Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

BACKGROUND AND AIMS: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. METHODS: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. RESULTS: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. CONCLUSIONS: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations.

C-reactive protein in migraine sufferers similar to that of non-migraineurs: the Reykjavik Study.

C-reactive protein (CRP), a marker of inflammation, has been associated with cardiovascular disease. Risk of cardiovascular disease is increased in migraineurs with aura. Results from a clinical report, case-control and a cohort study suggest that CRP is elevated in migraineurs compared with non-migraineurs. We examined the proposed association in a case-control study nested within two large population-based studies. The relationship between migraine and CRP (high-sensitivity CRP) was studied in 5906 men and women aged 55.0 +/- 8.5 years in the Reykjavik Study and 1345 men and women aged 27.7 +/- 5.5 years from the Reykjavik Study for the Young. A modified version of the International Headache Society's criteria was used to categorize people into migraineurs (two or more symptoms) or non-migraineurs. Migraineurs with visual or sensory symptoms were further defined as having migraine with aura (MA) or without aura (MO). Multivariable-adjusted CRP levels were similar in migraineurs and non-migraineurs for men (0.83 vs. 0.79 mg/l, P = 0.44) and for women (0.87 vs. 0.87 mg/l, P = 0.90). When further stratified by migraine aura and age, no differences were found between non-migraineurs, MO and MA among men. In women, CRP levels were borderline higher in those with MO compared with non-migraineurs and those with MA (1.01 mg/l vs. 0.81 and 0.75 mg/l, P = 0.08 and P = 0.08) in age group 19-34 years, but significantly lower in age group 60-81 years (0.52 mg/l vs. 1.07 and 1.01 mg/l, P = 0.007 and P = 0.03). CRP levels were not increased among migraine sufferers compared with non-migraineurs. Older women migraineurs without aura had lower CRP values than non-migraineurs and migraineurs with aura.

Migraine patients have lower systolic but higher diastolic blood pressure compared with controls in a population-based study of 21,537 subjects. The Reykjavik Study.

Several studies have explored a possible association between migraine and hypertension, with contradictory results. Because of this uncertainty the relation between blood pressure (BP) and migraine was studied in 10,366 men and 11,171 women in a population-based longitudinal study. A modified version of the 1988 International Headache Society criteria was used for diagnosis of migraine. Logistic regression analysis was used. The crude 1-year prevalence of migraine was 5.2% among men and 14.1% among women. No significant association was found between hypertension and migraine. For a one standard deviation (SD) increase in diastolic BP the probability of having migraine increased 14% (P = 0.11) for men and 30% (P < 0.0001) for women. For a 1-SD increase in systolic BP the probability of having migraine decreased 19% (P = 0.007) for men and 25% (P < 0.0001) for women. It was also found that for a 1-SD increase in pulse pressure the probability of having migraine decreased 13% (P = 0.005) for men and 14% (P < 0.0001) for women. In a population-based study of men and women it was found that subjects with migraine had lower pulse pressure, lower systolic BP and higher diastolic BP compared with controls.

Risk profiles and prognosis of treated and untreated hypertensive men and women in a population-based longitudinal study: the Reykjavik Study.

The aim was to examine the risk profiles and prognosis of treated and untreated hypertensive subjects and examine to what degree confounding by indication was present in a population-based cohort study with up to 30-year follow-up. The study population consisted of 9328 men and 10 062 women, aged 33-87 years at the time of attendance from 1967 to 1996. The main outcome measures were myocardial infarction (MI), cardiovascular disease (CVD) mortality and all-cause mortality. Comparing the risk profiles between treated and untreated subjects entering the study showed significantly higher values for some risk factors for treated subjects. During the first 10 years, hypertensive men without treatment, compared with those treated, had a significantly lower risk of suffering MI, CVD and all-cause mortality, hazard ratio (HR) 0.72 (95% CI; 0.57, 0.90), 0.75 (95% CI; 0.59, 0.95) and 0.81 (95% CI; 0.61, 0.98), respectively. No significant differences in outcome were seen during the following 20 years. In identically defined groups of women, no significant differences in mortality were seen between groups. Subgroup analysis, at two stages of the study 5 years apart, revealed that some cardiovascular risk factors had a higher prevalence in hypertensive men who were treated at the later stage, compared with those who remained untreated (P=0.004). In conclusion, hypertensive treated men had a worse prognosis during the first 10 years of follow-up than untreated ones, which is most likely due to worse baseline risk profile. Hypertensive men that were treated at a later stage had a worse risk profile than those not treated at a later stage.

Effects of [Na+]o, [Ca2+]o and cyclopiazonic acid on decline of post-extrasystolic potentiation and twitch kinetics in guinea-pig and human myocardial preparations.

The decline of post-extrasystolic potentiation was investigated in atrial and ventricular muscle of guinea-pigs and in human atrial muscle. This decline is described in terms of the recirculation fraction (RF) for calcium in myocardial cells. Under control conditions, the mean values for RF were as follows: 0.61 +/- 0.03 in the guinea-pig atrium, 0.32 +/- 0.05 in the guinea-pig ventricle and 0.51 +/- 0.10 in the human atrium. Upon increasing calcium concentrations within the range of 0.5-10 mM or decreasing the sodium to 70%, the steady-state force and recirculation fraction increased concomitantly in all three types of muscles. Cyclopiazonic acid (CPA), in a 5-20 microM concentration, decreased force in the guinea-pig preparations and decreased RF. The effects of CPA were great in atrial muscle, 20 microM CPA decreasing RF from 0.61 to 0. 39. In ventricular muscle, this effect was small and not statistically significant. When changing calcium or sodium concentrations, increased force was accompanied by slower relaxation in atrial muscle, but an unchanged or slightly faster relaxation in ventricular muscle. In guinea-pig myocardium, CPA (5-20 microM) prolonged the time to peak force (TPF), but it slowed relaxation only in the ventricle. Reducing the calcium outflow by Na/Ca exchange increased RF as expected, and reducing the SR calcium re-uptake decreased RF. These interventions were also expected to reduce the rate of decline of intracellular calcium, but relaxation was not consistently prolonged. This indicates that factors other than the SR calcium pump and sarcolemmal Na/Ca exchange determine, or at least influence, the rate of relaxation.

A pharmacokinetic evaluation of pravastatin in middle-aged and elderly volunteers.

The pharmacokinetics of pravastatin, a serum-cholesterol-lowering drug, were studied in 20 middle-aged (46-59 years old, n = 8) and elderly subjects (60-81 years old, n = 12). Pravastatin serum levels were determined by HPLC and solid phase extraction. Cmax was 48.9 +/- 7.1 ng/ml (mean +/- SEM, n = 20), and the mean AUC0-4.5h was 104.4 ng x h/ml (n = 5) for a 20 mg daily oral dose. A great interindividual variability was found for Cmax, which varied from 6.2 ng/ml to 117.8 ng/ml on the 20 mg dose. As could be expected, Cmax and AUC0-4.5h were dose-related, but Tmax and t1/2 were not. In six cases, the elimination of the drug in serum could be described by a single phase but in four cases with two phases. No significant difference was found in Cmax between the middle-aged and the elderly or between males and females.

Inotropic response of rat heart papillary muscle to alpha 1- and beta-adrenoceptor stimulation in relation to dietary n-6 and n-3 polyunsaturated fatty acids (PUFA) and age.

The effect of dietary n-6 and n-3 polyunsaturated fatty acids (PUFA) and age on inotropic responses of heart papillary muscle to alpha 1-or beta-adrenoceptor stimulation was examined in young (4 months), middle-aged (12 months) and senescent (27 months) male Wistar rats. From the age of two months the rats were fed a diet containing 2% or 12% of fat by weight varying in PUFA type: a) standard low-fat n-6 PUFA diet, b) high-fat n-6 PUFA diet or c) high-fat n-3 PUFA diet. The inotropic responses to alpha 1-adrenoceptor stimulation with phenylephrine were triphasic (positive, negative, then positive). Young, high-fat n-3 PUFA-fed rats exhibited significantly lower negative and higher positive responses to phenylephrine stimulation, and higher positive responses to isoprenaline stimulation than young, high-fat n-6 PUFA-fed rats. On the other hand, no such dietary-related difference was found between young rats fed a high-fat n-3 PUFA diet and a standard low-fat n-6 PUFA diet. The young high-fat n-6 PUFA-fed rats exhibited inotropic responses similar to those of the middle-aged and senescent rats within the three dietary groups. The time to peak force and the time of half relaxation did not differ within dietary and age groups. The findings indicate that dietary n-6 PUFA-rich supplementation at a young age induces changes resembling the effects of age, as evidenced by decreasing cardiac responses to adrenoceptor agonists, such as phenylephrine or isoprenaline.

Excitation and contraction in atrial and ventricular myocardium of the guinea-pig.

Several parameters of excitation-contraction coupling were compared in two types of muscle, using thin strips from the left atria and papillary muscles from the right ventricles of guinea-pigs. (1) The duration of the action potential and twitch is much longer in ventricular than in atrial muscle. (2) Mechanical restitution can usually be described by a monoexponential function in ventricular and biexponential function in atrial muscle. (3) Post-extrasystolic potentiation, when related to the steady state force, is greater in ventricular muscle. (4) When priming with paired-pulse stimulation, mechanical restitution can be studied after the short interval and after the long interval. In atrial muscle, mechanical restitution is very similar after the short and long intervals but in ventricular muscle they are different in size. (5) Ryanodine (10(-6) M) can decrease the steady state force to about 10% of control in atrial but only to about 35% in ventricular muscle. Ryanodine (10(-8) M) causes the slow phase of restitution in atrial muscle to disappear but in ventricular muscle only increases the rate of mechanical restitution. (6) Ca-antagonists (Cd2+ 0.2 mM) can decrease the steady state force to zero in atrial and ventricular muscle. Ca-antagonists, in low concentrations (Cd2+ 0.01 mM), mainly affected the fast phase of mechanical restitution. (7) The recirculation fraction of calcium was about 0.64 in atrial and 0.27 in ventricular muscle. The findings are discussed in the light of known ultrastructural differences between atrial and ventricular myocardium.

The metabolism of mebeverine in man: identification of urinary metabolites by gas chromatography/mass spectrometry.

The urinary metabolites of orally administered mebeverine hydrochloride (270 mg) were studied in five healthy volunteers with the aid of gas chromatography/mass spectrometry. Mebeverine, which is an ester of veratric acid and 4-(ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino)butan-1-ol, was completely hydrolysed to the corresponding acid and alcohol moieties. The acid moiety was subsequently O-demethylated to vanillic acid and isovanillic acid, which in turn were further O-demethylated to protocatechuic acid. The alcohol moiety was O-demethylated to the corresponding phenol 4-(ethyl-[2-(4-hydroxyphenyl)-1-methylethyl]amino)butan-1-ol. In 24 hr, 44% of the dose was accounted for as follows: Veratric acid 32%, vanillic acid 2.7%, isovanillic acid 6.5%, 4-(ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino)butan-1-ol 0.9% and 4-(ethyl-[2-(4-hydroxyphenyl)-1-methylethyl]amino)butan-1-01 2.1%. Only trace amounts of protocatechuic acid were found in the urine. The results indicated that the metabolites were mostly excreted as conjugates. The total excretion of the acid moiety, unchanged or in the form of metabolites was 97.6%. The corresponding value for the alcohol moiety was 5.5%.

Cholesterol-related counseling by registered dietitians in northern California.

BACKGROUND: An estimated 40 million Americans have serum cholesterol levels that warrant medically supervised dietary intervention. Although registered dietitians are expected to play an important role in treating these patients, current treatment practices in the community are largely unknown. METHODS: A questionnaire concerning treatment practices was mailed to all 377 registered dietitians listed in the directories of the American Dietetic Association for two large California districts. Number of patients seen and length and content of dietary counseling were ascertained for three types of patients: (a) hypercholesterolemic outpatients without heart disease, (b) hypercholesterolemic outpatients who have heart disease, and (c) inpatients with myocardial infarction. RESULTS: A return rate of 59% (n = 252) was obtained for the questionnaire. A total of 44% of the registered dietitians counseled hypercholesterolemic patients in any of the categories surveyed. About 30% of the respondents counseled hypercholesterolemic outpatients without heart disease. They saw an average of 4.9 such patients a week, spent an average of 53 min in an initial session, and usually did not see the patient again in follow-up. Fewer than 10% of patients had as many as four sessions. About 27% of the respondents saw hypercholesterolemic outpatients with heart disease, averaging 3.5 such contacts per week. The reported practices were similar to those provided to noncardiac outpatients. About 22% of registered dietitians worked with hospitalized myocardial infarction patients. They spent an average of a total of 41 min over 2.5 visits with each patient. CONCLUSION: Currently, outpatient registered dietitian counseling for hypercholesterolemia appears to be limited in both the number of patients reached and the duration of the counseling. Further research into the impact of, barriers to, and efficacy of alternative delivery methods of dietary counseling is needed.

The impact of public cholesterol screening on diet, general well-being, and physician referral.

Public cholesterol screenings have become common. To evaluate the public health impact of such events, we conducted a public cholesterol screening and, three months later, invited participants between the ages of 18 and 72 to return for follow-up. More than 77% (N = 143) returned. We collected information on diet and general well-being at baseline and follow-up, and we obtained information on further medical evaluation of the initial cholesterol value at follow-up. Diet improved regardless of baseline cholesterol level (overall diet score 2.10 baseline, 1.75 follow-up, P less than .001). There were no adverse psychosocial ("labeling") effects in persons told of elevated cholesterol levels. About one-third of individuals referred to their physicians for elevated cholesterol values discussed the cholesterol issue with their physicians, as did a similar proportion of those told of a desirable cholesterol level. Total cholesterol decreased from 218.5 to 211.6 mg/dL (P = 0.18, 95% CI for the change, -18.5 to +4.7 mg/dL). Public cholesterol screening did not appear to have any adverse effects and may lead to beneficial changes in diet in persons screened.

Short-term effects of stimulus interval changes in guinea-pig and rat atrial muscle.

Isometric force and action potentials were recorded in thin atrial strips from guinea-pigs and rats (32 degrees C). The restitution of peak force and action potential duration, after a regular contraction, was determined (test interval 0.1-120 s), together with the post-extrasystolic potentiation. The mechanical restitution could be described with an exponential function in two phases as: force = A(I-e-k1t) + B(I-e-k2t). By increasing the basic stimulation rate in guinea-pig atria from 0.2 to 2 Hz, the size of A was approximately doubled while B was only slightly affected. When [Ca2+] was increased from 0.9 to 3.6 mmol l-1, the size of A increased approximately 3.4 times while B decreased only slightly. There was a close correlation between steady-state contractility of the muscle and parameter A but not parameter B. In a similar fashion post-extrasystolic potentiation can be described as: force = Ce-kt + D. This potentiation was greater in guinea-pig than in rat hearts. In both species the rate of potentiation decay (k) was usually similar to the rate of the first phase of restitution (k1). It seems reasonable to interpret the parameters A and B as reflections of two separate intracellular compartments for activator calcium.

Determination of atenolol in plasma by dual-column liquid chromatography and fluorimetric detection.

A simple and rapid liquid chromatographic method for the determination of atenolol in plasma is described. Plasma proteins were precipitated with zinc sulphate and sodium hydroxide prior to injection onto a precolumn, which was connected to the analytical column by a switching valve. When atenolol was eluted onto the analytical column, the precolumn was cleaned by backflushing to eliminate strongly retained endogenous compounds. The atenolol fluorescence was measured after excitation at 197 nm. The limit of quantitation in plasma was 15 ng/ml. The within-day precision of atenolol was 1.6% at a level of 210 ng/ml, 5.0% at 25 ng/ml and the between-day precision was 3.3% at 50 ng/ml.

Mechanical restitution of the rat papillary muscle.

The experiments were performed on isometrically contracting rat papillary muscles paced at 1.0 Hz and at a temperature of 37 degrees C. The contractile response of a test contraction continuously rose when the duration of the preceding stimulus interval was gradually increased from 0.2 s. A maximum value was seen at intervals of 60--120 s. This phenomenon was called mechanical restitution of the papillary muscle. The insertion of a priming beat before the test contraction in order to increase the amount of contractile calcium elevated the mechanical restitution curve but it did not change the maximum contractile force seen after 60--120 s intervals. Lowering the extracellular calcium concentration from 2.0 mM to 1.0 mM, however, depressed this maximum contractile force to about 50%. The mechanical restitution is thought to reflect inflow of activator calcium to a cellular store, from which it is later released in response to the action potential. By using two test contractions a simple method is described to estimate the recirculating fraction of activator calcium between beats in this preparation. In 11 preparations the recirculating fraction of activator calcium was 0.72 +/- 0.03 (mean +/- SE). The results are consistent with the view that the same model of metabolism of activator calcium as previously proposed for rabbit papillary muscles is also applicable to the rat heart.

Cellular calcium as a determinant of action potential duration in rabbit myocardium.

It has been suggested that the amount of calcium in the myocardial cell determines force production as well as the duration of the action potential. We have examined two factors proposed to determine the action potential duration: (1) the inotropic state of the muscle and (2) the preceding stimulation interval. The experiments were performed on isolated papillary muscles from rabbits. The preparations were stimulated to contrast isometrically at a temperature of 37 degrees C and intracellular recordings of action potentials were made. An increased inotropic state produced either by raised external calcium concentration or by increased stimulation frequency was associated with shortened action potentials, confirming factor (1) above. The dependence of the action potential duration on the preceding stimulation interval (factor (2) above) disappeared over a wide range of intervals when the preparation was exposed to 4 microM D600. The action potential duration was, however, still dependent on the preceding stimulation interval when the extracellular calcium concentration had been lowered from 2.0 mM to 1.0 and 0.5 mM respectively. The results are discussed in terms of a model which postulates an inverse relationship between the amount of calcium in a membrane compartment and the action potential duration.

The contractile state of rabbit papillary muscle in relation to stimulation frequency.

1. The relationship between active force and stimulation frequency (0-25-5/sec) was studied at 36-37 degrees C in isolated papillary muscles of the rabbit. 2. The muscle's force producing capability at a given frequency was determined as the isometric twitch response to a test stimulus that was applied at various times after a priming period. The optimum contractile response was obtained at an interval of 0-8 sec between the test pulse and the last stimulus of the priming period. 3. The optimum contractile response exceeded the steady-state twitch amplitude at all stimulation frequencies higher than 1/sec. While the steady-state twitch resonse declined at frequencies higher than 4/sec, the optimum contractile response was steadily increased as the stimulation frequency was raised. 4. The optimum contractile response was also determined after priming the muscle with a sinusoidal a.c. pulse (field strength, 10 V (r.m.s.)/cm; frequency, 20 c/s; duration, 2-5 sec). The optimum contractile response obtained after a.c. stimulation was 2-2 times greater than the maximal steady-state response. Its absolute value was 67-3+/-6-1 mN/mm2 (mean +/-S.E. of mean, n = 6). 5. The twitch potentiation produced by priming the muscle at a given frequency decayed exponentially in two phases after optimum contractile response had been attained. The time constants of the two phases, determined after a.c. stimulation, were 2-6+/-0-8 (n = 4) and 92-0+/-13-3 sec (n = 7), respectively. 6. The optimum contractile response determined at various stimulation frequencies was linearly related to the fraction of time during which the cell membrane was depolarized (beyond -40 mV) by the action potentials. 7. The results are interpreted in terms of a two-component model of the metabolism of activator calcium in the excitation-contraction coupling.

Acid-base changes and excitation-contraction coupling in rabbit myocardium. I. Effects on isometric tension development at different contraction frequencies.

The effects of changes in acid-base parameters on the active force of isolated rabbit papillary muscles were studied at contraction frequencies of 12, 60 and 120/min. When extracellular pH was lowered from 7.4 to 7.0 and 6.7 in a bathing solution buffered with 10 mM histidine, the active force decreased at all contraction frequencies studied. After parallel increases of HCO3-minus concentration (up to 47 mM) and PCO2 at a constant extracellular pH of 7.4 the active force of the muscle increased at low and decreased at high contraction frequencies. None of these effects can be attributed to catecholamine release or to altered extracellular concentration of ionized calcium. The inotropic effects produced by bicarbonate were not reproducible by methyl sulfate (47 mM) or propionate (47 mM). It is concluded that: 1. a lowering of the extracellular pH has a negative inotropic effect at all frequencies, 2. HCO3-minus has a positive inotropic effect that is most pronounced at low contraction frequencies and 3. CO2 has a negative inotropic effect exceeding that produced by the mere reduction in extracellular pH. The cellular mechanisms involved in the various inotropic effects are discussed.

Acid-base changes and excitation-contraction coupling in rabbit myocardium. II. Effects on resting membrane potential, action potential characteristics and propagation velocity.

The effects of changes in acid-base parameters on the resting membrane potential, action potential characteristics and propagation velocity were studied in isolated rabbit papillary muscles. Lowering extracellular pH from 7.4 to 6.7 in a bathing solution buffered with 10 mM histidine did not alter the resting membrane potential or action potential characteristics but casused slight reduction in propagation velocity. A parallel increase in HCO3-minus concentration (up to 47 mM)and PCO2 at a constant extracellular pH of 7.4 caused a substantial decrease in action potential duration but did not alter the resting membrane potential or propagation velocity. The decrease in action potential duration was caused by the increase in HCO3-minus concentration. Propionate (47nM) caused a shortening of the action potential which was of the same magnitude as for HCO3-minus but methylsulfate (47nM) did not have this effect. The possible influence of these changes on the inotropic state of the myocardium and the cellular mechanisms involved are discussed.