The relationship between relapse, impairment and disability in multiple sclerosis.

OBJECTIVE: To describe the spatial relationship between relapse and disability in multiple sclerosis (MS). METHODS: 141 relapse onset MS patients were studied. For each patient an examination was performed and a relapse history obtained. Multivariate logistic regression examined whether there was an association between localizing clinical signs and a history of relevant relapse in order to explore the spatial relationship between relapse and subsequent disability. RESULTS: The presence of impaired vision or sensation was independently associated with a history of one or more anatomically related relapses. The presence of weakness or cerebellar ataxia in a limb was not associated with a single relevant relapse but was associated with multiple relevant relapses. A history of multiple episodes of weakness or ataxia in the same limb was uncommon. CONCLUSIONS: Our data suggest that motor pathways are relatively resistant to chronic impairment from acute relapse, whereas afferent pathways are more susceptible. This, in combination with prominent usage of the Expanded Disability Status Scale, which is dependent on mobility and motor function at higher scores, may explain the paradox between natural history studies that suggest relapses are irrelevant to long-term disability and shorter studies at lower disability levels suggesting relapses are responsible for disability accumulation.

Relationships of peri-partum, plasma concentrations of progesterone, oestrogens and 13,14-dihydro-15-ketoprostaglandin F2alpha in heifers and of anatomical measurements of dam and calf with difficulty of calving in early-bred Hereford x Friesian heifers.

Plasma concentrations of progesterone, oestradiol-17beta, oestrone, oestrone sulphate and PGFM have been measured daily during the first peri-partum period of 45 Hereford x Friesian heifers bred at 11 months of age. Anatomical measurements of dam and calf were also recorded. Twelve of the calvings were scored easy, 33 difficult. Each of five models (fitted by linear logistic regression) relating difficulty of calving to the hormonal and anatomical measurements, predicts with at least 94% accuracy the calving score (easy or difficult) among the calvings. The models predict that increases of progesterone concentration on the day before calving, of oestrone sulphate concentration on the day after calving and of heifer heart girth decrease the odds of difficult calving, whereas increases of heifer body length and of calf head circumference increase the odds of difficult calving.

Efficacy of once daily nitrendipine in mild hypertension: comparison with placebo.

A randomized, double-blind, parallel group study was carried out to compare the antihypertensive efficacy of nitrendipine with that of placebo in 80 mild hypertensives. The dose of nitrendipine was initially 10 mg once daily and was doubled to 20 mg once daily after four weeks in patients who responded poorly (33% of patients on nitrendipine and 49% of patients on placebo required doubling of dose). Blood pressure was assessed 20 to 24 h after dosing. Mean (+/- standard error) reductions in supine systolic and diastolic blood pressures for patients who completed 10 weeks of therapy were significantly greater for the nitrendipine group than for the placebo group (systolic blood pressure 18.1 +/- 2.7 mmHg versus 4.2 +/- 2.5, P less than 0.0001; and diastolic blood pressure 10.6 +/- 1.1 mmHg versus 6.6 +/- 1.3, P = 0.002). A comparison of mean reductions in standing systolic and diastolic blood pressures produced similar results. Goal of therapy (diastolic blood pressure no more than 90 mmHg or reduction of at least 10 mmHg) was achieved in 71% of nitrendipine-treated and 45% of placebo-treated patients (P less than 0.05). Nine of 80 patients randomized to therapy dropped out during treatment (nitrendipine: four adverse experiences and one moved from the area; placebo: two adverse experiences, and drug ineffective in two). Overall, the incidence of adverse experiences considered by the physician to be related to treatment was higher in the placebo group (32%) than in the nitrendipine group (23%). Only flushing had a higher incidence in the nitrendipine group; however, the overall incidence was low (9%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and tolerability of once versus twice daily nitrendipine in the treatment of mild to moderate hypertension. The Canadian Nitrendipine Study Group.

Improved measurement of plasma concentrations of nitrendipine demonstrates a plasma half-life of 17 to 21 h allowing once daily dosing for antihypertensive treatment. To determine the effectiveness and tolerability of nitrendipine given once versus twice daily, 78 patients with mild to moderate essential hypertension were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 20 mg once daily (n = 39) or nitrendipine 10 mg bid (n = 39). Blood pressures measured at the end of the dosing interval were similar on 20 mg once daily and 10 mg bid. Adverse events considered to be drug related (flushing and headaches) occurred mostly at the beginning of active treatment and more frequently on the once daily dosing, resulting in a greater number of patients being withdrawn from the once daily treatment group. Thus, nitrendipine 20 mg once daily lowered blood pressure as effectively as 10 mg bid but was associated with a higher incidence of adverse events. These could be minimized by starting at nitrendipine 10 mg once daily and increasing to 20 mg once daily after two to four weeks.

Once- vs. twice-daily nitrendipine in the treatment of mild to moderate hypertension, Canadian Nitrendipine Study Group.

Improved measurement of the plasma concentration of nitrendipine demonstrated a plasma half-life of 17-21 h, allowing once-daily (o.d.) instead of currently twice-daily (b.i.d.) dosing. To determine the effectiveness of nitrendipine given o.d. vs. b.i.d., 78 hypertensive patients, [supine diastolic blood pressure (DBP) of 95-114 mm Hg] were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 10 mg b.i.d. (n = 39) or nitrendipine 20 mg o.d. (n = 39) after a 2-week placebo baseline period. Blood pressures (BPs) were measured in the morning at the end of the dosing interval. Mean +/- SD reduction in supine systolic BP (SBP) and DBP in patients evaluable for efficacy (greater than or equal to 14 days treatment) were 7.2 +/- 16.5 and 7.7 +/- 10.3 mm Hg, respectively, after nitrendipine b.i.d. (n = 38) and 9.4 +/- 15.1 and 9.5 +/- 7.0 mm Hg, respectively, after nitrendipine o.d. (n = 36). Similar falls in BP were found for both regimens in patients completing the full 12 weeks of treatment period (n: o.d. = 28, b.i.d. = 32). Discontinuation due to adverse experiences (AEs) occurred in three patients on b.i.d. and eight patients on o.d., the latter mostly in the first 2 weeks of therapy. Overall, AEs were higher in the o.d. group (% AEs at least possibly related to study medication: o.d. = 44%, b.i.d. = 33%). Most frequent AEs were headache and flushing.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between planar and all-surface rate constants for drugs formulated in nondisintegrating cylindrical slow-release tablets.

The release of drug through the planar surface of a nondisintegrating tablet with an insoluble matrix has been described mathematically using the Higuchi release rate constant (kH). The release of drug through a similar all-surface tablet has been described by using a cubic equation and the all-surface rate constant (kr). Using sodium salicylate and quinidine sulfate as model drugs, the relationship between kH and kr was verified for cylindrical slow-release tablets. Accordingly, the rate constant obtained from a single exposed planar surface can be used to predict the rate constant (kr) when all surfaces of the tablet are exposed to dissolution fluid.

pH- and flow-rate-independent release of drug from uncoated slow-release tablets.

Slow-release tablets were prepared using a polyvinyl chloride--polyethylene matrix and sodium salicylate as a model drug. The in vitro release of salicylate was described adequately by a previously published equation. The release rate constant was independent of the pH of the dissolution fluid and the flow rate of the fluid past the tablet. Accordingly, the procedures used to test the in vitro drug release from this type of matrix tablet are not as critical as for conventional tablets. It may therefore be postulated that the in vivo performance of the tablet may be less subject to variations in the physiological parameters of the GI tract.

Ocular delivery of pilocarpine from erodible matrices.

The present study examined the feasibility of sustaining the release of a water-soluble drug, pilocarpine, to the tear film. Both gels and dried films were utilized as drug delivery systems. In vitro studies demonstrated significant prolongation of drug release from these systems as compared with simple aqueous or viscous solutions. The in vitro results were supported by in vivo miosis studies in albino rabbits.

Glucosylated albumin and its influence on salicylate binding.

Human serum albumin was incubated at 37 degrees in 0.01 M phosphate buffer (pH 7.4) under sterile conditions for up to 10 days with labeled [14C]glucose (1-25 mg/ml). Glucose incorporated into albumin was calculated following extensive dialysis of the incubation mixture. The results indicated that glucose reacted with albumin by a nonenzymatic process involving Schiff base formation and Amadori rearrangement to a stable ketoamine derivative. The degree of glucosylation was dependent on the reaction time, glucose concentration, and pH. Glucosylation was enhanced when albumin was fatty acid free. Glucosylated albumin was separated from unmodified albumin by cation exchange chromatography on carboxymethylcellulose and quantitated colorimetrically with 2-thiobarbituric acid. Salicylate binding studies revealed that the glucosylated component had a decreased salicylate binding capacity accompanied by a reduction in the number of classes of binding sites.

Accuracy of copper-reduction and glucose-oxidase tests for various glucose concentrations.

Three glucose-oxidase (Diastix) and two copper-reduction (Clinitest) urine tests for glucose were compared to determine the differences in accuracy for various concentrations of glucose. Fifty volunteers were assigned on a random basis to one of five urine-testing methods and to a testing order for eight glucose samples. The samples were assayed spectrophotometrically to verify the actual concentrations of glucose, ranging form 0.1 to 20.0%. Scale points were assigned to correspond to the different glucose concentrations. The deviation of the volunteers' determinations above or below the actual concentrations were recorded as error points. A one-way analysis was conducted on the error points to determine it there were significant differences among the five testing methods. Significant differences were found among the five testing methods (p less than 0.01). The five-drop Clinitest method was significantly less accurate than the 1:5 Diastix and the two-drop Clinitest methods. Significant differences were found among the five testing methods at low and medium glucose concentrations but not at the high concentrations. In the glucose concentration range of 0.1-0.25%, the Diastix method with no dilution was significantly less accurate (p less than 0.01) than the two-drop Clinitest method. In the 0.5-1.25% range, the two-drop Clinitest was more accurate than Diastix 1:5, 1:10, and five-drop Clinitest. Overall, the two-drop Clinitest procedure was most accurate, particularly at the lower concentrations of glucose.

Stability of methacholine chloride in bronchial provocation test solutions.

The stability of methacholine chloride (5 mg/ml) in 0.9% sodium chloride solution was measured. A reliable colorimetric assay (530 nm) based on the formation of a hydroxamic acid-iron complex was used. At appropriate time intervals, samples were removed from solutions stored at 4, 20, 37, 60, or 80 degrees C and assayed. The degradation of methacholine chloride followed apparent first-order kinetics of methacholine chloride followed apparent first-order kinetics at all temperatures, with observed half-lives ranging from 29.3 days at 80 degrees C to 693 days 4 degrees C. Methacholine chloride in 0.9% sodium chloride solution does not degrade as rapidly as previously suggested. According to an Arrhenius plot, storage of such solutions at 30 or 4 degrees C would result in not more than 10% degradation over a period of approximately two or five months, respectively. Thus, it should be possible to prepare stock solutions of this deliquescent drug.

The use of marker drugs to measure organ function: a theoretical interpretation.

An equation is presented which describes the changes in drug clearance through an isolated organ due to alterations in the blood flow to the organ or the intrinsic clearance of the drug by the organ. In the case of hepatic clearance, example calculations of alterations in both parameters are presented from literature data for marker drugs having high and low extraction ratios. The predicted hepatic clearance of d-propranolol based on these calculations compares with observed values. For the particular example of the kidney, the blood flow and the intrinsic clearance change in proportion and, therefore, yield a simple equation relating renal clearance of any drug to endogenous creatinine clearance. This equation, though used clinically, has previously not been derived theoretically.

Mathematical models for the release of drugs from matrix tablets.

A previously derived cubic equation describing the release of drugs from matrix tablets is compared with a more complex equation recently presented. Using data obtained from cylindrical hydrocortisone matrix tablets, it is shown that the simpler cubic equation affords an equally acceptable description of drug release. Because the cubic equation contains a release-rate constant Kr that is independent of tablet shape, a congruency between this equation and other historical models of diffusion may be demonstrated. It is suggested, given the complexity of drug disposition in vivo, that simplicity in modeling is a desirable goal.

The rapid reduction of disulfiram in blood and plasma.

A gas chromatographic assay procedure was developed to quantitate the reduction product of disulfiram, diethyldithiocarbamate (DDC), in blood and plasma. The procedure involved the in situ methylation of DDC prior to the extraction and chromatography of the methyl ester. The minimal sensitivity achieved was 0.2 microgram/ml from 1 ml of blood or plasma. The coefficient of variation about any concentration was 10.5%. Calibration curves having a reproducible nonlinear form were prepared up to 9 microgram/ml. The assay procedure was used to evaluate the stability of disulfiram and DDC in blood. Disulfiram was rapidly and quantitatively reduced to DDC within 4 minutes. The DDC thus formed decomposed in human and dog blood with half-lives of 70 and 100 minutes, respectively. The implications of these findings are discussed with respect to the chemical form of disulfiram responsible for the ethanol-sensitizing effect.

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. III. The concentrations of alcohol and meprobamate in the blood and their effects on performance; application of mathematical models.

The relations between the levels of alcohol and meprobamate in the blood and performance on a visual-motor coordination tracking task were analyzed by a general system of mathematical models, using data from Experiment V by Carpenter et al. [J. Stud. Alc., Suppl. No. 7, pp. 54-139, 1975]. The derivation of the models is described. In general, the relationship between blood alcohol concentration (BAC) and performance was nonmonotonic: best performance occurred at BACS of 10 to 20 mg per 100 ml. The relationship between meprobamate concentration (BMC) and performance was monotonic: performance deteriorated with increasing BMC. The results of the reaction latency measure, howevr, showed no consistent relationship with BAC or BMC. The action of alcohol can be represented by a model which involves 2 distinct sites of action; that of meprobamate, 1 site. It could not be determined whether the site of action of meprobamate is distinct from those of alcohol because the blood levels of the drugs were not high enough. The implications of the results are discussed, with particular reference to the quantitative description of the joint action of drugs and the design of future experiments.

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. IV. The concentrations of alcohol and meprobamate in the blood.

The absorption and elimination of alcohol and meprobamate from the blood during Experiments IV (E-IV) and V (E-V) of Carpenter et al. [J. Stud. Alc., Suppl. No. 7, pp. 54-139, 1975] were studied by means of mathematical models representing the relation between doses, concentration in the blood and time elapsing since drug ingestion. The blood concentrations of samples taken 2 and 5.5 hr after beginning to drink in E-IV and 1, 1.5, 2, 2.5, 3.5 and 4.5 hr in E-V were analyzed. The presence of meprobamate did not affect blood alcohol concentration (BAC) in either experiment. At 2 hr the mean BACS after 0.25, 0.50, 0.75 and 1.00 g of alcohol per kg were 6.8, 20.9, 37.7 and 53.7 mg per 100 ml in E-IV; 5.0, 34.1, 42.0 and 72.0 mg per 100 ml in E-V; and 8.1, 32.6, 41.3 and 71.3 mg per 100 ml when calculated by regression from E-V data. The calculated elimination rate of the 2 highest doses of alcohol in E-IV was 6.0 and 7.1 mg per 100 ml per hr; in E-V the mean calculated rates after 0.25-0.75 and after 1.00 g of alcohol per kg were 6.6 and 11.0 mg per 100 ml per hr. The blood meprobamate concentrations (BMC) in E-IV were not affected by alcohol. In E-V, 2.5 and 5.5 hr after meprobamate administration, the combination of 28 mg of meprobamate per kg and 0.75 g of alcohol per kg resulted in significantly lower BMC (7.83 and 12.63 mug per 100 ml) than after same dose of meprobamate with the other doses of alcohol (14.23 and 20.02 mug per 100 ml). The differences between these results and the findings of Carpenter et al. are discussed.