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Bilateral microinjections into the cerebellar flocculus of the rabbit of carbachol, a general cholinergic agonist, profoundly affect vestibuloocular (VOR) and optokinetic (OKR) reflexes. For sinusoidal stimuli (0.15 Hz, 5 deg peak to peak), the gain of the OKR was strongly increased, while the gain of the VOR was moderately increased. These effects were partially mimicked by floccular injection of the acetylcholinesterase inhibitor eserine. Floccular injection of the muscarinic blocker atropine significantly lowered the gain of the OKR. The effects of the nicotinic blocker mecamylamine were not significant. Optokinetic nystagmus (OKN) in response to constant stimulus velocities (1-30 deg/second) showed a markedly accelerated buildup and a shortened optokinetic after-nystagmus (OKAN) after floccular injections of carbachol. The steady-state gain of OKN remained unaffected. None of the described effects occurred after floccular injection of the solvent, saline. It is postulated that cholinergic cerebellar afferents, one probable source of which are the vestibular nuclei, enhance the optokinetic and vestibular modulation of floccular Purkinje cells.

Previous experiments show that altered visual feedback can change VOR gain. Such changes also presumably occur when eyeglasses are donned and doffed, or when bifocals are worn. In these cases, a nonvisual cue accompanies the required gain adjustment (frames on/off for eyeglasses, looking up/down for bifocals). We set out to show that a subject can establish two VOR gains, and to determine if one of the associated nonvisual cues alone is sufficient to subsequently determine which gain to employ. Each of three subjects sat in a rotating chair inside an OKN drum during 2 hours of sinusoidal rotation at 0.2 Hz, 30 degrees/s peak. For 10 minutes the chair and drum counterrotated , driving VOR gain toward 1.7, while subjects looked up 20 degrees. Chair and drum were then coupled for 10 minutes, driving gain toward zero, during which subjects looked down 20 degrees. This sequence was repeated for 2 hours. Immediately thereafter, VOR gains were measured while subjects looked alternately up and down, using 20 degrees to 40 degrees step rotations. A fixation target, presented before and after each step, provided accurate gain determination by measuring the size of the re-fixation saccade. Results show a consistent reduced VOR gain looking downward (average 6%) and increased gain looking upward (average 6%) and increased gain looking upward (average 8%). We conclude that humans can adjust their VOR gain dependent on a situational context; we speculate that this context can take many forms.

1. In the alert, pigmented rabbit, eye movements were recorded during optokinetic nystagmus (OKN) and during optokinetic after nystagmus (OKAN). These responses were elicited by steps in surround-velocity ranging from 5-110 degrees/s during binocular as well as monocular viewing. 2. In the baseline condition, OKN showed an approximately linear build-up of eye velocity to a steady-state, followed by a linear decay of eye velocity during OKAN after the lights were turned off. Build-up during binocular viewing was characterized by a constant, maximum eye-acceleration (about 1 degree/s2) for stimulus velocities up to 60 degrees/s. OKAN, instead, was characterized by a fixed duration (about 10 s) for stimulus velocities up to 20 degrees/s. Steady-state eye velocity saturated at about 50 degrees/s. 3. Monocular stimulation in the preferred (nasal) direction elicited a build-up that was on average twice as slow as during binocular stimulation. Steady-state velocity during monocular stimulation saturated at about 20 degrees/s. OKAN was of equal duration as during binocular stimulation. In the non-preferred direction, a very irregular nystagmus was elicited without velocity build-up. The stronger response to binocular stimulation, compared to the responses under monocular viewing condition in either nasal and temporal direction suggests potentiation of the signals of either eye during binocular viewing. 4. OKN and OKAN were re-assessed after intra-floccular micro-injection of the nonselective cholinergic agonist carbachol. In the binocular viewing condition, eye-acceleration during build-up was strongly enhanced from 1 degree/s2 before to 2.5 degrees/s2 after injection. The saturation level of steady-state eye velocity was also increased, from 50 degrees/s before to more than 60 degrees/s after carbachol. The duration of OKAN, however, was shortened from 10 s before to 6 s after injection. The response to monocular stimulation in the preferred direction revealed similar changes. 5. The flocculus appears to be involved in the control of the dynamics of OKN in the rabbit. Cholinergic mechanisms affect the floccular control of the rate at which slow-phase velocity can be built up and the rate of decay of eye velocity during OKAN. Cholinergic stimulation of the flocculus enhances the dynamics of OKN, while velocity storage is shortened.

Objectives: To report the incidence of elective total hip replacement and postoperative mortality, emergency readmission rates, and the demographic factors associated with these rates in a large defined population., Design: Analysis of linked, routine abstracts of hospital inpatient records and death certificates., Setting: 10 hospitals in six districts in Oxford Regional Health Authority covered by the Oxford record linkage study., Subjects: Records for 11,607 total hip replacements performed electively in 1976-85., Main Outcome Measures: Incidence of operation, postoperative mortality, relative mortality ratios, and incidence of emergency readmission., Results: NHS operation rates increased over time from 43 to 58 operations/100,000 population. Variation in operation rates between districts reduced over time. Operation rates were on average 25% higher in women than men. There were 93 deaths (11/1000 operations) within 90 days of the operation and 208 emergency readmissions (28/1000 operations) within 28 days of discharge. Postoperative mortality and emergency readmission rates increased with age. No significant trend with time was found. Mortality in the 90 days after the operation was 2.5-fold higher (1.9 to 3.0) than in the rest of the first postoperative year. This represented an estimated excess of 6.5 (4.2 to 8.8) early postoperative deaths/1000 operations. Most deaths were ascribed to cardiovascular events. Thromboembolic disease was the commonest reason for emergency readmission., Conclusions: The pronounced increase in operations in districts with initially low rates suggests a trend towards greater equity in the local provision of NHS hip arthroplasty. The early postoperative clusters of deaths attributed to cardiovascular disease and of readmissions for thromboembolic disease suggest that there is scope for investigating ways of reducing the incidence of major adverse postoperative events.

The effects of microinjection of alpha-noradrenergic agonists and antagonists in the flocculus on the basic gain and adaptibility of vestibulo-ocular and optokinetic responses were investigated. A complementary, previous investigation had shown that the adaptation, but not the basic performance, of compensatory oculomotor responses were markedly influenced by beta-noradrenergic mechanisms in the flocculus. In contrast, the present experiments with bilateral, intrafloccular injections of phenylephrine, prazosin, clonidine and idazoxan failed to reveal any effect of alpha 1- or alpha 2-noradrenergic mechanisms on either basic performance or adaptation of compensatory eye movements. Intravenous administration of clonidine, however, reduced the gain of the optokinetic and vestibulo-ocular responses by about 70 and 50%, respectively, at dosages of 0.07 mg/kg. Recovery from this effect took about 1.5 h. A higher dosage of clonidine (0.7 mg/kg) had a similar, but longer lasting effect, and also markedly increased the frequency of spontaneous saccades. Intravenous administration of phenylephrine did not affect the oculomotor responses. It is concluded that the control of oculomotor responses is not susceptible to alpha-noradrenergic influences at the level of the flocculus, but that alpha 2-agonistic action inhibits these responses through an extra-floccular structure.

A viscous organic phase, containing up to 65 per cent solid pigment, was dispersed into water with an emulsifier by a rotor-stator homogenizer and the droplets formed were encapsulated by interfacial polymerization. Microcapsules with volume median diameters d50 ranging from 10 to 25 microns and geometric standard deviation (GSD), from 1.25 to 1.65, were obtained depending on emulsification conditions. Larger impellers gave smaller d50 and slightly narrowed GSD; d50 decreased and GSD increased as volume fraction of dispersed phase is decreased. Higher homogenizer speed and emulsifier concentration decreased d50 but slightly increased GSD. Increasing pigment content in dispersed phase decreased d50 but had little effect on GSD. These effects were assessed quantitatively by fitting an empirical model to the data.

A study undertaken following recent reports of deaths in neonatal children associated with the use of benzyl alcohol resulted in the development of a stability-indicating high-performance liquid chromatographic assay of benzyl alcohol in plasma using benzocaine as internal standard. Thawed plasma samples were diluted and subjected to solid-phase extraction using Extrelut and eluted with ethyl acetate. The evaporated eluate was reconstituted with mobile phase and chromatographed on a C18 column with water-acetonitrile-glacial acetic acid as mobile phase and detection at 254 nm. Baseline separation was achieved within 12 min for benzyl alcohol, benzaldehyde, benzoic acid, hippuric acid and benzocaine. Peak-height ratios were linear over 80-640 ng of benzyl alcohol injected (r = 0.998) and over 10-80 ng of benzoic acid injected (r = 0.999). Benzaldehyde and hippuric acid were not quantitated because these compounds were not detectable in actual dog plasma. Validation studies by spiking dog plasma with benzyl alcohol and benzoic acid gave overall percent recoveries (+/- relative standard deviation, n = 4) of 98.3 +/- 3.0 and 101.4 +/- 7.6%, respectively. The method was applied to the assay of actual plasma samples. Since benzyl alcohol is very susceptible to oxidation to benzaldehyde and benzoic acid, its purity in bulk liquid samples can be determined by this method.

In spite of a large body of histochemical evidence for a cholinergic system in the cerebellum, particularly in lobules IX and X, the physiological role of such a system has remained obscure. In view of the important role of these same lobules in the control of the vestibulo-ocular (VOR) and optokinetic (OKR) responses, we tested the effect of microinjections of cholinergic (ant)agonists in the flocculus of the rabbit on these reflexes. Very marked effects were found. Bilateral floccular injection of the aspecific cholinergic agonist carbachol raised the gain of the OKR by about 0.46 above the baseline values, while the gain of the VOR in darkness was raised by about 0.14. These effects were statistically significant and persisted for several hours. Similar, but smaller effects were obtained after injection of eserine, an inhibitor of acetylcholinesterase. Thus, the effects could be produced by increasing the naturally present amount of acetylcholine. Microinjections of the nicotinic blocker mecamylamine reduced the gain of the VOR and OKR, although these effects did not reach statistical significance. The muscarinic blocker atropine significantly reduced the gain of the OKR, but not of the VOR. The present results argue strongly for an important physiological role of the cholinergic system in the cerebellum. Specifically, acetylcholine appears to be involved in the modulation of oculomotor reflexes through the flocculus.

Nonlactating Holstein and Jersey cows (n = 24) were superovulated and ovarian follicular development was monitored by transrectal ultrasound during the period after embryo recovery. Luteolysis was induced by two injections of prostaglandin F(2)alpha (PGF; 25 mg Lutalyse; 12-h interval) at specific times after superovulatory induced estrus (Treatment 1, Day 9; Treatment 2, Day 12; Treatment 3, Day 17; Treatment 4, Day 25; superovulatory estrus = Day 0 of Cycle 1). Follicular development was monitored during Cycle 1 before and after PGF injection and continued through the ensuing estrous cycle (Cycle 2). Superovulation led to more than one embryo collected in 14 cows (mean = 8.71 embryos: positive superovulatory response [PSR] cows), while 10 cows were not successfully superovulated (mean = 0.1 embryo; negative superovulatory response [NSR] cows). These cows differed in terms of number of unovulated follicles detected at embryo collection (4.21 vs 17.2, PSR vs NSR) and plasma progesterone during the superovulatory estrous cycle (32.3 ng/ml PSR vs 8.6 ng/ml NSR). Follicular development during Cycle 1 started sooner in NSR than in PSR cows (day by class by response P<0.03) and was initiated on Days 11 to 12 in NSR cows and on Days 19 to 20 in PSR cows. Interval to estrus after PGF averaged 6.3 d. Cows having short intervals to estrus had follicles at the time of PGF injection. Treatment influenced the length of Cycle 1, but it did not affect the interval to estrus after PGF, the length of Cycle 2, or follicular development during Cycle 2. The results indicate that 1) the timing of PGF injection after embryo collection does not influence subsequent follicular populations, 2) elongated estrous cycles and intervals to estrus after PGF in superovulated cattle are a function of decreased follicular activity, and 3) the presence of numerous corpora lutea and not the superovulatory treatment, per se, seem to attenuate follicular growth.

A rapid reversed-phase high-performance liquid chromatographic (HPLC) method was developed for the simultaneous assay of theophylline, ephedrine hydrochloride, and phenobarbital in a tablet matrix. A methanolic extract of the powdered sample containing salicylamide as the internal standard was injected into the chromatograph. The HPLC system used methanol-0.007 M monobasic potassium phosphate (37:63, pH 2.3) as the mobile phase. Detection was at 254 nm, and quantitation was based on the drug-internal standard peak area ratio. This ratio was linear over a concentration range of 20.9-83.5 microgram of theophylline, 4-15.9 microgram of ephedrine hydrochloride, and 1.3-5.1 microgram of phenobarbital. Overall recoveries (+/- SD) from three synthetic tablets were: theophylline, 99.8 +/- 1.3%; ephedrine hydrochloride, 100.2 +/- 0.6%; and phenobarbital, 99.4 +/- 0.7%. The method was compared to the compendial method and also was applied to the assay of commercial tablets containing these three active ingredients. The proposed method is applicable to the assay of individual tablets.

Noreximide, a sedative, is generally contaminated to some extent with its endo-isomer, norendimide, which produces excitation. A high-performance liquid chromatographic assay was developed to separate and quantitate these compounds on a 5-microns Ultrasphere ODS column with methanol-water (20:30) as mobile phase and detection at 254 nm. Assay of mixtures of these compounds in bulk material and tablets utilized isoniazide as internal standard. Peak area ratios were linear (r = 0.9999) over 1.4-66.2 micrograms of injected noreximide and 0.2-8.4 micrograms of injected norendimide. Overall percent recovery from simulated tablets containing noreximide alone was 99.6 +/- 0.8% (S.D., n = 3). Overall percent recoveries (+/- S.D.) from tablets containing a mixture of these compounds were 98.9 +/- 0.5% and 102.3 +/- 1.1% for noreximide and norendimide, respectively (n = 3). Noreximide in animal feed for long-term pharmacological studies was isolated by ether extraction and after work up, subjected to the same procedure, except that theophylline was the internal standard. Peak area ratios were linear over 0.2-19.3 micrograms of injected noreximide (r = 0.9999). Overall percent recoveries (+/- S.D., n = 3) of noreximide from spiked animal feed were 97.4 +/- 1.4% and 99.0 +/- 0.5% at the 500- and 5000-ppm levels, respectively. Limits of detection at the 95% confidence level (0.01 a.u.f.s., 20-microliters sample volume injected) were 1.67 microgram/ml and 2.56 micrograms/ml of noreximide and norendimide, respectively, in the final test solution.

A simple assay method for the quality control of some sunscreen products containing padimate-O and oxybenzone has been developed. A methanolic extract of the product containing sulfathiazole internal standard was subjected to reversed-phase high-performance liquid chromatography on a 10-micron Partisil ODS-2 column with methanol-acetonitrile (90:10, v/v) mobile phase. The drug-sulfathiazole peak height ratio was linear between 0.04-2.68 micrograms of padimate-O (r = 1.0003) and 0.02-1.05 micrograms of oxybenzone (r = 0.9997) injected. All peaks were well-resolved. Approximate retention times for sulfathiazole, oxybenzone and padimate-O were 3.9, 5.7 and 7.4 min., respectively. The height equivalent to a theoretical plate (+/- S.D.) were (n = 10) 0.79 +/- 0.07, 0.53 +/- 0.06 and 0.26 +/- 0.04 mm, for sulfathiazole, oxybenzone and padimate-O, respectively. Average percent recoveries (+/- S.D.) (n = 3) from simulated lotions containing 7% padimate-O and 3% oxybenzone were: padimate-O, 101.4 +/- 1.5%; oxybenzone 99.9 +/- 1.9%; from simulated lipsticks containing (a) 7% padimate-O and 3% oxybenzone: 103.8 +/- 1.2% and 100.1 +/- 0.9%, respectively; and (b) 7% padimate-O and 0.5% oxybenzone: 99.4 +/- 0.6% and 99.3 +/- 2.4%, respectively. The method was successfully applied to marketed products.

A modification of the USP method for the assay of systemic alkalizer solutions containing mixtures of citrate and citric acid is presented; it involves two titrations and ion-exchange chromatography. A diluted sample is tritiated with 0.02 N NaOH to find the free citric acid content. The eluate from cation-exchange chromatography of an equal volume of diluted sample is titrated with 0.02 N NaOH to assay for total citric acid. Subtracting the results of the first titration from the second provides the citrate content. Synthetic mixtures of potassium citrate-citric acid, potassium citrate-sodium citrate-citric acid, and sodium citrate-citric acid were prepared and assayed. The method was applied to commercially available preparations. The proposed method eliminates some significant errors of the compendial method, and the accuracy and reproducibility are equal or better than those obtained with the compendial method. Theoretically, the result obtained by the compendial method does not necessarily give the citrate content.

A highly specific and sensitive radioimmunoassay (RIA) for alpha-human atrial natriuretic peptide (hANP[1-28]) in plasma was developed. The assay used a [125I]monoiodotyrosyl-hANP[1-28] tracer, prepared with an immobilized glycouril agent (Protag) and purified by high pressure liquid chromatography (HPLC), and a highly specific antiserum raised against hANP[1-28], coupled to keyhole limpet haemocyanin, in sheep. Plasma was extracted using C-18 Seppak cartridges. A good parallelism was found after dilution prior to extraction of plasma of patients with congestive heart failure (CHF) or of plasma of healthy subjects. Recovery of hANP[1-28] added to plasma was 96%. The limit of detection was 0.8 pg/tube, intra- and inter-assay variation were 9 and 12%, respectively. Mean plasma ANP values in 25 normal persons with a normal salt intake was 26.0 +/- 15.5 (+/- SD) pg/ml. Plasma levels of 18 subjects (7 normals, 11 CHF) were measured using four different antisera after the extraction step. High correlations were found between the values obtained with these four antisera.

A spectrophotofluorometric method is described for the quantitative analysis of coumarin, umbelliferone, and mixtures thereof in whole blood. The two drugs were selectively isolated from blood by solvent extraction. Analysis of the isolated coumarin was based on the measurement of the fluorophore at activation and emission wavelengths of 361 and 491 nm, respectively. The fluorophore was obtained by irradiating an alkaline methanolic solution of the drug with UV light. A linear relationship between fluorescence and concentration existed over the concentration range of 0.02-0.2 mug of coumarin/ml. A mean recovery value of 94.8% was obtained from whole blood. The isolated umbelliferone was determined according to established methods at activation and emission wavelengths of 370 and 450 nm, respectively, and the limit of detection was 10 times more sensitive than previously reported. A linearity response was obtained between 1 and 10 ng of umbelliferone/ml. Good recovery data for mixtures of coumarin and umbelliferone in whole blood were obtained.

A high-performance liquid chromatographic (HPLC) method was developed for the assay of 2-chloro-5-(1H-tetrazol-5-yl)-4-[(2-thienylmethyl)amino]benzenesulfonamide (I) in animal feed diet mixtures. The sample is extracted with acetone, an aliquot of the extract is evaporated to dryness, and the residue is dissolved in chloroform. This solution can be subjected to either of two cleanup procedures. The first traps I on a sodium hydroxide-diatomaceuous earth column. Compound I is then recovered using an acetic acid-ethyl acetate-chloroform eluent, which is removed by evaporation, followed by dissolution of the residue in aqueous sodium hydroxide. The second procedure involves the direct extraction of I from the chloroform solution. A linear relationship exists between the HPLC UV detector response at 254 nm and concentration up to 170 microgram/ml. The sodium hydroxide extraction procedure resulted in an overall recovery (+/- SD) of 92.9 +/- 1.6 and 97.4 +/- 1.8% (n = 5) at levels of 200 and 6000 ppm, respectively. Overall recoveries (+/- SD) obtained by the diatomaceous earth column procedure for the 20- and 6000-ppm levels were 90.0 +/- 2.0 and 95.9 +/- 1.6% (n = 5), respectively.

The disposition pharmacokinetics of coumarin has been studied after i.v. administration in man, and might be described best by an open two-compartment model. Three dose sizes have been studied, 0.125, 0.2 and 0.25 mg/kg. The mean biological half-life was found to be 1.81, 1.45 and 1.49 h, respectively, for the three dose sizes. Coumarin is extensively distributed. The volume of the central compartment apparently comprises the extracellular and intracellular fluid. The study indicates dose-dependent (non-linear) pharmacokinetics with respect to distribution.

A sensitive procedure was developed for 3',4',7-tris[O(beta-hydroxyethyl)]rutoside (I) in urine. The method is based on the fluoresence behavior of the I-aluminum complex in absolute methanol. This complex has activation and emission wavelengths of 420 and 480 nm, respectively. Optimum conditions for the reaction were investigated. The fluorescence was linear (r = 0.998) in the range of 0.1-4.0 microgram of I/ml. At concentrations below 0.1 microgram/ml, a shift in the emission wavelength was observed. Replicate studies (n = 9) of spiked urine samples, each containing 0.4 microgram of I/ml, showed good precision with a relative standard deviation of 0.009. Overall percent recovery (+/- SEM) from five urine samples was 99.5 +/- 1.34%. Following a single 500-mg po dose of I to individuals, only traces of I were found in the urine. However, beta-glucuronidase treatment of urine resulted in a total cumulative urine excretion of 26.53 mg of I after 78.6 hr.

The disposition of nitroglycerin was studied in dogs using a crossover design for I.V. (0.85 mg/kg) and buccal (0.75 mg/kg) administration. The pharmacokinetic parameters after I.V. administration are comparable to those in man. The mean values are: t1/2 = 9.2 min; V beta = 3.8 L/kg, Cltot = 238 ml/kg. Similar values were obtained after buccal administration. The bioavailability buccally is 47%. After 7 days pretreatment with nitroglycerin (0.75 mg/kg twice daily, buccally), the area under the I.V. curve (0.85 mg/kg) decreased by about 23%, indicating possible enzyme induction.

The pharmacokinetics of a single dose of intravenous ampicillin were studied in nine patients during their third trimester of pregnancy. Each volunteer was given either 500 mg (5.7-8.8 mg/kg) or 1 g (15.4-21.4 mg/kg) of sodium ampicillin by rapid infusion. Postinfusion plasma concentration-time curves followed biexponential decay in all subjects. Calculated parameters included a mean plasma distribution volume of 177.1 +/- 97.5 ml/kg, tissue or peripheral distribution volume of 246.2 +/- 143.9 ml/kg, elimination half-life of 1.60 +/- 0.51 h, and total body clearance of 4.59 +/- 1.48 ml/min/kg. Dose-dependent disposition was not observed. Gestation-specific drug therapy research during pregnancy is discussed.

One hundred and ten consecutive patients with falciparum malaria were treated with Fansidar and primaquine. Of the 61 patients who were followed up at one week, 4 (6.6%) failed to clear their parasitaemia (1 R III and 3 R II treatment failures). Of the subsequent 40 patients who were seen again at one month, another 3 (7.5%) had recrudesced (R I treatment failure). A total of 7 patients thus experienced some form of treatment failure in the cohort of 40 who completed the one month follow up. Only 1 of these 7 patients (with R III treatment failure) failed to respond to repeat Fansidar treatment, and may be the only one with true Fansidar resistance. The overall treatment failure rate of 17.5% (95% confidence interval: 6-29%) in the cohort who completed the study is consistent with the known clinical efficacy of Fansidar. These results suggest no significant Fansidar resistance in falciparum malaria found in Sabah.

Unlabelled: Two patients with metastatic endocrine pancreatic tumours initially responded well to therapy with the long-acting somatostatin analogue SMS 201-995. In the first patient with an insulinoma both the number of hypoglycemic attacks and the increased insulin levels decreased initially, but returned to pretreatment intensity and concentrations within 9 days after the start of therapy with 200-300 micrograms SMS 201-995 daily. After a short interruption, no effect was observed of re-institution of therapy at a dose of 400 micrograms SMS 201-995 daily. In the other patient with a metastatic vipoma both diarrhea, hypokalemia and plasma VIP levels reacted initially well to SMS 201-995 treatment with 300 micrograms per day, but resistance to therapy developed after 2 weeks. An increase in the dose of the analogue to maximally 600 micrograms/day was followed by a transient improvement, but finally both the volume of diarrhea and the levels of vasoactive intestinal polypeptide were higher than those before the start of therapy., Conclusions: Development of resistance to SMS 201-995 both with regard to the clinical effect and to the inhibitory effect on tumour hormone secretion can be expected in some patients with metastatic endocrine pancreatic tumours. On the basis of our clinical observations down-regulation of somatostatin receptors is suggested to be one of the mechanisms of this development.

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.

Blood level versus time data upon i.v. and p.o. administration of coumarin in a cross-over study have been analyzed for extent of bioavailability (EBA) and first-pass effect (FPE). In whole blood the parent drug, coumarin (C), and its main metabolite, 7-hydroxycoumarin (7HC), after hydrolysis of the glucuronide were determined. Comparison of the areas under the curve (AUCO leads to infinity) for C and 7HC upon i.v. and p.o. administration revealed that all of the drug is absorbed; however, only approximately 2-6% of C reaches systemic circulation in intact form. Hence, extensive first-pass effect must be assumed. The fraction of unchanged drug reaching systemic circulation predicted from the i.v. study fFPE varied between 0 and 38% assuming a liver blood flow rate (LBF) of 1.53 1/min. When corrected for individual LBF the fPFE varied between 2.5 and 13%. The question whether the FPE is only due to metabolism in the liver or in part due to biotransformation in the intestinal lumen, gut wall and/or portal blood will be the subject of a further paper. It is suspected that C is the pro-drug and 7HC the pharmacologic active moiety.

A simple assay method for the quality control of appetite suppressant products containing phenylpropanolamine hydrochloride and caffeine has been developed. A methanolic extract of the product was evaporated to dryness and the residue was treated with aqueous solutions of sodium metaperiodate and disodium phosphate. Following addition of methyl p-hydroxybenzoate as internal standard and subsequent filtration, an aliquot of the filtrate was subjected to high-performance liquid chromatography on a 10-microns Partisil ODS-2 column with acetonitrile-water (30:70) as mobile phase. The drug: internal standard peak height ratio at 254 nm was linear over the ranges 0.3-2.0 micrograms of phenylpropanolamine hydrochloride and 1.1-16.0 micrograms of caffeine injected. All peaks were well-resolved. The heights equivalent to a theoretical plate (+/- S.D.) for phenylpropanolamine (as benzaldehyde) and caffeine were (n = 10) 0.42 +/- 0.08 and 1.31 +/- 0.23 mm, respectively. Overall per cent recoveries (+/- S.D.) from simulated formulations (n = 6) were 100.7 +/- 1.6% phenylpropanolamine hydrochloride and 99.1 +/- 1.4% caffeine. The method was applied to marketed products and is also applicable for single dose analysis.

We followed atrial natriuretic peptide (ANP) levels in 12 patients during anticoagulant treatment of pulmonary embolism. In each patient with this disorder ANP decreased during treatment. Concomitantly, plasma renin activity (PRA) markedly rose. The decrease in ANP was significantly related to the rise in PRA. No consistent changes in ANP or in PRA were observed in five patients with peripheral venous thrombosis receiving the same anticoagulant treatment. Plasma aldosterone levels did not change in either group.

A colorimetric procedure for benzocaine and a number of its dosage forms was developed; it offers improvement in ease, speed, and sensitivity over the official method. The method is based on the formation of a red Schiff base between benzocaine and p-dimethylaminocinnamaldehyde in a nonaqueous acidic medium. At the maximum absorption of 544 nm, the Beer-Lambert law was adhered to over the 0.025--2.5-microgram/ml range. Best accuracy can be obtained for solutions containing 0.25--1.25 microgram/ml. The color was stable for at least 2 hr. Analysis of benzocaine in the dosage forms studied can be directly performed without prior drug extraction.

The adsorption of quinidine onto kaolin was studied as a function of pH in aqueous solutions in which the ionic strength was adjusted to 0.1. The interaction of quinidine with pectin also was investigated in water and in phosphate buffer; the buffer pH and ionic strength were adjusted to 6.5 and 0.1, respectively. The in vitro results indicated that quinidine was adsorbed onto kaolin. At the highest concentration studied, the extent of adsorption increased from 3.64 mg of quinidine adsorbed/g of adsorbent at pH 2.4 to an average of 5.81 mg/g in the pH 5.5-7.5 range. In the presence of electrolytes, the interaction of quinidine with pectin was relatively small (3-13% bound) as compared to studies performed in water (66-90% bound). The data indicate that some quinidine may be adsorbed when this drug is administered concurrently with kaolin-pectin preparations.

The charge transfer complex formation between ethambutol and iodine was investigated and utilized as the basis for a sensitive spectrophotometric procedure for ethambutol and its dosage forms. The solutions exhibited blue-shifted iodine bands at 293 and 360 nm. A Job's plot of corrected absorbance against the mole ratio of ethambutol to iodine indicated a 1:2 drug-iodine ratio. At 293 nm, the absorbance was linear (r=0.9998) over the 0.25-15-microgram/ml concentration range, but the concentration range for best accuracy is 1.6-5.8 microgram/ml. The method can be applied successfully to the analysis of commercially available ethambutol tablets.