The potential use of markers in drug development.

There are at least three recurring questions crucial to the drug and drug formulation development processes that could be addressed by marker methodology: (1) Is the assessment of an effective dose or dose regimen correct? (2) Is an inadequate response or nonresponse secondary to pharmacology or to inadequate compliance? (3) Can various formulations provide significantly better therapy for certain populations? Characteristics of an ideal marker system would include: Simple and reliable to measure. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. Biologically inert. Samples for measurement can be obtained unobtrusively. Samples are painless to obtain (for patient and clinic staff). Absorption and kinetic characteristics approximate those of the therapeutic candidate. Able to be presented in multiple formulations. Current methodology for addressing these questions is far short of ideal. Therefore, if marker methodology that lacks the limitation of present technology could be developed, it potentially would find wide use during the drug development process.

'Osmosin' (sodium indomethacin trihydrate) in the treatment of elderly patients with osteoarthritis.

A 12-week, double-blind, multi-centre trial was carried out in 402 out-patients with osteoarthritis to compare the efficacy and tolerability of the osmotic-release formulation of indomethacin ('Osmosin') with that of indomethacin capsules. Data from a sub-set of 178 patients aged 60 years or over were analyzed separately. The results indicated that 'Osmosin', releasing the equivalent of 7 mg indomethacin per hour over approximately 10 hours, provided efficacy comparable to or better than that of indomethacin capsules (25 mg 3-times daily) and had a better tolerance profile. Fewer patients treated with 'Osmosin' developed adverse experiences (p less than 0.05), especially central nervous system symptoms (p less than 0.05), and fewer were withdrawn from treatment because of adverse experiences (p less than 0.05). A reduction in the number of patients having gastro-intestinal symptoms was also identified. The majority of the patients maintained on one daily dose of 'Osmosin' had a good or excellent therapeutic response.

Interaction between diflunisal and warfarin.

The effect of diflunisal on steady-state warfarin dynamics and kinetics was studied in five healthy men taking daily subtherapeutic doses of warfarin. Diflunisal 500 mg twice daily for 2 wk increased the percentage unbound warfarin from 1.02% to 1.24% and lowered total warfarin from 741 to 533 ng/ml, but did not alter the anticoagulant response (prothrombin complex activity, PCA). When diflunisal was discontinued but warfarin continued, there was a loss of anticoagulant effect and a difference in the rates at which percentage unbound warfarin and total warfarin concentration returned to prediflunisal levels. There was a correlation between plasma diflunisal and percentage unbound warfarin. Diflunisal reduced both the maximum plasma protein-binding capacity for warfarin and the apparent association constant.

A double-blind comparison of a novel indanone diuretic (MK-196) with hydrochlorothiazide in the treatment of essential hypertension.

1 The antihypertensive effect and tolerability of MK-196 (10 mg and 15 mg daily) was compared to hydrochlorothiazide (HCT; 50 mg daily) in a 4-week multiclinic, double-blind study involving 42 patients with mild to moderate, essential hypertension. 2 Both doses of MK-196 were as effective and sometimes more effective than HCT in lowering standing and supine systolic and diastolic blood pressures. 3 HCT consistently brought about significant increases in serum uric acid and significant decreases in serum potassium; both doses of MK-196 produced similar but less frequent and smaller changes in both of these parameters. 4 Both doses of MK-196 brought about significant decreases in body weight at Weeks 3 and 4 of drug treatment. 5 Patients taking MK-196 reported fewer adverse clinical reactions (10 mg = 15%; 15 mg = 13% than those taking HCT (21%). 6 MK-196 may offer a therapeutic advantage over HCT as an antihypertensive agent for use in the treatment of mild to moderate, essential hypertension.

Uricosuric properties of diflunisal in man.

1 The uricosuric effect of diflunisal was studied in eleven normal subjects. 2 Urine and serum uric acid levels were measured and used to assess the effect. 3 Diflunisal caused statistically significant decreases in serum uric acid levels and increases in uric acid clearance at 250 and 375 mg twice daily. 4 Diflunisal taken on an empty stomach caused epigastric discomfort in the high dose group which was obviated when the drug was taken with meals. 5 Diflunisal caused no abnormalities in the measured haematological, urological or biochemical parameters.

Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog, and rat.

The succinimidoethyl (Sm) and pivaloyloxyethyl (P) esters of methyldopa were evaluated as progenitors of the latter. Experiments in spontaneously hypertensive (SH) rats and humans demonstrated that a radioactive dose of progenitor was well absorbed. The metabolism of these progenitors appeared to be comparable in the SH rat; the urinary excretion of [3H]methyldopa was similar after oral administration of [3H]Sm or [3H]P. In humans the levels of [3H]methyldopa were higher in the urine following administration of [3H]P. Apparently Sm was more resistant than P to extrahepatic esterase action in man (and dog). In man the catechol nucleus of Sm was apparently conjugated prior to hydrolytic cleavage to release conjugated [3H]methyidopa. The progenitors possessed similar antihypertensive properties in the SH rat but preliminary results in humans suggested that Sm possessed less antihypertensive potency than P.

Gastrointestinal blood loss after diflunisal and after aspirin: effect of ethanol.

Fecal blood loss was evaluated in normal subjects with 51Cr-labeled red cells. In a double-blind parallel study in 10 subjects, 250 mg diflunisal twice daily did not significantly increase blood loss in two consecutive treatment periods, while 750 mg acetylsalicylic acid (ASA) 4 times daily did so. In a double-blind crossover study in 2 subjects, diflunisal, 250 mg twice daily again did not significantly affect fecal blood loss during a 4-day treatment period, and there also was no significant effth diflunisal during two additional treatment days. ASA, 600 mg 4 times daily, induced an increase in blood loss and this effect was significantly enhanced by the addition of alcohol. The difference between treatments in the way they interact with alcohol was also statistically significant.

The chemistry, pharmacology and clinical pharmacology of diflunisal.

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.

Pharmacology and therapeutic use of antihistamines.

The classes of antihistaminic agents, their pharmacology and therapeutic uses, adverse effects, drug interactions, toxic overdoses and abuse are reviewed. It is concluded that antihistamines are valuable drugs for treating a number of conditions and diseases (e.g. allergic rhinitis, motion sickness and parkinsonism), but proof of efficacy has not been established for the treatment of cardiac arrhythmias, peptic ulcers, insomnia and headaches. Because responses to antihistamines may vary, titration of each patient's dose is recommended.