Comparison of serum fructosamine vs glycohemoglobin as measures of glycemic control in a large diabetic population.

In diabetic patients, measurement of glycohemoglobin (HbA1C) is widely accepted as the standard method for determining long-term glycemic control. Another test, the serum fructosamine test, has been suggested as a less costly alternative. To compare these two tests, we evaluated how well each correlated with fasting blood glucose and how well each could predict the degree of glycemic control perceived by treating physicians. Among 222 diabetic subjects, fructosamine (r=0.74) and fructosamine corrected for serum albumin (c-fructosamine) (r=0.79) correlated better with fasting blood glucose than did HbA1C (r=0.68) (P<0.05). Among 450 diabetic subjects, fructosamine, c-fructosamine, and HbA1C showed similar error rates (23%-26%) when discriminating between subjects who had either poor vs not-poor control or poor-to-fair versus good-to-excellent control. However, receiver operating characteristic curves for these tests indicated that HbA1C was the best discriminator because it showed a 9% to 10% greater area under the curve (P<0.05).

Prevalence of hypothalamic-pituitary imaging abnormalities in impotent men with secondary hypogonadism.

PURPOSE: Because prevalence of structural lesions of the pituitary and hypothalamus in impotent men with secondary hypogonadism was undefined, we evaluated 164 men 27 to 79 years old whose chief complaint was erectile dysfunction and who repeatedly had low serum testosterone levels (less than 230 ng./dl.). MATERIALS AND METHODS: With computerized tomography or magnetic resonance imaging of the sella we detected potentially serious lesions (pituitary lesions greater than 5 mm. or any hypothalamic lesion) in 11 men (6.7%, 95% confidence interval 2.9 to 10.5%), including 5 pituitary microadenomas (5 mm. or larger), 4 pituitary macroadenomas and 2 hypothalamic lesions. RESULTS: Mean serum testosterone was lower in patients with (121 +/- 66 ng./dl., standard deviation) than without (177 +/- 39 ng./dl.) hypothalamic or pituitary imaging abnormalities (p < 0.001). For every 10 ng./dl. decrease in testosterone the risk of hypothalamic or pituitary imaging abnormalities increased 1.2-fold (p < 0.005). Macroadenomas and hypothalamic lesions were confined to 6 subjects with testosterone levels of 104 ng./dl. or less. CONCLUSIONS: The risk of hypothalamic or pituitary imaging abnormalities is low among men evaluated for erectile dysfunction and secondary hypogonadism. However, this risk increases markedly when the serum testosterone level is markedly decreased.

A [3H]2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo. Validation of the model and the absence of an insulin effect on brain.

In 1980 we described an in vivo method for estimating the rate of glucose uptake among selected tissues during an acute insulin response. The method was based upon the same principles as Sokoloff's 2-deoxyglucose (2DG) method. We now report further examination of the basic assumptions of the model and validation of its general applicability by comparing the response of brain and other tissues to prolonged insulin infusion (while glucose is held constant) with their response to a single injection of insulin. The method provides a reproducible estimate of relative insulin response in any tissue that can be anatomically separated at death. Tissues that are minimally sensitive to insulin such as spleen, lung, skin, and gut do not display increments in the calculated value for net rate of tissue uptake of 2DG. Insulin-sensitive tissues display increased rates of uptake that are characteristic for each specific tissue, ranging in magnitude from 1.7- to 17.9-fold over basal among an array of insulin-sensitive tissues. The duration of a unit response to a sub-maximal dose of insulin also varied among the tissues, persisting for 20-30 min after plasma insulin had returned to basal in heart and for 10-20 min in the other insulin-sensitive tissues. The method provides a reproducible measure of glucose metabolism in vivo and has been validated as a means of quantifying relative insulin sensitivity among the peripheral tissues. During steady-state conditions with plasma glucose held constant, brain glucose metabolism was unaffected by a 60-min infusion of insulin.

Insulin dose-response characteristics among individual muscle and adipose tissues measured in the rat in vivo with 3[H]2-deoxyglucose.

The dose-response characteristics of three skeletal muscles, three adipose tissue beds, and heart muscle to single i.v. injection of insulin were compared in vivo. Comparisons were made at 8 dose levels spanning the entire range for response by all tissues and for the integrated whole body response as reflected in the rate of disappearance of 3H-2-deoxyglucose from plasma. The insulin-sensitive tissues varied widely with respect to the magnitude of the maximal response and the sensitivity to insulin as judged by the effective dose 50% (ED 50). Among the muscles, a slow-twitch oxidative muscle, soleus, was more sensitive than the fast-twitch glycolytic muscle, extensor digitorum longus (EDL), while a mixed muscle, quadriceps femoris, displayed even lower sensitivity. Heart muscle sensitivity was comparable to EDL. Among the adipose sites, the rank order of sensitivity was subcutaneous greater than epididymal much greater than omental. The threshold for a detectable response to insulin was 0.013 U/kg rat.

Hepatic glucose production oscillates in synchrony with the islet secretory cycle in fasting rhesus monkeys.

Oscillations in the concentration of plasma glucose were found to reflect large fluctuations in hepatic glucose production. The fluctuations in glucose production were synchronous with fluctuations in the concentration of plasma insulin and glucagon. This synchrony suggests that hepatic pathways are entrained to the islet cycle with a minimal time delay.

Lack of effect of morphine, reserpine, and halothane on oscillation of plasma insulin in M. mulatta.

Oscillating plasma insulin levels, with periods averaging 9 min, in fasting rhesus monkeys have been previously reported by us. To test whether an oscillator in the central nervous system might be driving these oscillations, we subjected five male rhesus monkeys to morphine, reserpine, and halothane, agents known to affect the central nervous system, in an attempt to either disrupt or change the frequency of the oscillations. We could demonstrate no significant effect of any of the three drugs on the oscillations. We conclude, therefore, that the oscillations in plasma insulin are not driven by an oscillator in the central nervous system. Coupled with the results of others, these data suggest that these oscillations are probably due to an intrinsic pancreatic pacemaker.

Investigation of the effect of insulin upon regional brain glucose metabolism in the rat in vivo.

The hypothesis that insulin might promote increased glucose metabolism in putative glucoreceptor areas of the brain was investigated in the rat. Using tritiated 2-deoxyglucose (2-DG), unanesthetized fasted rats were injected with 0.1 U insulin and studied 30 min later. The local uptake of 2-DG into discrete brain areas was examined in serial frozen 400-micrometer sections. Areas 1.1 mm in diameter were punched from the region of the ventral medial, ventral lateral, and dorsal hypothalamus and from a control area from the cerebral cortex. The punched tissue segments were analyzed for total radioactivity and protein content. The results showed that insulin failed to influence the pattern of 2-DG uptake into these discrete brain regions. When the data were analyzed with a simple kinetic model to determine the net fractional rate of uptake of 2-DG by the tissues, brain tissues displayed a 75% rate increase compared to saline-treated controls. Heart muscle collected from the same rats showed a 700% increase after insulin, while lung, an insulin insensitive tissue, displayed a 30% increase. Because the nonsteady state conditions of the model dictate a number of assumptions, the modest increase in the calculated rate of uptake in brain tissue must be verified by a steady state model before it can be accepted as representing a real effect of insulin upon the overall metabolism of glucose in the brain. Regardless of these reservations, it may be concluded from the pattern of response, that insulin does not selectively increase glucose uptake or metabolism in the putative glucoreceptor areas of the hypothalamus under the conditions of these experiments.

Determination of meclizine hydrochloride by ion-pair extraction with methyl orange.

A method, based on ion-pair extraction, is described for the quantification of meclizine hydrochloride in various pharmaceutical dosage forms, for content uniformity determination, and for concentration monitoring in dissolution and bioavailability studies. Methyl orange, dissolved in pH 2.8 MacIlvaine buffer, gave excellent recovery of meclizine after its isolation from aqueous solutions of gelatin, urine, and blood serum. The chloroform-extracted molecular species appeared to be a 1:1 ion-pair. Beer's law was obeyed for a wide concentration range. Because the extracted species seemed well defined and stable and since a surface or an interphase adsorption phenomenon was not a problem, the reported method is considered sensitive, accurate, precise, rapid, and simple.

Separation and ultraviolet absorbance techniques for determining dihydrotachysterol in pharmaceutical preparations.

Three separation techniques and ultraviolet (UV) spectrophotometry are described for dihydrotachysterol (DHT). The absorbance procedure eliminates the necessity of establishing a regular baseline, which is advantageous in certain cases. The relative absorbance values obey Beer's law in the range of 1-10 mug DHT/ml ethanol. An absorbance ratio check ensures the applicability of the method with respect to the degree of allowable interference present. The absorbance ratio values at the indicated wave-lengths at this concentration range and in the absence of any interferences are relativiely constant. The UV absorbance could serve as the common final determinative step for the other techniques, either singly or in combination, for quantitating DHT in preparations that require varying degrees of cleanup through extraction, saponification, and thin layer chromatography. The respective mean per cent recoveries and their relative standard deviations for a 50 mug DHT standard sample treated by the 3 techniques are 99.6 -+/ 0.5, 98.5 -+/ 1.1, and 97.3 -+/ 3.3%. Content uniformity determination of DHT in tablets and in soft gelatin capsules is also presented, and precautions are discussed.

Soft gelatin capsules II: Oxygen permeability study of capsule shells.

A method is reported for studying the effects of several factors at room temperature on the oxygen permeability of soft gelatin capsule shell films. The method involves the use of a permeability cell assembly and the spectrophotometric determïnation of oxygen with an alkaline pyrogallic acid solution. Factors investigated were relative humidity, plasticizers, equilibrium water, an insoluble additive, and film thickness. Results from the effects of film thickness and oxygen partial pressure correlated well with the permeability equation. For greatest stability of encapsulated oxygen-labile materials, it is recommended that the soft gelatin capsule shells be prepared with a low plasticizer concentration and that the finished capsules be stored at low relative humidity.