Ambient and at-the-ear occupational noise exposure and serum lipid levels.

OBJECTIVES: Occupational and residential noise exposure has been related to increased risk of cardiovascular disease. Alteration of serum lipid levels has been proposed as a possible causal pathway. The objective of this study was to investigate the relation between ambient and at-the-ear occupational noise exposure and serum levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides when accounting for well-established predictors of lipid levels. METHODS: This cross-sectional study included 424 industrial workers and 84 financial workers to obtain contrast in noise exposure levels. They provided a serum sample and wore portable dosimeters that every 5-s recorded ambient noise exposure levels during a 24-h period. We extracted measurements obtained during work and calculated the full-shift mean ambient noise level. For 331 workers who kept a diary on the use of a hearing protection device (HPD), we subtracted 10 dB from every noise recording obtained during HPD use and estimated the mean full-shift noise exposure level at the ear. RESULTS: Mean ambient noise level was 79.9 dB (A) [range 55.0-98.9] and the mean estimated level at the ear 77.8 dB (A) [range 55.0-94.2]. Ambient and at-the-ear noise levels were strongly associated with increasing levels of triglycerides, cholesterol-HDL ratio, and decreasing levels of HDL-cholesterol, but only in unadjusted analyses that did not account for HPD use and other risk factors. CONCLUSION: No associations between ambient or at-the-ear occupational noise exposure and serum lipid levels were observed. This indicates that a causal pathway between occupational and residential noise exposure and cardiovascular disease does not include alteration of lipid levels.

Individual and work-unit measures of psychological demands and decision latitude and the use of antihypertensive medication.

PURPOSE: To analyse whether psychological demands and decision latitude measured on individual and work-unit level were related to prescription of antihypertensive medication. METHODS: A total of 3,421 women and 897 men within 388 small work units completed a questionnaire concerning psychological working conditions according to the job strain model. Mean levels of psychological demands and decision latitude were computed for each work unit to obtain exposure measures that were less influenced by reporting bias. Dispensed antihypertensive medication prescriptions were identified in The Danish National Prescription Registry. Odds ratios (OR) comparing the highest and lowest third of the population at individual and work-unit level, respectively, were estimated by multilevel logistic regression adjusted for confounders. Psychological demands and decision latitude were tested for interaction. Supplementary analyses of 21 months follow-up were conducted. RESULTS: Among women, increasing psychological demands at individual (adjusted OR 1.54; 95 % CI 1.02-2.33) and work-unit level (adjusted OR 1.41; 95 % CI 1.04-1.90) was significantly associated with purchase of antihypertensive medication. No significant association was found for decision latitude. Follow-up results supported an association with psychological demands but they were not significant. All results for men showed no association. Psychological demands and decision latitude did not interact. CONCLUSION: High psychological work demands were associated with the purchase of prescribed antihypertensive medication among women. This effect was present on both the work-unit and the individual level. Among men there were no associations. The lack of interaction between psychological demands and decision latitude did not support the job strain model.

Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses.

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans.

Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1).

The Six1 homeoprotein is an important mediator of normal development, where it is critical for the proliferation of precursor cell populations that ultimately constitute the muscle, kidney and inner ear, among other organs. Interestingly, its overexpression has been observed in numerous cancers, where it contributes to the proliferative and metastatic ability of the cancer cells. Here we show that Six1 not only regulates the cell cycle, but is itself regulated throughout the cell cycle via ubiquitin-mediated proteolysis. The protein is present from the G(1)/S boundary until mitosis, when it is degraded via the anaphase-promoting complex (APC) with its activating subunit Cdh1. However, unlike most identified APC(Cdh1) targets, Six1 does not contain functional destruction or KEN box motifs that are necessary for its degradation. Instead, the Six1 protein contains multiple, as yet undefined, sequences within its N- and C-termini responsible for its degradation, including an N-terminal region that binds to Cdh1. Cell cycle regulation of Six1 occurs both transcriptionally and post-translationally via phosphorylation; therefore, this study demonstrates a third and novel mechanism of cell cycle-specific regulation of Six1, underscoring the importance of confining its activity to a defined cell cycle window from the G(1)/S boundary to early mitosis.

Positive effects of aggressive vasodilator treatment of well-treated essential hypertensive patients.

Increased systemic vascular resistance and coronary microvascular dysfunction are well-documented in essential hypertension (EH). We investigated the effect of additional vasodilating treatment on coronary and peripheral resistance circulation in EH patients with high systemic vascular resistance index (SVRI) despite well-treated blood pressure (BP). We enroled patients on stable antihypertensive treatment that were given intensified vasodilating therapy (ACE inhibitor, angiotensin II receptor blocker or calcium channel blocker). Before and following 6 months of intensified therapy, coronary resting and maximal artery flow were measured by transthoracic Doppler echocardiography to calculate coronary flow reserve (CFR) and minimum vascular resistance (C-Rmin). Cardiac output was estimated by inert gas rebreathing to calculate SVRI. Maximal forearm blood flow was determined by venous occlusion plethysmography to calculate minimum vascular resistance (F-Rmin). Patients were assigned into two groups: high-SVRI and low-SVRI subgroups, based on a median split at baseline. Following additional treatment SVRI decreased more in the high-SVRI group than in the low-SVRI group (14.4 vs -2.2%: P=0.003), despite similar baseline ambulatory BP (132/81 mm Hg) and BP reduction (6.5 and 4.6%: P=0.19). F-Rmin remained unchanged (6.5 vs -2.0%: P=0.30), while C-Rmin decreased by 22 and 24% (P=0.80) and CFR increased by 23 and 17% (P=0.16). Thus, intensified vasodilating therapy improved SVRI more in patients with high SVRI than in those with low SVRI. Regardless of SVRI status, the treatment improved cardiac but not forearm dilatation capacity. The substantial improvement of the hypertensive cardiac microvascular dysfunction was not related to the reduction in SVRI.

Reducing pulse pressure in hypertension may normalize small artery structure.

To investigate the relation between the small artery structure and different blood pressure parameters, spontaneously hypertensive rats were treated from 4 to 24 weeks of age (20 weeks in total) with five different antihypertensive therapies: two angiotensin converting enzyme inhibitors (perindopril and captopril), a calcium antagonist (isradipine), a beta-blocker (metoprolol), and a vasodilator (hydralazine). At 24 weeks of age, 24-hour blood pressure was measured, and two mesenteric resistance vessels were taken from each animal. Blood pressure was 227/135 mm Hg (systolic/diastolic) and 161/106 mm Hg in untreated hypertensive and normotensive control rats, respectively. Heart rates were 376 min-1 and 295 min-1 for the two strains. All treatments reduced all blood pressure parameters except for metoprolol, which did not reduce pulse pressure. In the small arteries, the media cross-sectional area was unaffected by the treatments. When a simple correlation analysis was made, pulse pressure was found to correlate more closely (r = 0.64, p less than 0.001) to the resistance vessel media/lumen ratio than any of the other pressure parameters studied: systolic (r = 0.51, p = 0.011), mean (r = 0.41, p = 0.05), or diastolic (r = 0.28, p = 0.19). When an analysis of covariance was performed that included pulse pressure, mean blood pressure, and heart rate, which also correlated significantly to the media/lumen ratio, 81% of the variation in the media/lumen ratio could be accounted for by the variation in the three covariates (p less than 10(-5)), pulse pressure being the major factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Perindopril changes the mesenteric pressure profile of conscious hypertensive and normotensive rats.

Information about how antihypertensive therapy affects the arterial blood pressure profile in conscious animals is at present not available. Here we report measurements of part of the pressure profile in conscious spontaneously hypertensive rats (SHR, n = 7) and Wistar-Kyoto (WKY, n = 7) rats before and after treatment with the angiotensin-converting enzyme inhibitor perindopril. The previously developed technique that we used, provided simultaneous measurements of the undisturbed arterial blood pressure at the base of mesenteric arcades (P(arc); diameter, approximately 100 microns) and systemic mean blood pressure (MBP). The ratio P(arc)/MBP was 63 +/- 2% (mean +/- SEM) in SHR and 64 +/- 3% in WKY rats. When a bolus of perindopril (0.8 mg/kg) was injected into the aorta, P(arc)/MBP fell within 2 minutes to 51 +/- 2% (P < .05) for SHR and 56 +/- 2% (P < .05) for WKY rats, and these levels were maintained for the next hour. In contrast, MBP did not change for approximately 5 minutes in either strain, whereas after 1 hour MBP still had not changed significantly in WKY rats, but MBP had fallen by 16 +/- 2% (P < .05) in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent effects of perindopril on blood pressure and small-artery structure.

Long-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors has a persistent effect on blood pressure when treatment is withdrawn. The aim of the present study was to determine whether this effect could be mediated by the effect of treatment on resistance-artery structure. We determined the dose dependence of ACE-inhibitor therapy on blood pressure and small-artery structure during treatment and on the recovery of blood pressure when treatment was withdrawn. SHR (40 per group) were treated from age 4 to 24 weeks with one of three doses of perindopril (0.4, 0.8, or 1.5 mg/kg per day). Control groups were untreated SHR and Wistar-Kyoto rats. At 24 weeks, treatment was stopped and small arteries were taken from half of the rats from the mesenteric, femoral, cerebral, and coronary vascular beds for morphological and functional measurements. The blood pressure of the other half of the rats was followed until 36 weeks of age. During treatment, perindopril caused a dose-dependent reduction in blood pressure and in the media-lumen ratio and media area of the small arteries, whereas there was a dose-dependent increase in lumen diameter. The effect of treatment on the structure of arteries from the different vascular beds was homogeneous. Compared with values from Wistar-Kyoto rats, blood pressure normalization in SHR was not associated with full normalization of structure. After withdrawal of treatment, there was an inverse relation between perindopril dose and the persistent effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Early narrowed afferent arteriole is a contributor to the development of hypertension.

The kidney is probably critically involved in the development of essential hypertension, as in many genetic models of hypertension. We have investigated whether a narrowed renal afferent arteriole is involved in the pathogenesis of hypertension in spontaneously hypertensive rats. Systolic blood pressure of 37 F2 generation spontaneously hypertensive rats/Wistar-Kyoto rats was measured at age 7 weeks. The right kidney was removed, and lumen diameter and media cross-sectional area of the afferent arterioles were measured after having been fixed while relaxed and under a transmural pressure of 100 mm Hg. The uninephrectomized rats continued until age 23 weeks, when mean blood pressure was measured. Mean blood pressure at 23 weeks was negatively correlated with lumen diameter at 7 weeks. Quartile analysis based on lumen diameter at 7 weeks showed that compared with rats in the top lumen diameter quartile, rats in the bottom lumen diameter quartile had a reduced media cross-sectional area at 7 weeks (17%), the same systolic blood pressure at 7 weeks, and an increased (16%) mean blood pressure at 23 weeks. We conclude that in spontaneously hypertensive rats a narrowed lumen of distal afferent arterioles at 7 weeks contributes to later development of increased blood pressure. This reduced lumen could be caused by inhibited renal afferent arteriole growth.

Antitrophic properties of antihypertensive drugs may depend solely on their blood pressure-lowering capability. A comparative study of isradipine, hydralazine, and metoprolol.

The objective of this study was to examine the effect of antihypertensive treatment on the structure of intramyocardial resistance vessels in spontaneously hypertensive rats. The rats were divided into four groups: one was used as control and the other three were treated from the age of four to 24 weeks with isradipine, hydralazine, and metoprolol, respectively. Half of the animals in each group were examined at the end of active treatment and the rest were examined three weeks later. The rats were anesthetized and killed during constant flow perfusion with 1 percent glutaraldehyde. The media index was determined by point counting. The media indices of rats treated with isradipine and hydralazine were significantly smaller than those of age-matched spontaneously hypertensive rat controls, whereas the media indices of rats in the metoprolol group did not differ significantly. Three weeks after treatment withdrawal, the media index tended to increase in all three groups, but the values for the isradipine and hydralazine groups were still significantly reduced. Non-invasive blood pressure measurements taken at the same time demonstrated a significant blood pressure reduction in all groups, although differences within each treatment group were evident. All pressures had stabilized on the level of spontaneously hypertensive rats three weeks after withdrawal. Thus, it is evident that both isradipine and hydralazine were able to prevent hypertrophy of intramyocardial vascular structure and continue to do so even after treatment withdrawal. This finding is consistent with previous findings, suggesting a close relationship between the extent of blood pressure reduction and the degree of prevention of vascular hypertrophy.

Importance of nicotinamide dose on blood pressure changes in mice and humans.

PURPOSE: The importance of nicotinamide dose on inducing blood pressure changes in mice and humans was investigated. METHODS AND MATERIALS: Blood pressure measurements in human volunteers were made using an inflated cuff procedure after oral ingestion of 3 or 6 g nicotinamide. Animal blood pressure measurements were performed in fully awake nonanesthetized female CDF1 mice, 24 h after cannulation of the carotid artery. RESULTS: In humans, the average (+/- 1 SE) resting systolic and diastolic pressures were 122.8 mmHg (+/- 2.5) and 80.6 mmHg (+/- 2.1), respectively. They were unchanged during the first 3 h after ingestion of either 3 g or 6 g nicotinamide. The resting value (+/- 1 SE) in mice was 115.1 mmHg (+/- 4.0) and this was significantly reduced following intraperitoneal injection of 400-1000 mg/kg nicotinamide. This decrease was maximal within 15-30 min after injection and was linearly dependent on drug dose. At doses of 200 mg/kg or less, no significant effect on blood pressure was observed. CONCLUSION: Doses between 100-200 mg/kg in mice are known to be equivalent to 6 g in man and can also produce maximal radiosensitization in murine tumors. Our results, therefore, not only show that the mouse and human data are entirely consistent, but also suggest that nicotinamide-induced decreases in blood pressure are not necessary for radiosensitization.

Relationship between the hydralazine-induced changes in murine tumor blood supply and mouse blood pressure.

The relationship between hydralazine-induced changes in blood pressure and tumor blood flow was investigated in restrained but non-anesthetized CDF1 mice bearing C3H/Tif foot tumors. Mean arterial blood pressure measurements were made using the procedure of carotid cannulation, and tumor blood flow was estimated using laser Doppler flowmetry. Hydralazine doses from 0.1 to 5.0 mg/kg were tested. Following hydralazine administration the maximum changes in blood pressure and blood flow were apparent within 10-15 min and were maintained for at least 30 min after injection. Blood pressure decreased with increasing hydralazine dose, achieving a maximum reduction of 50% at 2.5 mg/kg. Tumor blood flow was found to be increased by 30% at the lowest hydralazine dose (0.1 mg/kg), even though blood pressure was decreased by 10% at this dose. At hydralazine doses producing a 15% or greater blood pressure drop, blood flow decreased, reaching an 80-90% reduction between 2.5 and 5.0 mg/kg.

Biochemical and physiological changes induced by nicotinamide in a C3H mouse mammary carcinoma and CDF1 mice.

We have continued our investigation into the mechanism by which nicotinamide can enhance radiation damage in tumors, using a C3H mouse mammary carcinoma grown in CDF1 mice. Biochemical analysis of tumor extracts showed that nicotinamide (1000 mg/kg; i.p.) increased the ATP/Pi and ATP/ADP + AMP ratios. This change in metabolic activity was consistent with nicotinamide increasing tumor oxygenation. Moreover, the greatest effect occurred 0.5-2.5 hr after drug injection, a time at which radiosensitization by nicotinamide in this tumor had previously been shown to be maximal. These changes were observed without any apparent modification in tumor blood perfusion, measured using the 86-RbCl uptake procedure, and occurred despite nicotinamide producing a 50% decrease in mean arterial blood pressure, estimated directly by a carotid cannulation technique.

Vasodilatation, not hypotension, improves resistance vessel design during treatment of essential hypertension: a literature survey.

Correction of structural abnormalities in resistance arteries of patients with essential hypertension is a potential treatment goal, in addition to blood pressure reduction. However, available evidence from human as well as from animal studies indicates that antihypertensive therapy is not always accompanied by normalization of resistance vessel structure, despite normalization of blood pressure. Thus, blood pressure is not the only factor determining resistance vessel structure, and experimental studies show that several factors could play a role, including shear stress and hormonal stimulation. To date, there has been no systematic review of the many published papers which have studied the structural effects of antihypertensive therapy, and it is not known which conditions are best able to normalize resistance vessel structure. We have therefore made a survey of the available literature. The survey shows that change in blood pressure in indeed a poor indicator of change in resistance vessel structure. However, it is a remarkably consistent finding that normalization of resistance vessel structure is obtained with therapeutic regimens which reduce blood pressure by vasodilation rather than by lowering cardiac output Thus, to the extent that normalization of resistance vessel structure is deemed a goal of antihypertensive treatment, the survey points towards the importance of considering not only the treatment effect on blood pressure, but also the haemodynamic effects within patients with essential hypertension.

Can mean arterial pressure be estimated from measurements of systolic and diastolic blood pressure, and vice versa?

We investigated the reliability of calculating the mean blood pressure (MBP) in spontaneously hypertensive rats (SHR) from the systolic and diastolic blood pressures (SBP; DBP), using a form factor, calculated as: (MBP - DBP)/(SBP - DBP). The mean values of this form factor, as determined by blood pressure curve integration, were 0.459 and 0.450 in awake and anaesthetized SHR, respectively. There was no change in the form factor with pulse frequency. When direct femoral artery MBP measurements (x) were compared with MBP values (y) calculated from tail-cuff measurements of SBP and DBP using the form factor, the linear relationship between the two parameters was: y = 0.91x + 1.5 mmHg (r = 0.98). Actually, direct measurements confirmed that the tail artery MBP was 6-7% lower than the femoral artery MBP. In awake Wistar-Kyoto (WKY) rats, the form factor was 0.468. We therefore concluded that an approximate form factor value of 0.46 could be used in rats to estimate the MBP from known values of SBP and DBP. We further suggest that, because pulse pressure in any given rat remains relatively constant with time, SBP and DBP can be estimated in experiments by initially measuring the pulse pressure; thus, only the MBP need be recorded thereafter.

Development of blood pressure in spontaneously hypertensive rats after withdrawal of long-term treatment related to vascular structure.

We have studied the effects of long-term treatment with different antihypertensive drugs on blood pressure and mesenteric resistance vessel structure of spontaneously hypertensive rats (SHR), both during treatment and after withdrawal of treatment. Young SHR were treated from 4 to 24 weeks with five different drugs: perindopril (1.5 mg/kg per day), captopril (60 mg/kg per day), hydralazine (25 mg/kg per day), isradipine (42 mg/kg per day) and metoprolol (130 mg/kg per day). At 24 weeks, 24-h mean blood pressures (MBP), measured invasively, were 121 mmHg (perindopril), 137 mmHg (captopril), 140 mmHg (hydralazine), 149 mmHg (isradipine) and 146 mmHg (metoprolol), compared to control values of 177 mmHg (SHR) and 132 mmHg (Wistar-Kyoto rats, WKY). Mesenteric resistance vessel structure, measured as media:lumen ratio (m:l), was also reduced to different extents: to WKY-level by perindopril (m:l = 4.4%), to midway between SHR- and WKY-levels by captopril, hydralazine and isradipine (m:l = 5.9%), and not at all by metoprolol (m:l = 6.8%). When treatment was discontinued, low MBP (ca 151 mmHg) persisted for 12 weeks in rats treated with the angiotensin converting enzyme inhibitors (perindopril and captopril), but rose rapidly in rats which had received the other treatments. At 3-12 weeks after withdrawal of treatment vascular structure was closely correlated with the blood pressure expected from the SHR- and WKY-control values, as were the left ventricle: body weight ratios. The results suggest that the ability of a drug to control vascular structure during treatment is not in itself a predictor of a persistent effect on blood pressure after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Physical stability of redispersible dry emulsions containing amorphous sucrose.

The objective of the present study was to estimate the stability of redispersible dry emulsions containing amorphous sucrose. Dry emulsions were prepared by spray drying liquid o/w-emulsions in a laboratory spray dryer. The effect of hydroxypropyl methylcellulose (HPMC) on the glass transition temperature T(g) of spray dried sucrose-HPMC mixtures, relative to the T(g) of amorphous sucrose, was investigated. For the sucrose-HPMC mixtures the values of T(g) followed the ideal Gordon-Taylor equation up to 30% HPMC. For dry emulsions containing 40% HPMC, 30% lipid and 30% sucrose, the T(g) was increased by 12 degrees C relative to the T(g) of amorphous sucrose. The stability of the dry emulsions was investigated by a conventional stability study and by an enthalpy relaxation study. The measured enthalpy recovery of amorphous sucrose below T(g) was used to calculate molecular relaxation time parameters based on the Williams-Watts equation. The molecular mobility of amorphous sucrose at temperatures 50 degrees C below T(g) was low and negligible with respect to the shelf life stability. It was concluded that the dry emulsions are physically stable with respect to the lifetime of a pharmaceutical product when stored in dry condition and at temperatures up to 28 degrees C.

Use of medical chemoprophylaxis and antimosquito precautions in Danish malaria patients and their traveling companions.

BACKGROUND: The number of malaria cases imported to Denmark has been increasing for some years. To analyze the background for this we assessed the use of protective measures in Danish travelers visiting malarious areas. METHOD: Post-travel questionnaires were given during hospitalization to malaria patients, and sent by mail to their traveling companions. RESULTS: In total, 142 persons participated. Only 32% of the travelers used chemoprophylaxis correctly, according to Danish recommendations. Twelve percent of the travelers did not use chemoprophylaxis. Average compliance was 52%. Insufficient drug dosage was reported by 13%, and use of nonrecommended drugs by 7% of the travelers. Thirty-seven percent used insufficient antimosquito precautions, a problem which often coincided with irregular use of chemoprophylaxis. Malaria patients, sole travelers, and travelers with other ethnical background than Danish, were subgroups using insufficient malaria prophylaxis more frequently than healthy traveling companions. CONCLUSION: Insufficient use of the available antimalaria precautions by Danish travelers contributes greatly to maintaining a high incidence of imported malaria. Increased attention from physicians in educating travelers is important for optimizing malaria prophylaxis.

Influence of temperature and storage time after light exposure on the quinine monohydrochloride chemical actinometric system.

The ICH guideline on photostability has proposed quinine monohydrochloride chemical actinometric system as a standard method for measuring light exposure during photostability testing. A change in the absorption at 400 nm of quinine monohydrochloride after light exposure corresponds to a defined dose of light. The present work investigated the effect of temperature, light exposure level and the dark reactions following light exposure on the change of absorbance obtained. The change in the absorbance was linear with respect to time, the rate increased threefold in the temperature range of 25-52 degrees C, and the calculated activation energy was 30 kJ/mol as calculated by the Arrhenius equation. For the dark reactions the change in absorbance was non-linear with respect to time. The rate of the dark reactions was smaller than during light exposure and dependent on the light exposure level prior to the dark reactions. The calculated activation energy of the dark reactions was 18 kJ/mol when calculated by the Arrhenius equation on the initial reaction rates. The different activation energy of the light reaction and the dark reactions indicated different degradation patterns of the two reactions. The present study shows that the absorbance change of quinine monohydrochloride chemical actinometric system is dependent on temperature during light exposure and on storage time and storage temperature after light exposure. The method proposed in the ICH guideline should therefore be optimized in terms of definition of temperature and limitations in storage time after light exposure.

Preparation of redispersible dry emulsions by spray drying.

Development of stable dry emulsions being able to reform the original o/w-emulsion by reconstitution in water is presented. Dry emulsions were prepared by spray drying liquid o/w-emulsions in a laboratory spray dryer. Three hydroxypropylmethylcellulose (HPMC) types were applied as solid carrier and emulsifier. The lipid phase was fractionated coconut oil. The ratio of solid carrier to lipid phase influenced the reconstitution properties. It was possible to prepare redispersible dry emulsions of a lipid content up to 40% dry powder mass. The different HPMC types had no noticeable effect on the reconstitution properties, but too viscous liquid o/w-emulsions were difficult to atomise. The type of rotary atomizer, or the rate of rotation did not affect the technical properties of the dry emulsions containing 40% lipid. It was concluded that low viscosity HPMC was a useful solid carrier. The dry emulsions remained physically stable for at least 6 months.