The chemistry,pharmacology and clinical pharmacology of diflunisal

Summary

Studies are reviewed on diflunisal, a new analgesic agent with an improved therapeutic index, compared with acetylsalicylic acid, in animals and humans. Pharmacokinetic data indicate that a twice-daily dosage regimen of diflunisal is adequate for therapeutic purposes. Diflunisal inhibits prostaglandin E synthesis, but in humans at clinically effective doses it does not alter bleeding time or platelet aggregation. Diflunisal is uricosuric at clinically effective doses. No clinically important drug interactions with diflunisal have been found to date, although some slight alterations in blood and urine drug levels have been noted. The slight increase in prothrombin time seen when diflunisal and acenocoumarol were co-administered is not considered to be of major clinical importance.     

The pharmacology of apoptosis

Apoptosis is an area of intense scientific interest, which encompasses the study of and triggers mechanisms involved in mediating the cell biology of programmed cell death. A number of low molecular weight compounds have been used to inhibit or enhance this fundamental cellular process and so apoptosis has now become amenable to pharmacological manipulation. In this review Ross Kinloch, Mark Treherne, Mike Furness and Iradj Hajimohamadreza will focus on the current literature describing the pharmacology of apoptosis, with particular reference to the therapeutic potential that could arise from the development of pro- and anti-apoptotic drugs. The pivotal role of apoptosis in such diverse pathological processes as tumour growth, the immune response and neurodegeneration suggests that an understanding of how apoptosis can be regulated by drugs will become increasingly important to the pharmaceutical industry.     

The pharmacology of adenosine

Adenosine is a purine nucleoside present in every cell of the human body. It is released into the extracellular space under physiologic and pathophysiologic conditions characterized by increased oxygen demand:supply ratio. Adenosine can exert a wide spectrum of effects in various organs and tissues. Exogenous adenosine has a wide spectrum of effects in experimental animal models as well as humans. The pharmacokinetics, pharmacodynamics, and the interaction of adenosine with other drugs are reviewed.     

The pharmacology of cough

Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as to this article.     

The pharmacology of methotrexate

Ectopic pregnancy (EP) is a major cause of maternal morbidity and mortality. The treatment of this condition is primarily surgical, but medical management in selected cases is safe, effective, cost-effective and eliminates the morbidity of surgery. Methotrexate (MTX) is a folate antagonist that can be used for non-oncologic purposes including the treatment of EP. The dose and duration of MTX therapy for EP is much lower than that used in oncology cases, thus reducing side effects and increasing safety. MTX selectively acts on rapidly dividing cells, such as trophoblast cells which comprise the implantation site of the early gestation. The two most common methods of administering MTX to patients with EP are im. administration of a single-dose, based on body surface area and calculated by the equation 50 mg/m(2) (without the need for leucovorin rescue), or the multiple-dose regimen of 1 mg/kg of MTX, alternating with 0.1 mg/kg of leucovorin rescue. Both methods have a similar side effect profile, resulting in the rare occurrence of nausea, vomiting, stomatitis, elevated liver function tests, anorexia and diarrhoea. The two methods yield success rates similar to those of conservative surgical therapy with similar future fertility. The potential single- and multi-dose methods have never been directly compared, but it appears that the success of multiple dosing is more effective. As the efficacy of MTX therapy is not 100%, women must be followed clinically until there is compete resolution of human Chorionic Gonadotropin (hCG) titres from their serum.     

The pharmacology of bosentan

This article describes the pharmacological properties and the overall preclinical and clinical profiling of bosentan (Ro 47-0203), a non-peptide endothelin receptor antagonist with oral activity. Bosentan is a combined and competitive antagonist of both ET_A and ET_B receptors that is selective for the endothelin system. In vitro and in vivo, bosentan potently antagonises the vascular response elicited by the endothelins. Preclinical efficacy is demonstrated in a variety of pathological models including pulmonary and essential hypertension, renal failure of ischaemic and nephrotic origin and cerebral vasospasm following subarachnoid haemorrhage. Effects are particularly marked in experimental models of heart failure (HF) where bosentan acts as a potent vasodilator that improves overall left ventricular performance. After chronic treatment, bosentan also improves survival in rats with HF. As a result of the first encouraging clinical results that show pulmonary and systemic vasodilation, long-term studies are ongoing in the treatment of congestive heart failure (CHF).     

The pharmacology of chloralose

Résumé Après revue des papiers publiés en anglais, français et allemand sur les chloraloses depuis 1893, les auteurs ont trouvé que la recherche a été concentrée sur les monoglucochloraloses alpha et beta (principalement alpha), et a été limitée en général à l'étude de leur action sur le système nerveux central et périphérique. Les résultats sont contradictoires, particulièrement en ce qui concerne leur activité pharmacologique. Les explications possibles de ces résultats contradictoires semblent indiquer que le concept couramment accepté des monoglucochloraloses comme des «convulsivants anesthésiques» est une hypothèse qui peut prêter à confusion.Comme alternative, les auteurs proposent une autre hypothèse qui explique la plupart des effets du chloralose alpha sur le système nerveux central comme résultant de son action sédative qui interrompt le «negative feedback» du circuit reticulo-cortical-réticulaire. Cette rupture proviendrait tout d'abord de l'effet sédatif du chloralose sur le cortex, supprimant son influence inhibitrice sur le thalamus et la formation réticulée mésencéphalique. A ce point, la dépression corticale, mise en évidence par de la tranquillité, un ralentissement du processus mental et l'augmentation du seuil convulsif, n'est pas accompagnée d'une dépression des zones subcorticales comme en anesthésie barbiturique mais d'une excitation de ces mêmes zones soit directement soit indirectement par libération de l'influence inhibitrice du cortex. Donc, en dépit de cette dépression, il a été observé de l'hyperexcitabilité motrice, une augmentation des réactions d'association évoquées, un maintien de l'effet accru de la stimulation réticulaire sur les potentiels évoqués et une réaction d'éveil à la stimulation sensorielle. De plus, il semble qu'à doses plus élevées, cette spécific facilitation ou hyperexcitation a tendance à disparaître.

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Supported by Public Health Service Grant MH-04137.