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.

Purification of MUC1 from bovine milk-fat globules and characterization of a corresponding full-length cDNA clone.

The highly glycosylated protein MUC1 was purified from bovine milk-fat globule membranes by a procedure involving detergent extraction, ion-exchange chromatography and reverse-phase chromatography. The identity of the purified mucin protein was confirmed by N-terminal sequencing and partial amino acid sequences obtained by peptide mapping. The complete amino acid sequence of MUC1 was determined by cloning and sequencing the corresponding bovine mammary gland cDNA, which was shown to encode a protein of 580 amino acid residues comprising a cleavable signal peptide of 22 residues. The deduced amino acid sequence demonstrated structural features characteristic for mucins, including an extracellular tandem repeat region with 11 partially conserved repeats (20 amino acids each), a membrane-proximal SEA module, a transmembrane domain, and a cytoplasmic C-terminal region. Monosaccharide composition determinations suggested significant structural differences between O-linked glycans of MUC1 originating from either bovine or human milk. Interspecies differences of the consensus repeat sequence in MUC1 and the physiological functions are discussed.

Isolation of adipophilin and butyrophilin from bovine milk and characterization of a cDNA encoding adipophilin.

The milk fat globule membrane-associated proteins adipophilin (alias adipocyte differentiation-related protein) and butyrophilin were purified from bovine milk by reverse-phase chromatography. The nucleotide sequence of bovine adipophilin was obtained via peptide mapping and sequencing of a mammary gland cDNA clone, which comprises 1841 nucleotides and has an open reading frame of 450 amino acids. By peptide mapping, 19% of the amino acid sequence was confirmed. The obtained amino acid sequence has 87 and 80% identical residues with human and mouse adipophilin, respectively. Alignment with the proteins perilipin and TIP47 revealed two highly conserved segments, which may assemble into amphipathic alpha-helices.

Preference segmentation of health care services: the old-fashioneds, value conscious, affluents and professional want-it-alls.

The results of a national segmentation study are reported. The findings extend the empirical work of Finn and Lamb and the benefit-seeking conjectures by Kotler and Clarke that consumers with preferences toward specific hospitals can be segmented into a few distinct groups. The groups described in the findings are identified as the value conscious, the affluents, the old-fashioneds, and the professional want-it-alls. Each segment has a unique demographic profile. The substantial importance of doctors' recommendations in influencing hospital choice is supported for all four consumer segments. Suggestions for additional research and hospital marketing strategies are provided.

Long-term metabolic control with insulin pump therapy. Report of experience with 127 patients.

To determine the long-term efficacy of insulin-pump therapy, we analyzed trends in glycosylated hemoglobin concentrations in 127 patients with Type I diabetes using insulin pumps for periods ranging from 13 to 47 months. In the first year of pump therapy the average glycosylated hemoglobin concentration improved in 83 per cent of the patients, as compared with the value before pump therapy. Although only 11 of the 127 subjects had normal glycosylated hemoglobin values before pump therapy, 33 had a normal average value during the first full year of pump use (P = 0.0001). This favorable trend persisted for the three-year duration of the study. Seventeen of the 19 patients who subsequently discontinued insulin-pump therapy had improved glycosylated hemoglobin values during the period of pump use. Eleven of the 19 patients remained available for follow-up study; the glycosylated hemoglobin concentration became worse in 7 when they returned to conventional treatment. We conclude that the improvement in metabolic control repeatedly demonstrated in short-term studies with the insulin pump can be maintained for a period of years.

Acute complications associated with insulin infusion pump therapy. Report of experience with 161 patients.

We determined the frequency of acute complications associated with insulin pump therapy in 161 insulin-dependent patients followed up for a total of 2,978 patient-months. Diabetes control improved substantively with pump therapy, but 42% of the patients experienced one or more acute complications while using insulin pumps. Infected infusion sites, ketoacidosis, and hypoglycemic coma occurred once in every 27, 78, and 175 patient-months, respectively. More patients experienced ketoacidosis after the onset of pump therapy than in an equivalent interval immediately before the onset of pump therapy. Ketoacidosis also occurred in more patients using pump therapy than in a comparison group of 165 patients receiving conventional insulin injections surveyed during an equivalent period. The frequency of hypoglycemic coma was not significantly changed by pump therapy.

Clinical use of the insulin infusion pump in 100 patients with type I diabetes.

We investigated the efficacy of insulin-pump therapy in insulin-dependent diabetics, aged 18 to 69 years, by comparing the metabolic control achieved in 100 patients using this technique with that previously obtained by conventional insulin therapy. Patients were followed during pump therapy for as long as 15 months. Fasting and nonfasting blood glucose levels (mean +/- S.E.M.) decreased from 201 +/- 6 and 213 +/- 6 mg per deciliter (11.2 +/- 0.3 and 11.8 +/- 0.3 mmol per liter), respectively, to 158 +/- 5 and 145 +/- 3 mg per deciliter (8.77 +/- 0.3 and 8.05 +/- 0.2 mmol per liter) after one month of pump therapy (P less than 0.001). Ninety-three patients had improved blood sugar control; 71 per cent had a mean blood sugar concentration of 150 mg per deciliter (8.3 mmol per liter) or less after six months. Glycosylated hemoglobin values became normal in 44 per cent of 88 patients who had follow-up determinations. In over 500 patient-months there were four episodes of ketoacidosis and five episodes of serious hypoglycemia. Three patients abandoned pump therapy. We conclude that insulin-pump therapy is acceptable to patients and that it can be successfully applied to clinical practice and large-scale research studies.

Hydrolysis of cefamandole nafate in dialysis patients.

The hydrolysis of cefamandole nafate was examined in vivo in five dialysis patients and five subjects with normal renal function. The plasma half-life of cefamandole was prolonged in the patients with renal failure compared with normal subjects (18.3 +/- 4.5 [standard deviation] versus 10.35 +/- 1.4 min, P less than 0.01). The pharmacokinetics of cefamandole nafate best fit two-compartment, open-model kinetics. We conclude that patients with severe renal failure are capable of hydrolyzing cefamandole nafate to cefamandole and formate at a rate sufficiently rapid so as not to allow an accumulation of cefamandole nafate. The difference in half-life may be related to urinary excretion of cefamandole nafate in normal individuals.

The use of exchange transfusions: a potentially useful adjunct in the treatment of fulminant falciparum malaria.

Fulminant falciparum malaria with greater than 500,000/mm3 parasites in the peripheral blood portends a poor prognosis. We recently managed a patient who had greater than 1.2 million/mm3 parasitized erythrocytes in her peripheral blood, following initially inadequate antimalarial therapy, with exchange transfusion in addition to conventional chemotherapy. This patient recovered from her disease despite severe cerebral involvement and acute failure. We feel that exchange transfusion was a useful adjunct and should be considered in patients with life threatening falciparum malaria when conventional measures fail to control the disease.

The assay of 1alpha,25-dihydroxyvitamin D3: physiologic and pathologic modulation of circulating hormone levels.

A sensitive radioreceptor assay for 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) is utilized to quantitate the circulating concentration of this sterol in experimental animals and humans. When weanling rats are grown for 2 weeks on low calcium or low phosphate diets, limited availability of either ion elicits a five-fold increase in the plasma level of 1alpha,25-(OH)2D3. The enhancement of 1alpha,25-(OH)2D3 in calcium deficiency is dependent upon the presence of the parathyroid and/or thyroid glands, which is consistent with parathyroid hormone (PTH) mediation of this effect. In contrast, the response to phosphate deficiency is independent of these glands and may result from a direct action of low phosphate on the renal synthesis of 1alpha,25-(OH)2D3. Studies in humans indicate that the normal level of 1alpha,25-(OH)2D is 2.1--4.5 ng/100 ml plasma. Patients with chronic renal failure have markedly lower circulating 1alpha,25-(OH)2D and this kidney hormone is undetectable in anephric subjects, but returns to normal within 1 day after successful renal transplantation. Hypoparathyroidism and pseudohypoparathyroidism are associated with reduced plasma 1alpha,25-(OH)2D while patients with primary hyperparathyroidism have significantly elevated sterol hormone levels. Thus, from measurements in rats and humans, it appears that circulating 1alpha,25-(OH)2D3 is regulated by PTH and/or phosphate and that abnormal plasma 1alpha,25-(OH)2D3 is a part of the pathophysiology of renal osteodystrophy and parathyroid disorders.