4-Aminoquinoline derived antimalarials: synthesis, antiplasmodial activity and heme polymerization inhibition studies.

A new series of 4-aminoquinoline derivatives have been synthesized and found to be active against both susceptible and resistant strains of Plasmodium falciparum in vitro. Compound 1-[3-(7-chloro-quinolin-4-ylamino)-propyl]-3-cyclopropyl-thiourea (7) exhibited superior in vitro activity against resistant strains of P. falciparum as compared to chloroquine (CQ). All the compounds showed resistance factor between 0.59 and 4.31 as against 5.05 for CQ. Spectroscopic studies suggested that this class of compounds act on heme polymerization target.

Synthesis and antimalarial activity of novel side chain modified antimalarial agents derived from 4-aminoquinoline.

Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decade's emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified.

A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol)

OBJECTIVE: To compare the pharmacokinetics of Tylenol Extended Relief (ER APAP) with those of immediate-release acetaminophen (IR APAP) at supratherapeutic doses. METHODS: A prospective, double-blind, randomized, crossover comparison trial involving 14 adult volunteers. Each subject ingested 75 mg/kg of either ER APAP or IR APAP and 1 week later received the other APAP preparation. On both occasions plasma APAP concentration ([APAP]) was determined 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours after ingestion. The times to maximum [APAP] (Tmax); the maximum [APAP] values (Cmax); the elimination half-lives 4-16 hours postingestion (t1/2), and the areas under the [APAP] vs time curve (AUC) for ER APAP and IR APAP were compared using the paired t-test. RESULTS: All the subjects completed both study phases. The mean APAP dose ingested was 5.6 g (range 4.2-7.8 g). Both the AUC and the Cmax were less after ER APAP than after IR APAP; otherwise, there was no evident difference in any measure. Graphically, ER APAP yielded a flatter, plateau-shaped curve initially, but after 4 hours the curve was nearly identical to that for IR APAP. Results are summarized in the table: [table: see text] CONCLUSION: In this model involving a single supratherapeutic dose, ER APAP evidenced no pharmacokinetic features that would suggest the need for an alternate poisoning screening strategy. When compared with IR APAP, ER APAP had a lower AUC, all peak [APAP] occurred in < 4 hours, and terminal eliminations were identical. The data suggest that, in most cases, the diagnostic approach to an overdose of ER APAP need not deviate from that used for an IR APAP overdose.

Acetaminophen. Concepts and controversies.

APAP poisoning is common, and despite the availability of a specific antidote, fatalities still occur. Early treatment using NAC is highly effective in preventing liver injury, but further study is needed to determine optimum indications, route of administration, dosage, and duration of treatment. Recent advances have changed traditional concepts regarding late treatment and mechanisms of NAC action, but significant gaps in understanding persist. Immediate challenges include refining the diagnosis and treatment of APAP toxicity after repeated ingestions, defining settings in which deviation from standard protocols is appropriate, and improving therapy of APAP-induced hepatic failure.

Delayed cardiotoxicity following quinine overdose: a case report.

Quinine poisoning typically results in a constellation of non-life threatening symptoms which include tinnitus, deafness, nausea, vomiting, vision changes, headache, and hypotension. Cardiac conduction defects, dysrhythmias, and cardiovascular collapse have all been reported after overdose and generally occur within 8 hours of ingestion. We report a unique case of delayed cardiotoxicity following quinine ingestion. Toxicity included marked ventricular conduction abnormalities for which serum alkalinization appeared to be therapeutically beneficial, and torsades de pointes requiring overdrive pacing for termination.

Osmol gaps revisited: normal values and limitations.

A study was designed to define the osmol gap in patients whose serum ethanol concentrations are known, to reevaluate several accepted equations for calculating osmolarity, and to apply the results to the theoretical clinical scenario of a toxic alcohol ingestion. The design for the study used consecutive, prospective enrollment of all patients presenting to a large inner city hospital who clinically required determination of their serum ethanol and electrolytes. Three hundred and twenty one consecutive adult patients were enrolled in the study, sixteen were excluded from the final analysis. A stepwise multiple linear regression analysis was performed to determine the best coefficients for sodium, blood urea nitrogen, and ethanol from the data set. Osmolarity was then calculated using these coefficients and traditional models. The osmol gap (measured osmolality minus calculated osmolarity [2*Na + BUN/2.8 + Glu/18 + Etoh/4.6]) was -2 +/- 6 mOsm. Although different equations produced different osmol gaps (ranging from -5 to + 15 mOsm) the standard deviations and correlation coefficients were similar. Large variations exist in the range of osmol gaps. Absolute values are very dependent on the equations used to calculate osmolarity. Because of the larger range of values, small osmol gaps should not be used to eliminate the possibility of toxic alcohol ingestion.

Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.

STUDY OBJECTIVE: To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute acetaminophen overdose. DESIGN: Nonrandomized trial open to all eligible patients. SETTING: Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban settings. TYPE OF PARTICIPANTS: Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol, and sufficient data to determine outcome. INTERVENTIONS: IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours. MEASUREMENTS AND MAIN RESULTS: Patients were grouped for analysis according to risk group based on the initial plasma acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L) developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in 27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose, hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in 32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the loading dose that did not require discontinuation of therapy. CONCLUSION: This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late.

Whole bowel irrigation and the cocaine body-packer: a new approach to a common problem.

Gastrointestinal drug smuggling is a common problem in many major cities. Though the majority of cases never require medical attention, the "body-packer" frequently presents with life-threatening symptoms of intoxication, including seizures and cardiorespiratory collapse, as well as mechanical obstruction from the ingested drug packets. The risk to asymptomatic smugglers may vary with packaging materials, and remains unknown. Lack of controlled studies, and variations in packaging materials and clinical outcomes have prevented formulation of a consistent management strategy. Current recommendations for asymptomatic body-packers vary from immediate surgical removal, to use of laxatives, to observation. The authors present the first reported case of an asymptomatic cocaine body-packer treated with whole bowel irrigation with polyethylene glycol electrolyte lavage solution. This strategy was safe, well tolerated, resulted in the rapid elimination of drug packets from the gastrointestinal tract, and facilitated assessment by contrast radiography. The potential benefits and limitations for the use of whole bowel irrigation in this difficult problem are discussed.