 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.)

The effectiveness of malaria chemoprophylaxis is limited by a lack of compliance in travellers. This study assesses the demographic, travel-related, and psychosocial determinants of non-compliance with chemoprophylaxis. 715 adults, who received a pre-travel malaria prophylaxis prescription, were invited to complete a post-travel digital questionnaire on non-compliance, demographics, travel-related and psychosocial variables. 330 travellers (53% response) reported 32% non-compliance with malaria chemoprophylaxis. Logistic regression analyses revealed that 3/11 assessed psychosocial variables uniquely predicted non-compliance: 'negative attitude towards chemoprophylaxis' (β = 0.694, OR 2.0, p < 0.01), 'low perceived severity of malaria' (β = 0.277, p = 0.04) and 'fatigue during travel' (β = 2.225, OR 9.3, p < 0.01). Furthermore, the age and education of the traveller were uniquely predictive of non-compliance (β = −0.023 (p = 0.02) and β = 0.684 (p = 0.04)). None of the travel-related variables predicted non-compliance. About one-third of the travellers in our study were non-compliant with malaria prophylaxis, especially young travellers and highly educated travellers. Fatigue during travel seems to lead to non-compliance. Further research should focus on addressing the psychosocial factors in pre-travel consultation, since these appear to be better predictors for intention to comply than travel-related variables. [ABSTRACT FROM AUTHOR]

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Background: The drug combination atovaquone–proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone–proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb). Case presentation: A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone–proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine–artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone–proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance. Conclusion: This is the first observation of a late clinical failure of atovaquone–proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone–proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone. [ABSTRACT FROM AUTHOR]