Primaquine revisited six decades after its discovery.

Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria.

Electrospray ionization-ion trap mass spectrometry study of PQAAPro and PQProAA mimetic derivatives of the antimalarial primaquine.

Electrospray ionization-ion trap mass spectrometry (ESI-MS) of imidazolidin-4-one peptidomimetic derivatives of the antimalarial drug primaquine (PQ) is reported. These compounds contain the imidazolidin-4-one moiety either at the N- or the C-terminal of a dipeptide backbone, thus respectively mimicking PQ-Amino Acid-Proline (PQAAPro) and PQProAA derivatives of PQ. Both the peptidomimetics and precursors previously developed by us are promising drug candidates, as they were found to be active against rodent Plasmodium berghei malaria and Pneumocystis carinii pneumonia.

Imidazolidin-4-one peptidomimetic derivatives of primaquine: synthesis and antimalarial activity.

The synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.

Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones.

A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 microg/mL and displayed slight to marked activity.

Cyclization-activated prodrugs.

Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intraindividual variability that affects enzymatic activity.

Thermochemical studies on 3-methyl-quinoxaline-2-carboxamide-1,4-dioxide derivatives: enthalpies of formation and of N-O bond dissociation.

The standard molar enthalpies of formation of the 3-methyl-N-R-2-quinoxalinecarboxamide-1,4-dioxides (R = H, phenyl, 2-tolyl) in the gas phase were derived using the values for the enthalpies of combustion of the crystalline compounds, measured by static bomb combustion calorimetry, and for the enthalpies of sublimation, measured by Knudsen effusion, at T = 298.15 K. These values have also been used to calibrate a computational procedure that has been employed to estimate the gas-phase enthalpies of formation of the corresponding 3-methyl-N-R-2-quinoxalinecarboxamides and also to compute the first, second, and mean N-O bond dissociation enthalpies in the gas phase.

[Adjuvant and alternative analgesia.].

Background And Objectives: Although acute and chronic pain are usually controlled with pharmacological interventions, 14 complementary methods of adjuvant and alternative analgesia (AAA) may reduce the abusive prescription of analgesics and the side effects that eventually compromise the patient's physiological status.

Contents: The action of every analgesic mechanism is through the spinal gate of Melzack and Wall and/or through signal transduction in the central neurotransmission and neuromodulation systems related to analgesia, relaxation, and mood: peptidergic, monoaminergic, gabaergic, cholinergic, and cannabinoid. Complementary adjuvant analgesia is normally used in physiatric, orthopedic, rheumatologic, and obstetric treatments and acupuncture.

[Serendipity in medicine and anesthesiology.].

Background And Objectives: This study has evaluated more than a hundred of the most fortunate couplings of a brilliant mind with fortunate luck (serendipity), through the re-reading of most relevant histories on science-related (n = 46) and anesthesiology-related (n = 16) inventions and discoveries.

Contents: This educational article encourages anesthesiologists to appreciate events related to scientific inventions and discoveries, showing that serendipity is possible, provided it is expected. Each discovery or invention includes history, references and scientific or anecdotal explanation.

Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarials.

Imidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.

[Anesthesia in the afro-american population].

Background And Objectives: A significant percentage of the 12 million Afro-Americans may present physiological, pathophysiological and pharmacological changes able to impact the success of anesthesia; Brazilian Afro-American population (40%) is subject to those changes for having the same ethnic and geographic origin. This review aimed at re-evaluating racial differences bias on potential anesthetic drug and adjuvant effect changes during anesthesia.

Contents: The analysis of pathophysiological studies inherent to the historical migration of the African gene as compared to Caucasians shows significant racial differences between Afro-American and African populations, suggesting a close interface between genetics and environment able to affect anesthesia.

[Could the understanding of racial differences prevent idiosyncratic anesthetic reactions?].

Background And Objectives: There are several unanswered questions about the interethnic variability in anesthetic and adjuvant drugs responses. Current pharmacogenetic developments are taking us to the verge of being able to identify inherited racial differences which could predict individual patients anesthetic response.

Contents: The understanding of interethnic factors affecting drug response will allow anesthesiologists to prevent idiosyncratic reactions: (1) Caucasian: increased dopamine diuretic effect; prolonged apnea following succinylcholine or mivacurium; cardiac arrhythmias after halothane and catecholamines in Riley-Day syndrome; acute porphyria episodes after thiopental.

[Nine Biblical anesthetic premises.].

Background And Objectives: The authors produced a historical analysis of nine anesthesia-related premises described in the Bible more than 3,500 years ago (Old Testament). Anesthetic drugs and adjuvants, patients, anesthesiologists attitudes and techniques are discussed in the light of Biblical and modern science.

Contents: To help understanding, the nine premises evaluated are correlated to the book of Bible citation: I - Jehovah, the pioneer of inhalational anesthesia - Gen 2; II - Alcoholic hypnosis and anesthesia - Prov 20, Gen 19, Marc 15; III - Anesthesia-related Chaos and Chronobiology - Gen 1, Ecles 3; IV - Anesthetic drugs Stereoisomerism - Ecle 42, Gen 1; V - Elijah s and Elisha s cardiopulmonary resuscitation - Gen 2, Kings III 17, Kings IV 4; VI - Tocoanalgesia - Gen 3, Rev 12, Gen 35 and Rachels post-partum death - Ex 1; VII - Jehovah s witnesses interpretation of blood transfusion forbiddance - Lev 7,17; VIII - Acidosis for epileptic seizure treatment - Math 17; IX - Death on the cross by hypovolemic shock - Marc 15, John 19.

[Is there still a place for pharmacobotany in modern anesthesiology?].

Background And Objectives: Recently, the use of medicinal teas - infusions, decoction, tisanes, dyeings - or drugs of vegetal origin are being systematically and increasingly revived to prevent and treat diseases together with conventional medicine in most Western countries. This review aimed at analyzing major herbs that were the basis for the progress of modern anesthetic therapy through their use as molecular models for organic synthesis in fine leading edge modern chemistry, as well as shedding more light on the advantages, potential adverse effects, interactions and risks for side-effects which may affect anesthesia in surgical patients users of phytotherapy.

Contents: Selected anesthesiologic considerations are discussed focusing a brief review of popular herbs essentials on the development of anesthetic pharmacology and the potential drug-herb interactions between synthetic drugs used in anesthesia and the medicinal herbs used by patients in their illness and symptoms management.

Decreased susceptibility to local anesthetics-induced convulsions after paradoxical sleep deprivation.

The effect of 50% convulsant (CD50) and 50% lethal (LD50) doses of lidocaine, bupivacaine and pentylenetetrazol were determined in mice stressed by paradoxical sleep deprivation (PSD). The results showed a reduced mortality after high doses of local anesthetics and decreased seizure susceptibility induced by bupivacaine after 48 h and 72 h of PSD. On the other hand this stressful manipulation increased the susceptibility to pentylenetetrazol-induced convulsions.