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.

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.

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.

The contribution of diet to total bisphenol A body burden in humans: results of a 48 hour fasting study.

Human biomonitoring studies measuring bisphenol A (BPA) in urine have shown widespread exposure in the general population. Diet is thought to be a major route of exposure. We studied urinary BPA patterns in five individuals over a 48-h period of fasting (bottled water only). Personal activity patterns were recorded with a diary to investigate non-dietary routes of exposure. All urine void events during the fast were collected, as well as events before and after the fast. The pattern of BPA concentrations was similar for all participants: they rose near the beginning of the fast (after the pre-fast meal), declined over the next 24h, fluctuated at lower levels during the second day, and then rose after the post-fast meal. Concentrations (~2 µg/g creatine) and calculated BPA intakes (~0.03 µg/kg-day) in these individuals during the first 24h were consistent with general population exposures. For the second 24h, concentrations and intakes declined by about two-thirds. One of the individuals had an extraordinary pre-fast exposure event with concentrations rising as high as 98 µg/g creatine but declining to <5 µg/g creatine by day 2. Given patterns found in day 1 and the subsequent decline to lower levels in day 2, we hypothesize that BPA exposures in these individuals were diet-driven. No events in the diary (use of personal care products, e.g.) appear associated with exposures. On day 2, non-dietary sources may still be present, such as from dust. Another hypothesis is that small reservoirs of BPA from past exposures are released from storage (lipid reservoirs, e.g.) and excreted.

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.

Forearm plethysmography in the assessment of vascular tone and resistance vasculature design: new methodological insights.

AIM: High peripheral resistance and structural alteration in resistance arteries are central phenomena in essential hypertension and have been widely examined by forearm venous occlusion plethysmography; at rest for studying vascular tone, and during reactive hyperaemia for studying vascular structure. This work concerns the influence of venous pressure on hyperaemic vascular resistance (Rmin), the reproducibility of hyperaemic and resting vascular resistances (Rrest) and the relation between forearm and total peripheral vascular resistance (TPR). METHODS: In four healthy subjects, intravenous and intra-arterial blood pressures were measured simultaneously with plethysmographic recordings of hyperaemic and resting forearm blood flows. Reproducibility was examined in 15 young and 14 middle-aged healthy subjects and in 21 untreated hypertensive patients. RESULTS: Rmin remained low in the first recorded cardiac cycle, but rose in the second, even though corrected for the venous pressure rise, suggesting vascular tone recovery along with venous congestion. Between-day reproducibility of Rmin was high in middle-aged normotensive (8.7%) and hypertensive subjects (10.6%), but Rmin fell significantly between successive days in the young subjects. Rrest correlated with TPR, but required up to 40 min to reach steady state and showed high day-to-day variation in young (21.8%) and hypertensive subjects (16.2%). CONCLUSIONS: During hyperaemia, vascular resistance should be measured in the first cardiac cycle following venous occlusion to minimize influences of venous pressure rise and possible tone recovery. Rrest seems to reflect TPR. About 20 subjects may be needed to detect 15% changes between days in Rrest, fewer when concerning Rmin and TPR.

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.

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.

Location of resistance arteries.

Thickening and narrowing of resistance arteries must, by definition, be key elements in the control of the cardiovascular system. However, the precise location of resistance arteries is difficult to establish. This is due to technical problems related to the small size of the vessels, to the measurement conditions disturbing the hemodynamics, and to the status of the animals while the measurements are being made. Furthermore, due to large data heterogeneity, previous studies do not give unequivocal information concerning the pressure profile in the vascular system, or the level of arterial diameter responsible for blood flow. Finally, and importantly, there is little evidence regarding the conscious state, which is thus a major limitation to understanding the mechanisms of blood distribution and the pathogenesis for disease processes such as genetic hypertension. This review first summarizes briefly the techniques which are available for identifying resistance arteries and the inherent technical limitations which are involved. The review then provides a critical assessment of the available data, both as regards measurement of local blood pressures and as regards control of peripheral resistance. The evidence suggests that, at least as regards rats and other small animals, feed arteries as well as more distal microvessels contribute to the maintenance and regulation of blood flow and resistance. Evidence from larger animals is however lacking, and it is thus unclear if resistance function should be based on arterial diameter or anatomic location. Furthermore, evidence concerning man is not available. We therefore conclude the review with suggestions for future research in this area.

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.

Technical optimisation of redispersible dry emulsions.

Preparation of dry emulsions suitable for tablet processing was examined in this study. Liquid o/w-emulsions were spray dried in a laboratory spray dryer applying hydroxypropylmethylcellulose (HPMC) as a solid carrier and emulsifier. As the lipid phase, fractionated coconut oil was used. The ability of various excipients to increase the density of dry emulsions was investigated. Adding sucrose to the formulation, redispersible dry emulsions with higher density were obtained. The type of rotary atomizer did not affect the dry emulsions containing sucrose nor the rate of rotation of the atomizer applied in the spray drying process. By wet granulation, using ethanol as a binder, free-flowing and compactable dry emulsions were obtained and simultaneously the reconstitution properties were preserved. It was concluded that dry emulsions could be optimised for tablet processing by wet granulation. Tablets having a lipid content up to 20% had proper tablet properties.

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.

Intestinal blood flow is controlled by both feed arteries and microcirculatory resistance vessels in freely moving rats.

1. In freely moving rats, intestinal blood flow, aortic blood pressure and blood pressure at the base of mesenteric arcades were measured simultaneously so as to determine the role of feed arteries and of the microcirculation in the control of intestinal vascular resistance. Segmental resistances of feed arteries (Rfeed) and of microcirculatory vessels (Rmicro) were calculated. 2. At rest, Rfeed and Rmicro were 32 and 68%, respectively, of the total intestinal vascular resistance. 3. Injection of noradrenaline (2 micrograms i.v,) increased Rfeed by 151% and Rmicro by 243%. Angiotensin II (400 ng i.v.) did not increase Rfeed significantly, but increased Rmicro by 239%. Conversely, serotonin (15 micrograms i.v.) increased Rfeed by 414% but did not affect Rmicro significantly. 4. Spontaneous physical activity increased Rfeed by 29% and Rmicro by 39%, while sudden environmental stress increased Rfeed by 116% and Rmicro by 129%. Infused noradrenaline (1 microgram min-1 i.v.) or adrenaline (0.8 microgram min-1 i.v.) reduced intestinal flow by 21 and 16% respectively, while noradrenaline, but not adrenaline, increased intestinal resistances. 5. alpha 1-Blockade with prazosin (0.1 mg i.v.) reduced Rfeed and Rmicro by 43 and 16%, respectively. Thereafter, environmental stress decreased Rfeed by 24% while Rmicro was unaffected. Intravenous noradrenaline and adrenaline responses were attenuated. 6. We conclude that in freely moving rats, mesenteric feed arteries, as well as microcirculatory vessels, are true resistance vessels, and that both participate in the control of intestinal blood flow.

[Primary sclerosing cholangitis with itching treated during pregnancy with ursodeoxycholic acid]. / Primaer skleroserende cholangitis med kløe behandlet under graviditet med ursodeoxykolsyre.

A 23-year old woman with primary sclerosing cholangitis was being treated with ursodeoxycholic acid (URSO). When pregnancy was diagnosed, she was already through the first trimester. The treatment was discontinued, but her symptoms including severe pruritus recurred immediately, and the biochemical markers of bile duct obstruction worsened. It was necessary to start URSO-treatment again, which relieved her symptoms and improved the biochemistry. The remaining part of the pregnancy was uncomplicated, there were no malformations and so far, the baby is doing fine. URSO may be a possible treatment for severe intrahepatic cholestasis and pruritus during pregnancy.

[Contributing causes of malaria among Danish travellers]. / Medvirkende årsager til malaria blandt danske rejsende.

A retrospective evaluation of contributing causes of malaria among Danish travellers, based on patient files and telephone interviews, is presented. Four centres participated, and 33% of all malaria cases reported to the Danish authorities in 1993 and 1994 were included (in total 82 patients). Ten out of 52 patients with falciparum malaria had not taken any chemoprophylaxis at all. Among the 42 patients who had, only 14 were both correctly advised and fully compliant. Within the remaining 28 patients, lack of compliance concerning the chemoprophylaxis was reported in 16, inadequate chemoprophylaxis was prescribed to 12 patients, and a further eight (19%) were underdosed. Only four out of 30 patients with vivax, ovale or malariae malaria had not used chemoprophylaxis. The distribution of contributing causes of chemoprophylaxis failure was similar to that of falciparum malaria, although noncompliance was more predominant in patients developing vivax, ovale or malariae malaria (58% compared to 38% in falciparum malaria).

Mesenteric blood pressure profile of conscious, freely moving rats.

1. Blood pressure has been measured in the aorta and at four points in the mesenteric circulation of conscious, freely moving rats under physiological, resting conditions. 2. Using small polythene catheters, blood pressure was measured simultaneously in the aorta and either distally in the superior mesenteric artery (group A), at the base of a mesenteric arterial arcade (vessel diameter ca 100 microns) (group B), at the base of a mesenteric venous arcade (group C) or distally in the superior mesenteric vein (group D). Local blood flow distribution proximal and distal to the measurement point was restored after the cannulations through appropriate ligations. 3. In conscious animals 5-17 h after surgery, systemic mean blood pressure was 121 +/- 2 mmHg. Local pressures at the four locations (as a percentage of systemic pressure) were: 95 +/- 1% in group A, 64 +/- 2% in group B, 13 +/- 1% in group C and 7 +/- 1% in group D. Thus, large arteries dissipated 5% of the total pressure drop, arcade small arteries 31%, the intramural circulation 51%, arcade veins 6% and the remaining veins plus the hepatic circulation 7%. 4. Immediately after surgery, the corresponding pressure drops were 4, 16, 66, 5 and 9%, respectively, thus emphasizing that the pressure profile can be profoundly affected by surgery and anaesthesia. 5. The data indicate that under resting conditions in conscious, freely moving rats, half the mesenteric vascular resistance resides outside the intramural circulation, primarily in the arcade small arteries.

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.

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.