Chronopharmacokinetics of nicotine.

RATIONALE: For high-clearance drugs such as nicotine, hemodynamic changes throughout the day may be expected to influence the rate of metabolism. MATERIAL AND METHODS: To assess the effects of meals and diurnal rhythms on nicotine clearance, an intravenous infusion of nicotine bitartrate was administered for 48 hours to 11 subjects. Two models to determine nicotine clearance variation throughout the day are described. Both models were used to estimate the mean effect of meal and diurnal rhythms on nicotine clearance and individual parameters that were regressed against baseline covariates. Clearance was modeled as a function of time [CL(t)] and split it in three components: a (constant) baseline value (theta 1), its circadian (diurnal) variation, and the effect of meal: CL(t) = [theta 1 + circadian(t)] [1 + meal(t)]. A two-compartmental (time-variant) model incorporating CL(t) was then fitted to the data providing estimates of CL(t) conditional on literature values of the time-invariant parameters (volume of distribution and intercompartmental clearances). RESULTS: The estimated circadian(t) showed a maximum at approximately 11 AM and a flat minimum from 6 PM to 3 AM; the estimated meal(t) showed a sharp increase up to 1 hour (after the meal), at which point clearance is increased 42%, and a slower decrease thereafter, returning to baseline (zero) after 2.8 hours. Individual estimates of baseline clearance are found to have a linear relationship with body weight. No other covariate, sex in particular, effect could be found.

A pooled analysis of CD4 response to zidovudine and zalcitabine treatment in patients with AIDS and AIDS-related complex.

INTRODUCTION: This article reports a meta-analysis focused on the efficacy of zalcitabine and zidovudine alone or in combination as reported by three AIDS Clinical Trial Group trials. We analyzed the log CD4 count (LCD4) response to therapy up to 1 year after the beginning of therapy. One of the purposes of this article was to illustrate a meta-analysis method that permits pooling of original data from trials with different designs. METHODS: To effectively eliminate obvious differences due to design, we first estimated complete (1 year) individual LCD4 versus time curves using a sophisticated smoothing technique. Then several summary descriptors were computed from the completed LCD4 curves. Those descriptors were corrected for baseline covariate differences, and the corrected values were then related to measures of drug exposure. RESULTS: Significant baseline covariates were LCD4 baseline count and AIDS-related complex or AIDS diagnosis. The predictor, corrected for baseline covariates, that correlated best with drug exposure was intensity, the initial rate of rise of LCD4, estimated as the slope of LCD4 between pretreatment and peak LCD4. CONCLUSION: Using intensity as a single response measure, we found weak evidence for synergism of zalcitabine and zidovudine: combination therapy increased response by 20% over that expected from a purely additive interaction.

Synthesis and antihypertensive activity of new 6-heteroaryl-3-hydrazinopyridazine derivatives.

The synthesis and pharmacological activity of new 6-heteroaryl-3-hydrazinopyridazines with antihypertensive action are described. The introduction of pyrrole, pyrazole, imidazole, triazole, tetrazole, thiophene, indole, and carbazole heterocyclic rings into the 6 position of the pyridazine nucleus has been carried out by three different methods of synthesis. The hypotensive action has been examined on normotensive and spontaneously hypertensive rats by comparison with dihydralazine (I). 6-Imidazol-1-yl derivatives have proved particularly active. Of these derivatives, 3-hydrazino-6-(2-methylimidazol-1-yl)pyridazine (7c) achieves 4.9 times the activity of dihydralazine when administered orally to spontaneously hypertensive rats. The LD50 values of 7c and dihydralazine are very similar.

2-(Isoxazolylethenyl)phenoxypropanolamines: a new class of beta-receptor antagonists with antihypertensive activity.

The synthesis of a series of (E)-1-amino-3-[2-(2-isoxazolylethenyl)phenoxyl-2-propanols is described. These compounds were found to have beta- and alpha-adrenergic blocking properties, as well as hypotensive and antihypertensive properties. The beta-adrenoceptor antagonism of all these compounds was more pronounced than their alpha-sympatholytic and hypotensive activity. 3a was 16 times more potent than labetalol in beta-adrenergic receptor blockade and was effective in lowering blood pressure in acute trials on spontaneously hypertensive rats at a dosage of 15 mg/kg. Structure-activity considerations showed that antihypertensive potency was more sensitive to structural variations than beta-adrenoceptor antagonistic activity. However, in general, those compounds having the most potent beta-adrenoceptor blocking activity also lowered blood pressure most effectively.

6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities.

This paper reports on the synthesis and pharmacological activity of 6-aryl-4,5-dihydro-3(2H)-pyridazinone derivatives. The compounds exhibit an aggregation inhibiting action on human platelets in vitro and on rat platelets under ex vivo conditions, as well as a hypotensive action on rats. The strongest pharmacological effects were found with dihydropyridazinones, which have a 6-[p-[(chloroalkanoyl)amino]phenyl] substituent, together with a methyl group in the 5-position. The antiaggregation activity of compounds of this type is in vitro up to 16000 times and ex vivo up to 370 times greater than that of acetylsalicylic acid; the hypotensive action is up to 40 times as great as that of the comparative substance dihydralazine.

Relationship between graft cytochrome P-450 3A content and early morbidity after liver transplantation.

Cytochrome P-450 3A metabolizes CsA into several metabolites with very limited pharmacological activity and toxicity. In 40 liver donors, the relative concentrations of P-450 3A was assessed by immunoblot analysis using a specific monoclonal antibody exhibited a 10-fold variation (mean = 92 +/- 50 arbitrary units [AU]/mg) in levels. Problems consequent upon CsA usage (nephrotoxicity, neurotoxicity, and hypertension) occurred in 8 of 34 transplant recipients in the immediate postoperative period, and in these 8 patients the problems were always associated with low graft P-4503A levels (mean = 52 +/- 19 A.U./mg, P = 0.0003, cf. patients with no toxicity). Four of these patients had CsA levels that were also high, but 4 had CsA levels in the therapeutic range. Episodes of early graft rejection were related to higher P-450 3A levels (mean = 110 +/- 24 A.U./mg). Cytochrome P-450 3A levels were also found to be inversely related to CsA whole blood levels (assessed with a specific antibody 12 hr after the intravenous infusion of CsA at 1 mg/kg in the recipients (P < 0.02). Cytochrome P-450 3A can provide information that should allow individualized immunosuppression with CsA maintaining therapeutic levels but avoiding toxicity in susceptible individuals.

A descriptive tool to characterize nonlinear kinetics, with applications to meperidine and lidocaine.

We describe an explorative data analysis tool which can detect and describe the presence of nonlinearities in multiple dose kinetics studies. The method is nonparametric (i.e. not dependent on modeling assumptions), uses regression to estimate the functions representing the kinetics, and makes the detection of nonlinearity a part of the model selection process. Flexible functions (splines) are used to describe the kinetics corresponding to the lowest given dose, and to describe the (possible) departure of the kinetics corresponding to higher doses from the reference kinetics. The estimated kinetics and departures can be examined to offer possible insight into the nature of the nonlinearity. The methodology is applied to the analysis of meperidine and lidocaine kinetics through the lungs and the heart. We find that the lung kinetics of lidocaine and meperidine are linear. However their myocardial kinetics are complex and nonlinear.

Cimetidine does not alter sparfloxacin pharmacokinetics.

The interaction between cimetidine and sparfloxacin was studied in 10 healthy volunteers who received a single oral dose of 400 mg sparfloxacin on the third day of an 8 day cimetidine (400 mg t.i.d.) or placebo randomly assigned treatment. No statistically significant differences were observed in the pharmacokinetic parameters (Cmax-AUC-T1/2-urinary excretion and metabolic ratio) of sparfloxacin following the 2 treatment. Cimetidine does not affect absorption, metabolism or urinary excretion of sparfloxacin; consequently, patients exposed to this drug combination are not at risk.

[Relationship between hepatic cytochrome P-450 3A and acute cyclosporine toxicity in liver transplantation]. / Relations entre cytochrome P-450 3A hépatique et toxicité aiguë de la ciclosporine en transplantation hépatique.

Despite the availability of whole blood cyclosporine assays, the different response of individual patients to its administration following transplantation continue to pose clinical problems, particularly in respect of toxicity. The aim of this study was to know if the inter-individual variations in the hepatic concentration of cytochrome P-450 3A, that metabolizes cyclosporine into several metabolites with very limited immunosuppressive activity, could be associated with cyclosporine toxicity. 59 consecutive liver transplant recipients were studied. Immunosuppression was with cyclosporine, azathioprine and methylprednisolone. The relative concentration of P-450 3A was assessed by immunoblot analysis using a specific monoclonal antibody on liver graft biopsy. Twelve patients experienced toxic neurological and renal complications. Six of these patients had cyclosporine levels in the therapeutic range. There was an excellent correlation between the occurrence of complications and cyclosporine whole blood levels (P < 10(-4), the first day post-op after a standard dose of cyclosporine (1 mg/kg). Cytochrome P-450 3A hepatic content assessed in a groups of 34 patients exhibited a 10-fold variation (m = 94 +/- 47 AU (Arbitrary Units)/mg). Eight of these patients who developed cyclosporine toxicity had a lower graft P-450 3A levels (m = 52 +/- 19 AU/mg, P = 3.10(-4), cf. patients with no toxicity). This highlights the importance of the first dose of cyclosporine and indicates that cytochrome P-450 3A can provide information which should allow individualized immunosuppression with cyclosporine maintaining therapeutic levels but avoiding toxicity in susceptible individuals.

Effect of ribavirin on intracellular and plasma pharmacokinetics of nucleoside reverse transcriptase inhibitors in patients with human immunodeficiency virus-hepatitis C virus coinfection: results of a randomized clinical study.

The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.

Linear mixed-effect multivariate adaptive regression splines applied to nonlinear pharmacokinetics data.

In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.

Pharmacology of amezinium, a novel antihypotensive drug. III. Studies on the mechanism of action.

Pharmacological studies on the mechanism of action of 4-amino-6-methoxy-1-phenyl-pyridazinim methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, are presented. 1. Amezinium increases the arterial blood pressure and heart rate of anaesthetized animals and of pithed rats by stimulating vascular alpha- and cardiac beta 1-adrenoceptors. The action was not modified by ganglionic blockade with hexamethonium. The alpha-adrenergic blocking drug phentolamine antagonized the blood pressure increasing effect and the beta-adrenergic blocking drug propranolol antagonized the heart rate increasing effect. 2. Noradrenaline depletion by pretreatment with reserpine reduced the pressor effect of amezinium to approximately the same extent as it reduced the effect of tyramine. It completely abolished the heart rate increasing effect. Under these conditions, high doses of amezinium reduced the heart rate. 3. Amezinium is taken up by adrenergic neurones. Inhibition of uptake 1 with desipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimulation (endogenous noradrenaline). It diminished the effect of indirectly acting sympathomimetic drugs (tyramine). It did not modify the action of the sympathomimetic drugs methoxamine and isoprenaline, which are not subject to uptake 1. 5. Amezinium inhibits monoamine oxidase (MAO). As a result of being concentrated in sympathetic neurones via uptake 1 amezinium causes specific inhibition of intraneuronal MAO; this was demontrated by enhanced restoration of the effects of tyramine and amezinium by noradrenaline infusion in reserpinized animals. The effective doses of amezinium here were lower than the doses necessary to inhibit tyramine and to exert a pressor effect. This is in accordance with the blood pressure increasing effect of amezinium itself by amezinium pretreatment and noradrenaline-infusion. 6. Pretreatment with a MAO inhibitor (nialamide) enhanced the pressor effect of amezinium, probably by also inhibiting extraneuronal MAO...

Development of hypertension and life span in stroke-prone spontaneously hypertensive rats during oral long-term treatment with various antihypertensive drugs.

In stroke-prone spontaneously hypertensive rats, oral long-term treatment with verapamil, propranolol, hydrochlorothiazide, and dihydralazine attenuated the development of hypertension. The various antihypertensive drugs caused comparable reductions in blood pressure but the calcium antagonist and the beta-receptor blocker prolonged the life span more than the diuretic and vasodilator. The relative heart and lung weights at the time of death were slightly diminished in the verapamil and the high-dose propranolol group. It is assumed that calcium antagonism and beta-receptor blockade prolong the life span, not only due to their blood-pressure-lowering mechanism, but also to the additional protective effects.

[Chemistry and biological properties of substituted 3-amino-1H-isoindoles (author's transl)]. / Chemie und biologische Eigaenschaften substituierter 3-Amino-1H-isoindole.

Several 1-, 3-, and 6-substituted 3-amino-1H-isoindoles have been synthesized and screened for biological properties. In pharmacological testing significant and long-lasting local-anesthetic activity was found even in low concentrations. Subsequently, investigations for antiarrhythmic properties were carried out. The same or even higher activity compared to quinidine sulfate was found on isolated guinea pig atria (refractory period prolongation), anaesthetized rats (aconitine induced arrhythmias), guinea pigs (electrically induced cardiac fibrillation) and in conscious dogs with arrhythmias due to coronary artery occlusion. Unfortunately, antiarrhythmic doses caused toxic symptoms in dogs.

Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems.

Circadian and meal effects on nicotine kinetics determine in part blood nicotine concentrations and in doing so may influence cigarette smoking behavior throughout the day. We have shown previously that nicotine clearance varies by approximately 17% (from peak to through) due to diurnal factors throughout the day and that meals increase nicotine clearance by about 42%. Until now pharmacokinetic analyses of nicotine absorption from patches have assumed a constant clearance of nicotine over 24 hr. Using 11 individual kinetic estimates from a previous study, we analyzed plasma nicotine concentrations vs. time data of two nicotine patch studies, and conducted a set of simulations to determine the extent to which time-varying kinetics would influence the design of transdermal drug delivery systems, intented to maintain a constant plasma nicotine concentration over 24 hr. Not incorporating time-varying kinetics leads to biased estimates of the delivery rate of the nicotine patches, and increases the variability in the delivery rates estimates. The hypothetical transdermal drug delivery systems designed assuming constant nicotine clearance results in a systematical underdosing during the first 12 hr after beginning therapy. The transdermal drug delivery systems obtained assuming the correct time-varying clearance shows three components: 1) an early high delivery rate, followed by 2) a rather constant, but slightly decreasing at night, release rate and 3) transient increases in delivery rate for 2 hr after each meal. The effect of circadian variations in clearance could be compensated for in patch design by decreasing the delivery rate during the night. Transient variations in clearance due to meals would require the corresponding use of rapid drug delivery dosage forms. The methods we devise to predict optimal dosing regimens in presence of chronopharmacokinetics might be useful for other medications in which blood levels need to be precisely controlled.

Recruitment to a university alcohol program: evaluation of social marketing theory and stepped approach model.

BACKGROUND: This study was a first initiative to evaluate the application of social marketing theory (SMT) to increase attendance at an alcohol abuse education program for university residence hall students and to ascertain whether aggressive recruitment strategies are necessary as part of the stepped approach model (SAM) of service delivery. METHOD: SMT and public health strategies that include focus groups, in-depth interviews, and intercept interviews were used to develop recruitment materials in a Test Hall. These new recruitment materials were introduced to the residents in the Treatment Hall (N = 727) and were compared to the Usual Care, Control Hall (N = 706) which received the recruitment materials normally provided to residents as well as to three Historical Halls separately and combined which had used the Usual Care recruitment materials in the past. RESULTS: The Treatment Hall percentage attendance was significantly superior (0.001 < p < 0.05) in all comparisons. The percentage attendance did not differ significantly from marketing literature expectations. The projections for campus-wide attendance for residence hall students were between 207 and 243 participants and for nationwide attendance, 36,900 +/- 8,185. CONCLUSIONS: The results suggest that the SMT and public health methods used are helpful in developing recruitment strategies and are an important initial step of the SAM and that a "minimal intervention" recruitment strategy is a cost-effective approach that can have a dramatic impact.

[Pharmacology of N-(2-imidazolin-2-yl)-N-(4-indanyl)amino (indanazoline), a new vasoconstrictive imidazoline compound]. / Zur Pharmakologie von N-(2-Imidazoline-2-yl)-N-(4-indanyl)amin (Indanazolin), einer neuen vasokonstriktorisch wirksamen Imidazolinverbindung.

In animal experiments the new imidazoline derivative N-(2-imidazolin-2-yl)-N-(4-indanyl)amine (indanazoline, E-VA-16, as monohydrochloride active substance of Farial) is characterized by a pronounced vasoconstrictive action after local or intravenous application. This is due to a direct action of the compound on alpha-adrenergic receptors. When applied systemically E-VA-16 being a peripherally acting alpha-sympathomimetic induces a rise in blood pressure and a reduction of heart rate and exerts antiphlogistic, spasmolytic, hyperglycemic and diuretic actions. When given by the intranasal route the substance influences blood pressure and heart rate only at concentrations considerably higher than those intended for use in therapy. After enteral administration the effective doses also markedly exceed the single therapeutic doses. There was no evidence of side-effects restricting the use of the drug as compared to other imidazoline derivatives. Studies on the isolated perfused rabbit ear, however, indicated a broader therapeutic range in local application.

[New beta-sympatholytic agents. Synthesis and pharmacological activity of isomeric benzthiazole and benzoxazole derivates (author's transl)]. / Neue beta-Sympatholytika: Synthesen und pharmakologische Wirkung isomerer Benzthiazol- und Benzoxazol-Derivate.

The synthesis and comparative pharmacological studies concerning structure-activity relationship of new benzothiazole, benzisothiazole, benzoxazole, and benisoxazole derivatives with beta-sympatholytic activity are reported. Most of the 4-benzisothiazole derivatives studied strongly act on cardiac beta 1-receptors in rats in situ (2.6-8.3 times propranolol). On the other hand derivatives of 4-benzisoxazole and 5-benzisothiazole are less potent. A strong decrease in activity was observed going from the benzisothiazoles and benzisoxazoles to the isomeric benzthiazoles and benzoxazoles. The active substances also block vascular beta 2-receptors. In the most cases they have little intrinsic adrenergic activity. The observed tendency concerning beta 1-selectivity in rats could not be confirmed in cats. The most potent 4-benzisothiazole derivatives in rats show also - beside some minor differences - very good beta-sympatholytic activity in cats after i.v. as well as after i.d. administration. Similar to the results in rats and cats the 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole (LU 24329) was found to possess a high activity in conscious dogs by oral or i.v. application. Both in dogs (i.v.) and in isolated perfused guinea pig hearts LU 24329 is eleven times more active than propranolol in blocking beta 1-receptors. A negative inotropic effect as an expression of non-specific membrane-stabilizing action of LU 24329 is also demonstrated in guinea pig hearts. The effective concentration is 4650 times higher than that effective on beta 1-adrenoceptors. The active compounds have a moderate acute toxicity. The LD50 values in mice after i.p. administration are ranging from 55-174% of the propranolol toxicity.