Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (−)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (−)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(R)-PQ may have a better safety margin than the racemate in human

Effectiveness of Household Lockable Pesticide Storage to Reduce Pesticide Self-Poisoning in Rural Asia: a Community-Based Cluster Randomised Controlled Trial

Background Agricultural pesticide self-poisoning is a major public health problem in rural Asia. The use of safer household pesticide storage has been promoted to prevent deaths, but there is no evidence of effectiveness. We aimed to test the effectiveness of lockable household containers for prevention of pesticide self-poisoning. Methods We did a community-based, cluster-randomised controlled trial in a rural area of North Central Province, Sri Lanka. Clusters of households were randomly assigned (1:1), with a sequence computer-generated by a minimisation process, to intervention or usual practice (control) groups. Intervention households that had farmed or had used or stored pesticide in the preceding agricultural season were given a lockable storage container. Further promotion of use of the containers was restricted to community posters and 6-monthly reminders during routine community meetings. The primary outcome was incidence of pesticide self-poisoning in people aged 14 years or older during 3 years of follow-up. Identification of outcome events was done by staff who were unaware of group allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT1146496. Findings Between Dec 31, 2010, and Feb 2, 2013, we randomly assigned 90 rural villages to the intervention group and 90 to the control group. 27 091 households (114 168 individuals) in the intervention group and 26 291 households (109 693 individuals) in the control group consented to participate. 20 457 household pesticide storage containers were distributed. In individuals aged 14 years or older, 611 cases of pesticide self-poisoning had occurred by 3 years in the intervention group compared with 641 cases in the control group; incidence of pesticide self-poisoning did not differ between groups (293·3 per 100 000 person-years of follow-up in the intervention group vs 318·0 per 100 000 in the control group; rate ratio [RR] 0·93, 95% CI 0·80–1·08; p=0·33). We found no evidence of switching from pesticide self-poisoning to other forms of self-harm, with no significant difference in the number of fatal (82 in the intervention group vs 67 in the control group; RR 1·22, 0·88–1·68]) or non-fatal (1135 vs 1153; RR 0·97, 0·86–1·08) self-harm events involving all methods. Interpretation We found no evidence that means reduction through improved household pesticide storage reduces pesticide self-poisoning. Other approaches, particularly removal of highly hazardous pesticides from agricultural practice, are likely to be more effective for suicide prevention in rural Asia

A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol

BACKGROUND: The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. METHODS/DESIGN: A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. DISCUSSION: This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects

Investigating the Photochemistry of Azobenzene and Nitrobenzyl Compounds

Azobenzene undergoes reversible cis↔ trans photoisomerization upon irradiation. Substituents often change the isomerization behavior of azobenzene, but not always in a predictive manner. We have synthesized several (aminomethylpyridine)azobenzene (AzoAMP) derivatives with unusual optical properties. These AzoAMPs exhibit minimal trans →cis photoisomerization, extremely rapid cis→trans thermal recovery and enhanced fluorescence emission. Computational and x-ray crystallographic data indicate intramolecular hydrogen bonding and electronic effects of substituents are responsible for the unusual behavior of AzoAMPs. Confirmation that AzoAMPs retain excited state photochemistry analogous to azobenzene was provided by ultrafast transient absorption spectroscopy. Photoactivity of AzoAMPs can be restored by chemical modification of functional groups and substituents. Our findings indicate the preferred mechanism for isomerization of AzoAMPs to be concerted-inversion. ^ Caged complexes are metal ion chelators that release analytes when exposed to light of a specific wavelength. We are interested in designing and synthesizing cages for Zn2+ that fragments upon photolysis. The general uncaging strategy involves integrating a nitrobenzyl group on the backbone of a ligand so that a carbon-heteroatom bond is cleaved following illumination. Several caged complexes (ZinCleavs) were obtained using a new synthetic strategy involving a Strecker synthesis to prepare a key aldehyde intermediate. The ability of ZinCleavs to increase free [Zn2+] was demonstrated practically by using fluorescent sensors to image the liberated Zn 2+. Dissociation constant and quantum yield measurements indicate ZinCleavs are capable of perturbing zinc homeostasis in live cells under experimental conditions. Free Zn2+ may function as a neurotransmitter and have a role in the pathology of several neurological diseases. Studying these physiological functions remains challenging because Zn2+ is silent to most common spectroscopic techniques. ZinCleavs are the first cages reported for Zn2+ and will facilitate biological investigations.

Hypertensive Crisis in Pregnancy with COVID19: Confirmed with rt-PCR for Nasopharyngeal Swab

The novel coronavirus has already spread across the geographical borders to 213 countries and self-governing territories. However, the effect of SARS-CoV-2 infection on pregnant mothers is still poorly understood and sparsely documented. Here, we present a case of a primi mother, who presented with diarrheal episode and proceeded to a hypertensive crisis and placental abruption with rt-PCR (nasopharyngeal swab) confirmed for COVID19. SARS-CoV-2 enters and downregulates host cell-bounded enzyme ACE2 (angiotensin-converting enzyme). This activates the renin angiotensin aldosterone mechanism (RAAM). The activation of RAAM plays a pivotal role in the pathophysiology of hypertensive emergencies. Hence, there is a theoretical possibility of hypertensive crisis associated with ACE2/RAAM dysfunction in pregnant mothers who have COVID19. Therefore, close monitoring of blood pressure and early intervention are of paramount importance in anticipating and preventing serious complications related to hypertension in pregnancy in mothers who have tested positive for SARS-CoV-2, especially in this pandemic situation. Emergency hospital admission and urgent care must be afforded to mothers presenting with high blood pressure with the features suggestive of COVID19 as they are at a risk of rapid deterioration

Non-Directed, Pd-Catalyzed C-H Amination of Simple Arenes

We describe the first Pd catalyzed method for theone-step C H amination of simple arenes. The activity of thecatalysts is highly dependent on the Pd:ligand ratio and theidentity of the used ligands. Turnover numbers up to 12 can beachieved