Gemcitabine induced digital ischaemia and necrosis.

A 70-year-old woman presented with a 7-day history of severe pain, paresthesia, oedema, acrocyanosis and punctate haemorrhagic lesions on her fingertips. The complaints began 2 days after the second cycle of a first-line chemotherapy consisting of cisplatin or carboplatin, and gemcitabine due to advanced urothelial carcinoma. At the fingertips of both hands, haemorrhagic and partly ulcerative lesions were found; these were attributed to vascular toxicity of gemcitabine. Therapeutically sympathicolysis by bilateral blockade of the brachial plexus was performed, accompanied by intravenous administration of the prostacyclin analog iloprost, fractionated heparin subcutaneously and oral therapy with corticosteroids and aspirin. Digital amputation could be avoided. Acral ischemia is a rare but probably underreported adverse effect of gemcitabine therapy and a potential source of misdiagnosis.

An improved method for estimating cholecystokinin in human serum.

Because of difficulties encountered in setting up radioimmunoassays for cholecystokinin (CCK) a sensitive and reliable biological method for estimating this hormone is still needed. The principles of such a biological technique and an improvement to it have already been described, but the serum levels of CCK reported were high and the technique required further refinement and validation. The strips of rabbit gall-bladder used to estimate the concentration of CCK increased in sensitivity to standard solutions of CCK over a 6--8 period before stabilizing, but a single sample of serum increased the sensitivity of the strips of gall-bladder to their maximum immediately. These two problems were eliminated by 'priming' the strips of gall-bladder by exposure to two serum samples before exposure to the standard solutions used for production of a dose--response curve. Thirdly, it was discovered that some non-peptide substances in serum possessed CCK-like activity; by extracting all the small peptides from serum with dextran-coated charcoal the residual activity could be measured and subtracted from the total CCK activity. Finally, the activity of CCK in the serum increased during processing before freezing. This increase was eliminated by taking the blood samples into aprotinin which has been shown to cause dramatic reduction in CCK activity in some experiments. When all these factors were taken into account and the technique suitably modified, the mean level of CCK in the serum of ten normal fasting subjects was found to be 28 milli Ivy Dog units/ml (2.4 pmol/ml), which is only one third of that reported previously.

Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes.

In patients with Type 2 diabetes, the appropriate intensity of glucose control is determined by age, life expectancy, and the presence of concomitant disease. Geriatric patients are especially susceptible to hypoglycaemia and therefore particular care should be taken in this group characterized by polypharmacy, renal or hepatic dysfunction, cardiovascular multimorbidity and malnutrition. As hypoglycaemia is a significant cause of morbidity and mortality, treatment regimens for diabetes should minimize the occurrence of hypoglycaemic episodes and be tailored to the patient's individual needs. The pharmacological options for treating Type 2 diabetes have increased considerably and the risk of hypoglycaemia of the currently available drugs varies considerably. Metformin, thiazolidinediones, and acarbose, oral antidiabetic drugs that decrease insulin resistance or postprandial glucose absorption, are associated with a low risk of hypoglycaemia. These drugs can also be used effectively in various combination regimens; however, by improving insulin sensitivity, combinations of metformin and thiolidinediones with sulphonylureas or meglitinides may considerably increase the risk of hypoglycaemia. On account of its complex pharmacoprofile glibenclamide is a problematic substance carrying a high risk of hypoglycaemia. There are limited preliminary data indicating that, under routine conditions, glimepiride may be associated with a lower risk of hypoglycaemia than glibenclamide and is no more likely to cause hypoglycaemia than other shorter-acting agents such as gliclazide and glipizide. Nateglinide and repaglinide as short-acting insulin secretagogues may be associated with a reduced risk of hypoglycaemia compared with glibenclamide, in particular when dosed flexibly. Repaglinide might be beneficial in individuals with renal impairment.

Clinical characterisation of severe hypoglycaemia--a prospective population-based study.

AIM: To determine the clinical characteristics of severe hypoglycaemia (SH) in a nonselected German population. SH was defined as an event requiring intravenous glucose or glucagon injection. METHODS: The prospective population-based study screened sensitively for SH in a region with 200,000 inhabitants between 1997 and 2000. All 30,768 patients who presented to the regional central hospital emergency department, and 6,631 (85 %) of 7,804 patients attended by the emergency medical service in the region were given an initial blood glucose test to detect atypical hypoglycaemia. RESULTS: Altogether, 264 cases of SH were registered, which occurred either spontaneously (n = 14; 5 %), in subjects with type 1 (n = 92; 35 %) or type 2 diabetes (n = 148; 56 %), or in subjects with a non-classified form of diabetes (n = 10; 4 %). On the basis of the estimated local number of diabetic patients the annual rate of SH was 1.5 episodes per 100 patients in insulin-treated type 2 diabetics compared with a rate of 0.4 episodes per 100 patients for the overall group of type 2 diabetic patients. Nocturnal hypoglycaemia accounted for 44 % of episodes in patients with type 1 diabetes on intensified therapy but for only 25 % in patients with type 2 diabetes. 26 % of the hypoglycaemic individuals with type 1 diabetes had an impaired awareness of hypoglycaemia and thus recurrent hypoglycaemic episodes. Irrespective of the treatment, the most frequent contributing factors for SH in type 2 diabetic patients were advanced age (76 +/- 12 years), multimorbidity (3.6 +/- 2.6 concomitant diseases)--in particular renal impairment (54 % [80/148])--and polypharmacy (4 +/- 2.7 concomitant drugs). 34 % (50/148) of the subjects with type 2 diabetes lived in nursing homes or were cared for by a home nursing service. With standardised treatment zero mortality of SH in diabetic patients was achieved, only one non-diabetic died due to hepatic failure. CONCLUSION: In elderly, multimorbid patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the risk of developing SH increases considerably, nearing that in patients with type 1 diabetes. In order to avoid SH in geriatric patients, the treatment targets should be defined critically, taking into account individual quality of life and life expectancy. Hypoglycaemia unawareness is a major risk factor for SH in type 1 diabetes.

Lipodystrophy and metabolic disorders as complication of antiretroviral therapy of HIV infection.

Peripheral lipodystrophy, central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus, in varying constellations, are frequent complications of highly active antiretroviral therapy in HIV1-infected patients. The pathogenetic significance of protease inhibitors toxicity has been demonstrated by the partial reversal of metabolic disorders after switching to other antiretroviral regimens. The therapeutic and prognostic implications of these metabolic disorders are not yet clear. The dramatic improvements in the prognosis and quality of life of people with HIV since the introduction of highly active antiretroviral therapy call for evidence based concepts for the management of treatment-related metabolic disturbances.

Hormonal counterregulation during severe hypoglycaemia under everyday conditions in patients with type 1 and insulin-treated type 2 diabetes mellitus.

AIM: To determine the counterregulatory hormonal responses to severe hypoglycaemia (SH) in type 1 versus insulin-treated type 2 diabetic patients under everyday conditions. METHODS: Counterregulatory hormones were determined in 28 consecutive type 1 and thirteen insulin-treated type 2 diabetic patients (age 54 +/- 18 vs. 75 +/- 13 yrs; diabetes duration 27 +/- 16 vs. 21 +/- 6 yrs) with SH requiring emergency treatment. Blood samples were taken prior to and after effective treatment of SH. SH was defined as an event with neuroglycopenic presentation requiring external intervention by administration of intravenous glucose or oral carbohydrates. 68 % (19/28) of type 1 diabetic patients but none of those with type 2 diabetes had reduced awareness of hypoglycaemia. RESULTS: Plasma glucose levels were 30 +/- 14 prior to and 179 +/- 82 mg/dl after treatment of SH; the time between the two measurements was 54 +/- 26 minutes. With the exception of higher levels of human growth hormone in type 1 patients - which were attributed to younger age - the other counterregulatory responses to SH showed no significant differences in type 1 vs. type 2 diabetic patients. In both groups glucagon responses were virtually absent while moderate catecholamine responses could be demonstrated. Treatment with beta-blockers did not affect hormonal counterregulation in type 1 diabetic patients. CONCLUSIONS: In patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the hormonal responses to SH are comparable to those in patients with longstanding type 1 diabetes. Thus, in advanced type 2 diabetes the risk of developing SH may be similar to that in individuals with type 1 diabetes.

Blood glucose self-monitoring from abdominal skin: a precise and virtually pain-free method.

For many diabetic patients, years of blood glucose self-monitoring (SM) with readings taken several times daily is an inevitable aspect of insulin therapy. We investigated whether SM from abdominal skin might be an alternative to the established fingertip method. A total of 63 diabetic patients and 16 nondiabetic volunteers determined their blood glucose in parallel in capillary blood from the tip of the finger and from abdominal skin 5 times daily on 5 successive days. The blood samples were collected from the two test regions using lancing devices, and the SM determinations were all done with a meter. Consecutive specific enzymatic glucose determinations in blood from the fingertip served as the reference method. The results of the SM from abdominal skin, a method perceived as virtually painless, were in close correlation with the control laboratory determinations and with SM from the finger (Pearson's r, 0.94 and 0.95). The comparison of SM method for abdomen vs. finger laboratory control gave a linear regression equation of y=8.35+0.94x (r=0.94). Error grid analysis revealed: range A, 93.6%; range B, 5.4%; range C, 0.05%; range D, 1.0%; and range E, 0%. Bland and Altman analysis yielded the mean of the differences, 0.2 mg/dl; 2 SD, 32 mg/dl; minimum, -162 mg/dl; maximum, 148 mg/dl. Laboratory glucose determinations in capillary blood from the fingertip and from abdominal skin led in 99.7% of the cases to concordant therapeutic decisions in the diabetics; the sample material was therefore equivalent. The practical aspects (afterbleeding, number of punctures, test strip consumption) of SM from the two regions showed no essential differences. However, only 22% of the diabetic patients investigated continued to perform SM from abdominal skin on a longer basis. In a further 5 adipose diabetic patients (BMI, 32 kg/M2), SM from abdominal skin was not practicable, as there was insufficient blood to collect. SM from abdomal skin is a simple, virtually pain-free and precise method. It provides certain diabetic patients with an alternative to the established method of SM from the fingertip.

Muscle PO2 in the initial phase of increased local oxygen demand (rhythmical muscle contraction) in rats with portacaval shunt (PCA).

The influence of a hyperdynamic syndrome caused by PCA on PO2 distribution in skeletal muscle of rats during the initial phase of muscle activity was examined. Rhythmical muscle contraction of the m. biceps femoris was induced by direct electrical stimulation. Tissue PO2 of the contracting muscle was recorded continuously from the start of the 210 s-long activity period up to 140 s after the last contraction using a multiwire surface electrode. In comparison with controls no different behaviour of mean muscle PO2 in the initial phase of contraction was found. After muscle activity mean PO2 decreased to a lower level in rats with PCA than in controls. This might be a further indication of the disturbing influence of a hyperdynamic syndrome on the regulating mechanisms of the microcirculation.

Circadian course of PO2-oscillations in skeletal muscle of intact and portacaval shunted (PCA) rats.

In rats several circadian rhythms such as heart rate, body temperature, and locomotor activity are known. Several authors found a loss of day-night-rhythm (locomotor activity, EEG) after portacaval shunting (PCA). The aim of this study was to evaluate whether muscle PO2 oscillations are circadian and whether they are altered after time-limited hypercirculation caused by PCA. 126 days after operation tissue PO2 of m. rectus abdominis of 9 rats with PCA and 10 controls was measured with a multi-wire surface electrode. All animals were kept under constant conditions and each animal was measured 6 times at intervals of 4 hours in order to get a circadian PO2 course. In controls the circadian course of mean muscle PO2 resembled a sine oscillation with high values at night and low values in the afternoon. In PCA-rats the time course of mean muscle PO2 showed 3 oscillations with different amplitudes, each with a period length of 24 hours. Our results indicate that oscillations of muscle PO2 are determined principal by circadian locomotor activity and that time-limited hypercirculation influences the circadian course of mean muscle PO2.

Characteristic pattern of free amino acids in plasma and skeletal muscle in stable hepatic cirrhosis.

Free amino acid (AA) concentrations in plasma and quadriceps femoris muscle were determined in 19 healthy volunteers and in 16 patients with hepatic cirrhosis and portal hypertension. Nutritional state was impaired as judged by overt muscle wasting (9/16), triceps skinfold thickness less than 70% of normal in 8/14 (57%), and creatinine-height index below 70% in 5/12 (42%). In the plasma of patients the typical amino acid pattern of cirrhosis was to be observed: Elevation of tyrosine and methionine (p less than 0.01), uniform reduction of branched chain amino acids (p less than 0.001) resulting in a decreased molar ratio of BCAA/AAA from 2.85 +/- 0.05 in normal individuals to 1.35 +/- 0.12 in cirrhotics (p less than 0.001). Levels of the gluconeogenic AA glutamine, glutamate, aspartate, alanine, glycine, threonine, serine and lysine were lowered (p less than 0.05). In muscle of cirrhotics, intracellular AA concentrations exhibited a similar pattern with two major exceptions: Tyrosine and phenylalanine were augmented (p less than 0.001). Surprisingly, BCAA levels were altered heterogeneously; those of gluconeogenic BCAA decreased: Valine from 0.34 +/- 0.03 to 0.20 +/- 0.03 mmol/l (p less than 0.001), isoleucine 0.09 +/- 0.01 to 0.05 +/- 0.02 mmol/l. However, the concentration of ketogenic leucine remained unaltered in muscle. Nevertheless, the molar ratio of BCAA/AAA was considerably reduced from 3.70 +/- 0.04 to 0.81 +/- 0.08 (p less than 0.001). Most of the gluconeogenic AA exhibited reduced intramuscular concentrations, but glutamine levels were normal. The pattern of plasma and muscle free AA in hepatic cirrhosis is thus characterized by accumulation of aromatic AA and by depletion of gluconeogenic AA, especially BCAA.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic pitfalls in sulfonylurea-induced neuroglycopenic syndrome with hemiparesis, dysphasia and somnolence]. / Diagnostischer Irrweg bei sulfonylharnstoffinduzierten neuroglukopenischen Syndromen mit Hemiparese, Dysphasie und Somnolenz.

BACKGROUND: The neuroglycopenic syndrome, which is often due to sulfonylurea-induced hypoglycemia, is frequently overlooked or misinterpretated as cerebral ischemia. PATIENTS: Two women aged 81 and 83 years, respectively, with type II diabetes treated with sulfonylureas presented with hemiparesis, dysphasia and somnolence. Both, general practitioner and emergency room physician first interpretated the symptoms as clinical signs of stroke without determination of blood glucose. After hours of delay due to unnecessary and expensive examinations including cerebral computed tomography the correct diagnosis of hypoglycemia was finally made. After injection of i.v. glucose the symptomatology was completely reversible. CONCLUSION: In every case of disturbance of consciousness, acute neurologic deficits and psychiatric abnormalities an immediate blood glucose test should be performed to exclude hypoglycemia.

[CNS symptoms caused by hypoglycemia: frequent misdiagnosis: "stroke". Pitfall of the neuroglycopenia syndrome]. / ZNS-Symptome durch Hypoglykämie: häufige Fehldiagnose "Schlaganfall", Chamäleon neuroglukopenisches Syndrom.

Hypoglycemia may occur without classic symptoms, especially in elderly patients hypoglycemia may imitate nearly every neurological symptom. The neuroglycopenic syndrome, which is often due to sulfonylurea-induced hypoglycemia, is frequently overlooked or misinterpreted as cerebral ischemia. Therefore in every case of disturbance of consciousness, acute neurologic deficits and psychiatric abnormalities an immediate blood glucose test should be performed to exclude hypoglycemia.

[Traditional contraindications to the use of metformin -- more harmful than beneficial?]. / Traditionelle Metformin-Kontraindikationen -- mehr Schaden als Nutzen?

For fear of lactic acidosis the currently listed contraindications to the use of metformin exclude a large number of people with type 2 diabetes from efficacious anti-hyperglycemic and cardioprotective treatment. Yet recent data call the traditional contraindications to metformin into question. As the incidence of lactic acidosis in patients with type 2 diabetes is the same with or without metformin therapy (about 9 per 100,000 patient years) there is no evidence that metformin therapy is associated with an increased risk of lactic acidosis. Similarly, despite disregard internationally of major metformin contraindications, there has been no corresponding increase in the incidence of lactic acidosis. Metformin treatment of elderly diabetics with multiple comorbidities and explicit contraindications has led to significantly better clinical parameters in them than in the control group without metformin; and there were no cases of lactic acidosis. The two groups did not differ with regard to progression of renal failure, patient-oriented endpoints or overall mortality. Compared with its predecessors phenformin and buformin, metformin is considerably less lipophilic and has a shorter plasma half-life; it is eliminated renally in unchanged form. In type 2 diabetics treated with metformin -- even those over 70 years of age and those in mild renal failure -- no relevant increases in lactate levels were found. In patients with lactic acidosis there was no correlation between the levels of metformin and lactate. The prognosis of lactic acidosis is determined less by the serum concentrations of metformin and lactate than by the hypoxia caused by the underlying disease and comorbidities. These findings raise doubts about the significance of metformin in the pathogenesis of lactic acidosis. On the basis of the current data, advanced age per se, mild renal impairment and stable heart failure can no longer be upheld as contraindications to the use of metformin. It should be safe to withdraw metformin the evening before radiological examinations with intravenous contrast media or surgical procedures under general anaesthesia in diabetics with normal renal function.

Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents.

AIMS: The genetically polymorphic cytochrome P450 (CYP) enzyme CYP2C9 metabolizes most sulphonylurea oral hypoglycaemic agents. The aim of this study was to test the hypothesis that individuals with genotypes predicting low CYP2C9 activity may be at a higher risk of severe drug-associated hypoglycaemia. METHODS: In a case-control study, 20 diabetic patients admitted to the emergency department with severe hypoglycaemia during sulphonylurea drug treatment were compared with a control group of 337 patients with type 2 diabetes but without a history of severe hypoglycaemia. A large sample of 1988 healthy Caucasian subjects served as a second control group. RESULTS: The CYP2C9 genotypes *3/*3 and *2/*3 that are predictive of low enzyme activity were more common in the hypoglycaemic group than in the comparison groups (10%vs <2%, respectively: odds ratio 5.2; 95% confidence interval 1.01, 27). Furthermore, the diabetic patient group with severe hypoglycaemia exhibited lower body mass indexes, higher rates of renal failure, were older compared with the diabetic group without severe hypoglycaemia, and were being treated with higher doses of glibenclamide. CONCLUSIONS: These findings suggest that among other factors, individuals with genetically determined low CYP2C9 activity are at an increased risk of sulphonylurea-associated severe hypoglycaemia. Thus, genotyping might be a tool for the better prediction of adverse effects caused by oral hypoglycaemic agents.

[Therapeutic studies with branched-chain amino acids in portasystemic encephalopathy]. / Therapeutische Studien mit verzweigtkettigen Aminosäuren bei portosystemischer Enzephalopathie.

Published controlled clinical trials with branched chain amino acids (BCAA) in patients with portosystemic encephalopathy (PSE) are described and their results discussed. A positive effect on PSE by BCAA seems probable but without altering mortality rate. Improvement of nutritional state cannot be finally evaluated.

[Therapy of hepatic encephalopathy]. / Therapie der hepatischen Enzephalopathie.

Hepatic encephalopathy is a clinical syndrome which appears in the course of hepatic failure. It is due to porto-caval shunts. The major symptoms of hepatic encephalopathy are alterations of intellectual functions, changes of personality and an impairment of neuromuscular functions. The morphological basis of all these changes are a cerebral atrophy, partial cortico-medullary necrosis and the occurrence of macroglial cells. Pathogenetically either an augmented influx of toxic substances from the gut or an increased production of false neurotransmitters might be responsible. Therapeutically restriction of protein intake, sterilisation of the gut and application of branched-chain amino acids or their keto analogs are the major steps for an improvement of the disease.

The effect of cholecystokinin on human taenia coli.

Superfusion of twelve human Taenia Coli strips with cholecystokinin (CCK) (boots and GIH Karolinska), CCK-octapeptide and glucagon at doses of 25--1,000 mIDu/ml evoked muscular contractions. Dose-dependent response to acetylcholine (ACH) (0.15--1.0 mug/ml) was not altered by an underlying contraction induced by CCK, CCK-octapeptide or glucagon. Though atropine (0.1 mug/ml) abolished ACH effects, hormonal responses were unaffected. The muscles' sensitivity was highest of CCK (Boots) and lowest to CCK-octapeptide, and the sigmoid colon was more sensitive than other parts of the bowel to both. Addition of glucagon had no effect on CCK-induced (Boots) responses. The results suggest (1) CCK and CCK-octapeptide act directly on the Taenia coli; (2) biologically active impurities in the whole CCK preparations explain their apparent increased activity; (3) glucagon does not block ACH or CCK, nor inhibit, directly, muscle contractions; (4) atropine (0.1) mug/ml)) does not interfere with CCK or CCK-octapeptide on colonic muscle.

[Carbohydrate infusions in internal diseases. A comparative study in metabolically healthy, liver diseased and diabetic patients. VIII. Continuous infusions of low dosage carbohydrate mixtures in patients with liver cirrhosis]. / Kohlenhydratinfusion bei internistischen Erkrankungen. Eine vergleichende Studie bei stoffwechselgesunden, leberkranken und diabetischen Patienten. VIII. Dauerinfusionen niedrig dosierter Kohlenhydratmischungen bei Kranken mit Leberzirrhose.

Basic caloric needs of patients with compensated liver cirrhosis and healthy controls were supplied for 48 h with mixtures of glucose, fructose, sorbite, and xylit. Mixed solutions (20% w/v) containing glucose + fructose (n = 6), glucose + sorbite (n = 36), glucose + xylit (n = 37) in a 1:1 ratio, and glucose + fructose + xylit (n = 6) in a 1:2:1 ratio as well as glucose alone (n = 6) were administered in a dosage of 0.25 g/kg/h each. Utilization of the monosubstances, corresponding blood levels, and the effects on parameters of carbohydrate and lipid metabolism were frequently controlled. In contrast to mixed solutions, infusion of glucose alone caused a pronounced increase of the insulin levels and hyperglycemia in some patients suffering from liver cirrhosis. In both groups infusion of glucose + xylit was accompanied by a rise of uric acid levels. In liver cirrhotics a permanent decrease of phosphate as well as an increase of xylit concentrations were observed. These changes were not seen with xylit lowered to 50%, in glucose + fructose + xylit infusion. Therefore, we recommend to restrict xylit in liver cirrhotics to 100/24 h. No significant changes of blood gas measurements, ph values, hyperlactatemia, or lactic acidosis were seen. There was no difference in the anticatabolic, antilipolytic, and antiketogenic effect of the solutions. The least changes of all controlled parameters were observed with glucose + fructose and glucose + fructose + xylit infusions.