Appetite stimulation with cannabis-based medicine and methods for assessment of glomerular filtration in older patients with medical illness: A study protocol.

BACKGROUND AND AIM: Malnutrition in older patients is linked to poor appetite. Cannabis-based medicine may have orexigenic properties in older patients, but this has to our knowledge never been investigated. In older patients, uncertainty applies to the accuracy of estimated glomerular filtration rate (eGFR) based on creatinine, which is crucial for medication prescribing. In older patients with poor appetite, the study aims (1) to assess the efficacy of Sativex® (8.1-mg delta-9-tetrahydrocannabinol [THC] and 7.5-mg cannabidiol [CBD]) to stimulate appetite and (2) to compare the performance of various GFR-estimates and measured-GFR (mGFR) for determining gentamicin clearance utilizing population pharmacokinetic (popPK) modelling methods. METHODS AND OBJECTIVES: This study is composed of two substudies. Substudy 1 is an investigator-initiated single-center, double-blinded, randomized, placebo-controlled, superiority, cross-over study. Substudy 1 will recruit 17 older patients with poor appetite, who will also be invited to substudy 2. Substudy 2 is a single-dose pharmacokinetics study and will recruit 55 patients. Participants will receive Sativex® and placebo in substudy 1 and gentamicin with simultaneous measurements of GFR in substudy 2. The primary endpoints are as follows: Substudy 1-the difference in energy intake between Sativex® and placebo conditions; substudy 2- the accuracy of different eGFR equations compared to mGFR. The secondary endpoints include safety parameters, changes in the appetite hormones, total ghrelin and GLP-1 and subjective appetite sensations, and the creation of popPK models of THC, CBD, and gentamicin.

Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition.

Hyperglycemia causes enhanced glucose metabolism by the polyol pathway in tissues not requiring insulin for glucose uptake. It has been suggested that the high level of aldose reductase activity may cause functional and structural abnormalities in diabetes and may be involved in the development of late complications. To elucidate the effect of an aldose reductase inhibitor (ponalrestat) on kidney function in uncomplicated insulin-dependent diabetes mellitus (IDDM), 20 normoalbuminuric IDDM patients were randomized to follow either 6 mo of treatment with ponalrestat (n = 11, mean +/- SD age 30 +/- 8 yr, diabetes duration 10 +/- 6 yr) or 6 mo of placebo (age 33 +/- 7 yr, diabetes duration 12 +/- 6 yr). The glomerular filtration rate (clearance of [125I]iothalamate) was significantly reduced from 140 +/- 18 to 129 +/- 10 ml.min-1.1.73 m-2, 2P = 0.02) in the ponalrestat-treated patients, whereas no change was seen after placebo (142 +/- 12 vs. 141 +/- 12 ml.min-1.1.73 m-2). The renal plasma flow (clearance of 131I-labeled hippuran), urinary albumin excretion rate (radioimmunoassay), fractional albumin clearance, and renal vascular resistance were unchanged in both groups. HbA1c showed a modest increase during ponalrestat (7.9 +/- 1.8 vs. 8.7 +/- 1.5%, 2P = 0.01) but was unchanged during placebo. No side effects of ponalrestat were observed. Thus, inhibition of aldose reductase may reduce the characteristic hyperfiltration in uncomplicated IDDM.

Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM.

In this article, we analyze the blood pressure (BP) threshold for the start of antihypertensive treatment in insulin-dependent diabetes mellitus (IDDM) patients, with particular emphasis on those with persistent microalbuminuria or proteinuria (incipient and overt nephropathy, respectively). In such individuals, there is a clear increase in the prevalence of hypertension and in actual measured BP values that is not observed in normoalbuminuric patients. In 94 young healthy adults (less than 45 yr of age), average mean +/- SD arterial pressure (MAP; diastolic + 1/3 pulse pressure) was approximately 90.0 +/- 8.1 mmHg, closely corresponding to large population studies. In microalbuminuric IDDM patients, MAP values between approximately 105 and approximately 95 mmHg have been found in different studies, and the level has progressively decreased in various studies between 1984 and 1990 with similar BP-measuring techniques. Somewhat higher values are seen in patients with proteinuria, who are also consistently characterized by reduced glomerular filtration rate (GFR). A clear correlation is found between MAP plotted against the increased rate of microalbuminuria (%/yr) in incipient nephropathy and against fall rate of GFR (ml.min-1.mo-1) in proteinuric patients. In the natural history of renal disease, different cutoff points in MAP for start of progression are observed: greater than 95 mmHg for the start of progression of microalbuminuria and greater than 105 mmHg for the decrease in GFR. During antihypertensive treatment, there is reduction or no progression in microalbuminuria with MAP of approximately 90-95 mmHg and only a limited fall in GFR with MAP of approximately 100 mmHg. However, certain antihypertensive drugs (angiotensin-converting enzyme inhibitors) may have specific renoprotective actions, reducing microalbuminuria at rather low BP levels or even independent of BP reduction. The optimal way of monitoring BP may be by 24-h ambulatory recording.

A randomized comparison of intranasal and injectable octreotide administration in patients with acromegaly.

Fifteen acromegalic patients received four single doses of octreotide in random order (500 micrograms, 1000 micrograms, and 2000 micrograms applied intranasally and 100 micrograms given sc). Serum octreotide and GH data were subjected to pharmacokinetic analyses, and local nasal effects were evaluated by acoustic rhinometry. Average areas (+/- SEM) under the serum octreotide curves were: 2000 micrograms: 4597 +/- 536; 1000 micrograms: 1923 +/- 439; 500 micrograms: 957 +/- 168; and 100 micrograms sc: 896 +/- 81 micrograms.L-1.min (n = 13). The calculated relative availability was 27% +/- 0.03; 22% +/- 0.05; 22% +/- 0.03, respectively, for the three nasal doses. The rate of absorption after intranasally administered octreotide was greater than after sc application: t1/2 ka: 7.1 +/- 1.6; 7.9 +/- 1.6; 11.3 +/- 1.9, respectively, vs. 24.1 +/- 2.5 min, whereas the rates of disappearance were similar. GH suppression started immediately after application and reached minimum levels 1-2 h later. The average intervals during which serum GH was below 50% of preadministration values were: 2000 micrograms: 544 +/- 47; 1000 micrograms: 423 +/- 56; 500 micrograms: 289 +/- 52 vs. 351 +/- 34 min after sc injection of 100 micrograms. With 2000 micrograms intranasally all but one of the 15 patients attained constant suppression of serum GH below 5 micrograms/L for 273 to 680 min. Pharmacokinetic analysis demonstrated that 100 micrograms sc and 1000 micrograms intranasally induced the same GH suppressive effect and that 2000 micrograms intranasally approximately doubled the duration of action. Acoustic rhinometry was performed after nasal application of the largest dose of 2000 micrograms and after carrier (n = 9). A highly significant tumescence of the nasal mucosa was maximal after 10 min and gradually receded over the next 2 h. However, this was felt by the patients to be acceptable. The effect was caused by octreotide per se and was probably due to vasodilation.

Effects of felodipine on urinary albumin excretion and metabolic control in hypertensive non-insulin-dependent diabetics.

The effect of a blood pressure reduction by 10 mg extended release felodipine once daily on urinary albumin excretion (UAE) as well as the possible diabetogenic effect of felodipine was studied. A 2 X 12 week placebo-controlled double-blind crossover study was performed in 12 hypertensive non-insulin-dependent diabetic (NIDDM) patients without nephropathy on concomitant treatment with beta-blocker and/or a diuretic agent. Metabolic control as estimated by fasting plasma glucose, hemoglobin A1c and fasting plasma C-peptide was unaltered after felodipine. Blood pressure was significantly reduced by felodipine: systolic 166 +/- 26 mm Hg (placebo) v 153 +/- 26 mm Hg (felodipine) (P less than .05) and diastolic 95 +/- 7 mm Hg v 90 +/- 8 mm Hg (P less than .05). Heart rate was unchanged. There was no correlation between blood pressure and UAE, but the relative change in UAE expressed as UAE placebo/UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, P = .03) and mean blood pressure (r = 0.66, P = .02). Since microalbuminuria predicts proteinuria and reduced survival, early antihypertensive treatment may be beneficial in NIDDM as it is in IDDM. Long-term consequences on kidney function and mortality remains, however, to be elucidated.

Renal effects from limitation of high dietary protein in normoalbuminuric diabetic patients.

Glomerular hyperfiltration may be a risk factor for late nephropathy. It has been shown that considerable protein restriction can lower glomerular filtration rate (GFR). To elucidate the effect of moderate protein limitation in type 1 (insulin-dependent) diabetics with normoalbuminuria, eight such patients were selected for the study (age 38 +/- 7 years SD, diabetes duration 21 +/- 9 years). The patients were randomized to follow, alternately, four weeks of their usual protein intake (19% of energy) and four weeks of a limited protein intake (12% of energy). Kidney function was investigated after the two dietary periods. GFR and renal plasma flow (RPF) were measured using a constant infusion technique (125I-iothalamate/131I-hippuran), and urinary albumin excretion (UAE) by radioimmunoassay. It was found that the limited protein diet reduced GFR from 146 +/- 23 to 132 +/- 24 ml/min/1.73 m2 (2P less than 0.005). A tendency towards a fall in RPF was seen (549 +/- 128 vs. 503 +/- 125 ml/min; 2P = 0.06), while total renal resistance rose from 0.17 +/- 0.03 to 0.20 +/- 0.05 mm Hg/ml/min (2P = 0.05). No significant changes in filtration fraction, UAE and blood pressure were seen. HbA1c, fructosamine, insulin dose and body weight were unchanged during the two diets; also serum protein, albumin, phosphate and calcium remained unaltered. Serum urea was significantly reduced on the limited protein intake. Patients were generally pleased with the limited protein diet. Thus, limitation of the often high protein intake in diabetics might be valuable and realistic. The long-term renal protective effect remains to be investigated.

Acute renal effects of angiotensin converting enzyme inhibition in microalbuminuric type 1 diabetic patients.

The renal effects of intravenous injection of 10 mg enalapril were investigated in 16 normotensive microalbuminuric type 1 (insulin-dependent) diabetic patients. After enalapril the following changes were observed: fractional albumin clearance (theta Alb) decreased from 9.9 (3.0-23.8) to 8.2 (2.0-18.3) x 10(-6) (2 P < 0.01); filtration fraction (FF) decreased from 0.260 (0.225-0.312) to 0.253 (0.190-0.297) (2 P < 0.01); renal plasma flow (RPF) increased from 565 (411-690) to 623 (449-785) (2 P < 0.01); and glomerular filtration rate (GFR) remained stable at 149 (128-181) versus 150 (124-185) ml.min-1 (NS). These values were unchanged after placebo (n = 8), except for RFP which decreased from 606 (401-701) to 559 (381-677) ml.min-1 (2 P < 0.05) and GFR which was reduced from 148 (111-173) to 138 (111-167) (2 P < 0.05). A reduction in mean blood pressure from 94 (87-103) to 89 (79-101) mmHg (2 P < 0.05) was found in the enalapril group and a minor reduction in the placebo group from 97 (83-106) to 96 (81-104) mmHg (2 P < 0.05) was also noted. The relative changes in systolic blood pressure in the enalapril group correlated with changes in theta Alb (Spearman's r = 0.66, 2 P < 0.02) and FF (r = 0.53, 2 P < 0.05). Acute inhibition of angiotensin converting enzyme does not reduce the pathological hyperfiltration in these patients and a reduction in theta Alb and FF can not be dissociated from the reduction in blood pressure.

In-vivo validation of fast spectral velocity estimation techniques.

Spectrograms in medical ultrasound are usually estimated with Welch's method (WM). WM is dependent on an observation window (OW) of up to 256 emissions per estimate to achieve sufficient spectral resolution and contrast. Two adaptive filterbank methods have been suggested to reduce the OW: Blood spectral Power Capon (BPC) and the Blood Amplitude and Phase EStimation method (BAPES). Ten volunteers were scanned over the carotid artery. From each data set, 28 spectrograms were produced by combining four approaches (WM with a Hanning window (W.HAN), WM with a boxcar window (W.BOX), BPC and BAPES) and seven OWs (128, 64, 32, 16, 8, 4, 2). The full-width-at-half-maximum (FWHM) and the ratio between main and side-lobe levels were calculated at end-diastole for each spectrogram. Furthermore, all 280 spectrograms were randomized and presented to nine radiologists for visual evaluation: useful/not useful. BAPES and BPC compared to WM had better resolution (lower FWHM) for all OW<128 while only BAPES compared to WM had improved contrast (higher ratio). According to the scores given by the radiologists, BAPES, BPC and W.HAN performed equally well (p>0.05) at OW 128 and 64, while W.BOX scored less (p<0.05). At OW 32, BAPES and BPC performed better than WM (p<0.0001) and BAPES was significantly superior to BPC at OW 16 (p=0.0002) and 8 (p<0.0001). BPC at OW 32 performed as well as BPC at OW 128 (p=0.29) and BAPES at OW 16 as BAPES at OW 128 (p=0.55). WM at OW 16 and 8 failed as all four methods at OW 4 and 2. The intra-observer variability tested for three radiologist showed on average good agreement (90%, kappa=0.79) and inter-observer variability showed moderate agreement (78%, kappa=0.56). The results indicated that BPC and BAPES had better resolution and BAPES better contrast than WM, and that OW can be reduced to 32 using BPC and 16 using BAPES without reducing the usefulness of the spectrogram. This could potentially increase the temporal resolution of the spectrogram or the frame-rate of the interleaved B-mode images.

Comparison of two methods for measurement of chemotaxis of neutrophil polymorphonuclear leukocytes in vitro.

Measurement of chemotaxis of neutrophil polymorphonuclear leukocytes (PMNs) is often performed by micropore-filter methods. However, most of these methods seem to involve considerable inter-individual, intra-individual, and day-to-day variations. The aim of this study was to compare two frequently used micropore-filter methods - the Lower Surface Count (LSC) and the Leading Front (LF) methods - in order to find the more reproducible one. Blood samples from the same individual were drawn on two different days. PMN chemotaxis and random migration was tested by a micropore-filter assay. The chemotaxis chambers were incubated for 60, 90, 120, and 150 minutes, respectively. In all, 144 filters were read by both methods. The LSC method showed large variations both among identically treated filters and among readings from the same filter. These variations were as much as 10 times higher than the variations shown by the LF method. Also, the day-to-day variation was higher with the LSC method than with the LF method. Furthermore, data from the LF method were normally distributed, in contrast to data from the LSC method. Thus, the present study suggests the LF method to be superior to the LSC method in terms of reproducibility.

Chemotactic response of neutrophil polymorphonuclear leukocytes in juvenile periodontitis measured by the Leading Front method.

Previous studies have implied that chemotaxis defects of neutrophil polymorphonuclear leukocytes (PMNs) can be found in approximately 75% of patients with juvenile periodontitis (JP). In the present study, the Leading Front (LF) method was used to study whether the chemotactic response of PMNs from JP-patients differed from that of adult periodontitis (AP) patients and periodontally healthy control individuals (C). Sixteen JP-patients, 21 AP-patients, and 13 C-individuals were studied. PMNs from each individual, and from a daily reference person were tested against three chemoattractants (N-f-Met-Leu-Phe (FMLP), casein (CA), bacterial chemotactic factor (BCF] and a neutral buffer (Gey's solution (GEY]. Regardless of the test solution a greater difference among individuals could be observed in the JP-group than in the other groups. Apart from this, there were no differences among the groups as regards CA, BCF, and GEY. However, with FMLP, the PMNs of the JP-group had a significantly greater migration distance as compared to the other groups. This finding can probably be ascribed to the fact that the LF method detects other aspects of the PMN response than do the methods used for earlier studies of JP. The finding, in this study, of an enhanced PMN response in JP as regards FMLP may be a reflection of the presence of a non-uniform PMN population whose composition in JP differs from that of the other groups.

Characterization of bacteria by their degradation of amino acids.

A procedure for detecting the degradation of amino acids by microorganisms is described, and examples of its use in the characterization of bacteria are presented. The procedure involves inoculating a buffered solution of amino acids with a suspension of bacteria, incubating, chromatographing a sample of the suspension, and detecting degradation in terms of absence of ninhydrin-positive spots.

Blood pressure by 24 h ambulatory recordings in type 2 (non-insulin dependent) diabetics. Relationship to urinary albumin excretion.

The relationship between blood pressure and microalbuminuria, both associated with cardiovascular disease and death, is sparsely studied in Type 2 (non-insulin-dependent) diabetes, and results may be interfered by the phenomenon of "white-coat-hypertension". We therefore investigated blood pressure by 24h ambulatory recordings (oscillometry) and examined whether blood pressure related to the level of urinary albumin excretion rate (UAER) by synchronous 24h collections. Seventeen diabetics (50-75 years of age) with microalbuminuria (15 less than UAER less than 200 micrograms/min) (DM), 15 with normal urinary albumin excretion (DN) and 10 healthy controls (C) participated. All groups were of comparable sex, age degree of obesity and had normal serum creatinine, and the groups of diabetics were of similar known duration, glycemic control and frequency of antihypertensive treatment. Blood pressures measured at the clinic were significantly higher (p less than 0.01) than 24h recordings. An average systolic pressure of 142 +/- 11 mmHg in DN was increased (p less than 0.01) as compared to C: 130 +/- 10 mmHg, but no further increase was seen in DM: 146 +/- 19 mmHg. Diastolic pressures were not different among the groups (C: 77 +/- 8 mmHg, DN: 80 +/- 11 mmHg, DM: 79 +/- 9 mmHg). Average 24h systolic pressure correlated to the UAER r = 0.61, p = 0.009 in DM, whereas not in DN. By the present method we found isolated systolic hypertension in Type 2 diabetes which may express "vascular stiffness". There was, however, no further rise in blood pressure in patients with microalbuminuria, but in these patients albuminuria may be pressure dependent and/or expressive of vascular pathology.

Ambulatory blood pressure measurement in type 2 diabetic patients: methodological aspects.

Ambulatory blood pressure was measured over 24 h on two occasions in 29 Type 2 diabetic patients age 65 (range 52-74) years, and the reproducibility compared with that of ordinary clinic measurements recorded by Hawskley's random zero sphygmomanometer. The variability of the difference between blood pressure measurements on the two occasions was twice as large for clinic measurement as for ambulatory measurement (2p less than 0.01). If applied to clinical trials this would allow a fourfold reduction of patient numbers without losing test power. In the group of patients treated with antihypertensive medication (n = 16) the spontaneous decline in blood pressure after leaving the hospital proved to be most prominent in those patients with the highest clinic blood pressure, a phenomenon with importance for the management of hypertension. The individual difference between clinic measurements and ambulatory day-time measurements from the same day was unpredictable. Ambulatory blood pressure measurement in the outpatient clinic may be a practicable approach for optimizing antihypertensive treatment in Type 2 diabetic patients.

Reducing protein in the diabetic diet.

Long-term protein intake may have pathogenic influence on development of late diabetic complications. A review of the latest results in insulin-dependent diabetic patients shows that short-term lowering of protein intake reduces the characteristic early glomerular hyperfiltration as well as microalbuminuria and proteinuria in diabetic nephropathy. A sustained beneficial effect on the progression rate of nephropathy may be achieved. Based on this evidence it is advisable to avoid the traditionally high protein intake in diabetes. We suggest a protein-controlled diet--with protein comprising 14 energy %--as a goal in uncomplicated diabetes. In patients with progressive albuminuria or proteinuria prescription of a low-protein diet with 10% protein should be considered as supplementation to antihypertensive treatment. At present we do not find sufficient evidence for suggesting an intake of 10% protein (corresponding approximately to recent recommendations on 0.8 g prot/kg body weight) also in uncomplicated diabetes. Both a 10 and 14% protein diet will differ somewhat from the diet of the background population and the present diet of many diabetic patients. Therefore the introduction of such diets requires a careful individualized diet therapy in which repetitive evaluation and estimation of compliance are performed. A reduction of protein intake to 10 energy % represents a profound diet intervention.

Diurnal blood pressure variations in normoalbuminuric type 1 diabetic patients.

OBJECTIVE: To test the hypothesis that normoalbuminuric type 1 diabetic patients segregate into groups with normal and elevated ambulatory blood pressure. To evaluate diurnal variation of blood pressure assessed by individual or fixed night-time periods. DESIGN: Cross-sectional study. SETTING: Tertiary referral centre. SUBJECTS: Inclusion criteria for type 1 diabetic patients (n = 33): normal urinary albumin excretion (UAE age < 45 < 20 micrograms min-1), diabetes duration < or = 20 years, age 45 years. Healthy controls (n = 33) were matched for sex and age. MAIN OUTCOME MEASURE: Twenty-four hour, day-time, night-time and night/day ratio of ambulatory blood pressure. RESULTS: Twenty-four-hour blood pressure in diabetic patients did not differ significantly from a normal distribution. The 24-h systolic blood pressure was higher in diabetic patients than in healthy controls (difference: 6 mmHg, 95% confidence interval (CI) from 1 to 10 mmHg, P < 0.05), while no significant differences were found for diastolic values. The 24-h systolic blood pressure in diabetic patients with UAE above the median value (5.8 micrograms min-1) was higher than for those with lower UAE (difference: 7 mmHg, 95% CI from 0.5 to 13 mmHg, P < 0.05). The night/day ratio of diastolic blood pressure based on individual informations of the night period was (mean +/- SD) 80 +/- 6% in diabetic patients and 78 +/- 8% in controls (difference: 2%, 95% CI from -1 to 5%, not significant [NS]). This ratio increase significantly (P < 0.00001) to 90 +/- 5% in diabetes and to 84 +/- 7% in controls if a fixed night period from 22.30 hours to 06.30 hours was assumed. CONCLUSIONS: It was not possible to identify a well-separated group of normoalbuminuric type 1 diabetic patients with elevated ambulatory blood pressure. Values of UAE above the median in diabetic patients are associated with higher ambulatory blood pressure. Assessment of the night/day variation from fixed time-points should be abandoned because this leads to a serious underestimation of the nocturnal reduction in blood pressure.

Lipoproteins and diuretics in type II diabetes.

This double-blind cross-over study was performed to investigate whether the lipoproteins in plasma were different on furosemide (Lasix Retard) and thiazide (hydrochlorthiazide) treatment in patients suffering from type II diabetes. Twenty-four patients were randomly allocated to either furosemide-hydrochlorthiazide (LR-HCT) or HCT-LR treatment. The treatment period was 12 months: 6 months on each sequence. After inclusion, the patients were seen every second month. Laboratory data were recorded at each visit. The only significant treatment effect was observed for high-density-lipoprotein3 cholesterol concentration (HDL3 cholesterol concentration), which was higher when patients were on furosemide therapy (p less than 0.05). We conclude from the present study that blood-glucose HbA1c, and the concentration of lipoproteins connected to development of atherosclerosis is unaffected whether type II diabetes patients are treated with HCT or furosemide.

Night blood pressure and cigarette smoking: disparate association in healthy subjects and diabetic patients.

Cigarette smoking and diabetes are well known risk factors for cardiovascular disease. The relation of nocturnal blood pressure (BP) to cigarette smoking is unclarified. We examined ambulatory BP in 18 healthy smokers matched for sex and age to 18 non-smokers. Sixteen smoking type 1 diabetic patients matching 16 non-smoking patients with normal urinary albumin excretion were also investigated. None of the healthy subjects or diabetic patients had a clinic BP > 160/95 mmHg. Night BP (systolic/diastolic mmHg) in healthy smokers (mean +/- SD) 102 +/- 9/57 +/- 5 was lower than in healthy non-smokers 108 +/- 10/61 +/- 6 (p = 0.06/p < 0.05). The difference between smokers and non-smokers was most prominent in the 3 h period just before rising (99 +/- 9/57 +/- 6 versus 108 +/- 8/62 +/- 7, p < 0.01/p < 0.05). Daytime BP was similar between groups. The night/day ratio (%) of systolic (84 +/- 7) and diastolic (74 +/- 7) BP in healthy smokers was lower than in non-smokers (88 +/- 5 versus 80 +/- 5, p < 0.05 and p < 0.01) indicating an altered diurnal rhythm of blood pressure. No statistical significant difference was found for night or day BP in diabetic smokers versus non-smokers. The finding of a significantly lower BP in healthy (supine) smokers at night speaks against dysautonomia explaining the lower clinic BP found in epidemiological studies, as recently proposed. Alternatively a rebound effect or the existence of a substance with vasodilating properties in non-diabetic smokers is suggested.(ABSTRACT TRUNCATED AT 250 WORDS)