A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression.

One hundred and sixty-three patients with major depression were randomly assigned to treatment with mirtazapine or doxepin for 6 weeks in a double-blind clinical trial. Initially, patients received mirtazapine 20 mg/day or doxepin 75 mg/day; dosages were then titrated up to a maximum of 60 mg/day and 300 mg/day, respectively. Both drugs produced considerable improvement in depressive symptoms with no statistically significant differences between the two patient groups. In the mirtazapine group only two patients prematurely terminated the study due to adverse drug experiences, as compared to six in the doxepin-treated group. Moreover, doxepin-treated patients complained more frequently of dry mouth and movement disorders. In conclusion, mirtazapine is an effective treatment for major depression and appears to offer advantages in tolerability over doxepin.

Do intramedullary rods of self-reinforced poly-L-lactide or poly-DL/L-lactide cause lactic acid acidosis in rabbits?

Intramedullary rods of self-reinforced poly-DL/L-lactic acid or poly-L-lactic acid were implanted in both femurs of ten rabbits for 60 weeks. Levels of arterial blood L- and D-lactate, pyruvate, pH, pCO2, base excess, standard bicarbonate, pO2 and O2-saturation were determined before implantation and 1, 3, 6, 12, 24, 36, 48 and 60 weeks after implantation. No significant increase in blood L- and D-lactate level was observed at any follow-up. Also, the blood acid-base balance remained normal throughout the study. Further studies on larger implants and on larger animals with follow-ups up to 5 years are recommended.

Enhanced cerebral substrate pools in the fetus and neonate of the diabetic canine mother.

Energy stores and intermediates of carbohydrate metabolism were investigated in the freeze-clamped cerebral cortex of the fetus and fasted neonate born to a diabetic canine mother. Prior studies in these same pups demonstrated circulating hyperinsulinemia, depressed free fatty acid levels, and attenuated gluconeogenesis. Hepatic and muscle tissue also demonstrated augmented levels of glycogen, triglycerides, and amino acids. In the present investigation, cerebral tissue from these same pups of diabetic mothers also demonstrated enhanced fetal cerebral glucose and glycogen content. After 24 h of neonatal fasting, cerebral glycogen content declined to values lower than in control pups. Cerebral cortical levels of glucose-6-phosphate, fructose-6-phosphate, lactate, citrate, alpha-ketoglutarate, and malate were not altered, while oxaloacetate was higher at 3 and 9 h and fructose-1,6-diphosphate was higher at 9 and 24 h in the IDM pups. Adenine nucleotide levels and the energy charge were equivalent to those in control pups at each time interval. In contrast, cerebral cortical amino acids of the glutamate group were enhanced in the fetus or neonate of the diabetic mother. Cerebral cortical alanine was increased from 3 to 24 h while aspartate and glutamate were augmented in the fetus and fasted IDM newborn pup. Glutamine was increased at 6 and 24 h, while gamma-aminobutyrate was elevated in the fetus. Cerebral ammonia concentration was not altered. The augmented stores of cerebral carbohydrate and amino acid pools in the fetus and neonate after maternal canine diabetes may serve as oxidizable substrates for the brain during periods of attenuated systemic fuel availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal and neonatal metabolism in the pup of a canine diabetic mother. Fasting circulating fuels and neonatal glucose turnover.

The metabolic effects of previously induced alloxan diabetes were investigated among fasted newborn dogs during the first day of life. Maternal insulin-dependent diabetes resulted in enhanced maternal and fetal blood glucose and ketone bodies, while postnatal levels of these substrates were not altered. Plasma insulin levels were augmented in the fetus and neonate (3 and 6 h of age) of the diabetic mother, while pancreatic insulin content was also enhanced at fetal and 3 h of age. Circulating free fatty acid levels were diminished among pups born to diabetic mothers (IDM pups) at 3 and 6 h of age, while glycerol levels were unaffected. Nevertheless, plasma triglyceride concentrations were elevated in pups of diabetic mothers during fetal and at 3 and 6 h of newborn fasting. Systemic glucose turnover was not altered in pups of diabetic mothers at 3, 9, or 24 h, while at 6 h, glucose turnover appeared enhanced in IDM pups, which was due in part to a decline of glucose production between 3 and 6 h among controls. Gluconeogenesis was attenuated at 9 h of age among IDM pups, but increased by 24 h of age. Hyperinsulinism in the presence of unaltered glucose turnover with attenuated free fatty acid levels suggest that neonatal canine glucose production from hepatic glycogen is less sensitive to insulin's effect than is the lipolysis-lipid reesterification cycle. Gluconeogenesis from lactate may be unnecessary if glycogenolysis is able to support systemic and hepatic substrate requirements, while insulin mediated lipid synthesis may augment tissue triglyceride deposits.

Potential role of galactokinase in neonatal carbohydrate assimilation.

Glucose given to the newborn human may result in hyperglycemia, suggesting that its utilization is impaired at this developmental stage. Galactose is thought to be a more appropriate carbohydrate source for the newborn. The enzymes involved in hexose phosphorylation may, in part, be responsible for these observations. A key regulatory enzyme of hepatic glucose assimilation, glucokinase, is diminished in newborns compared to adults, whereas galactokinase activity is increased. When newborn dogs were fasted and then fed either glucose or galactose, their plasma insulin responses to glucose were similar, but the pups fed galactose demonstrated an attenuated systemic appearance rate of glucose. Hexose incorporation into hepatic glycogen and net glycogen synthesis was augmented in the galactose-fed dogs. In vitro, liver from neonatal dogs showed enhanced galactokinase activity relative to that for hexokinase or glucokinase. Neonatal hexose assimilation may be independent of insulin action and, instead, be related to the developmental presence of hexose phosphorylating enzymes.

Hepatic and cerebral energy metabolism after neonatal canine alimentation.

Intrahepatic and intracerebral metabolic responses to neonatal fasting or enteric carbohydrate alimentation were investigated among newborn dogs. Pups were either fasted or given an intravenous glucose infusion (alimented) before an enteric feeding of physiologic quantities of either glucose or galactose. These pups were also compared to another group which was completely starved throughout the study period. Gastrointestinal carbohydrate feeding resulted in enhanced hepatic glycogen content among pups after a prior state of fasting. Though there were no differences of glycogen content between glucose or galactose feeding in this previously fasted group, combined intravenous glucose and enteric galactose administration produced the greatest effect on hepatic glycogen synthesis. Intrahepatic fructose 1, 6-diphosphate and phosphoenolpyruvate levels were increased among previously fasted pups fed enteric monosaccharides compared to completely starved control pups, whereas intrahepatic phosphoenolpyruvate and pyruvate levels were elevated after combined intravenous and enteric carbohydrate administration. Of greater interest was the observation that hepatic levels of ATP were significantly elevated among all groups given exogenous carbohydrates compared to the completely starved control group. In contrast to the augmented hepatic glycogen and ATP levels, there were no alterations of cerebral glycogen or ATP after alimentation. Nevertheless, cerebral pyruvate and/or phosphoenolpyruvate concentrations were elevated after enteric or combined intravenous and enteric alimentation compared to the totally starved control pups.

The effect of enteric galactose on neonatal canine carbohydrate metabolism.

Newborn pups were assigned to a fasting group or to a group receiving intravenous glucose alimentation. Glucose turnover was determined during steady state equilibration of simultaneously infused [6-3H] glucose. Thereafter, pups from each group received 0.625 g/Kg of either oral [U-14C] galactose or [U-14C] glucose. In fasted or intravenously alimented pups enteric glucose resulted in a rapid and sustained elevation of blood glucose concentrations. Systemic appearance of carbon-14 label from enteric glucose increased rapidly as did the enrichment of blood [14C] glucose specific activity. In those pups given enteric galactose, blood glucose values were equivalent to that in the glucose fed groups, however carbon-14 appearing in blood glucose and blood glucose specific activity was significantly lower. The peak values for rates of appearance and disappearance of systemic glucose were significantly lower in pups fed galactose than among pups fed glucose. Glucose clearance was also significantly lower in these pups despite equivalent plasma insulin responses. Among fasting pups hepatic glycogen content was significantly higher in those given either oral glucose or galactose when compared to a completely starved control group. In contrast, among alimented pups galactose administration significantly enhanced hepatic glycogen content compared to those fed glucose. Similarly, enteric substrate label incorporation into hepatic glycogen was enhanced in both groups given oral labeled galactose. In addition, hepatic glycogen synthase (glucose-6-phosphate independent) activity was increased only among alimented pups fed galactose when compared to completely fasted pups. In conclusion these data suggest that following gastrointestinal galactose administration, hepatic carbohydrate uptake is augmented while glycogen synthesis may be enhanced. Augmented glycogen synthesis following galactose administration may reflect alterations in hepatic glycogen synthase activity or enhanced hepatic carbohydrate uptake.

A rapid, simple, and sensitive procedure for the determination of free fatty acids in plasma using glass capillary column gas-liquid chromatography.

A rapid and sensitive method for the analysis of plasma free fatty acids with glass capillary column gas-liquid chromatography and flame ionization detection is described. The plasma sample, together with n-pentadecanoic acid as an internal standard, was treated with 2,2-dimethoxypropane and hydrochloric acid. 2,2-Dimethoxypropane serves as water scavenger, deproteinizing agent, and as a methylating agent. Under the assay conditions, only free fatty acids were converted to their methyl esters; esterified fatty acids, such as those in triglycerides and phospholipids, were not significantly transmethylated. This advantage eliminated the need for thin-layer chromatography for the separation of free and esterified fatty acids. The methyl esters of fatty acids were then extracted into isooctane and analyzed with a 10-meter glass capillary column coated with SP-2100. Splitless mode of injection was used to increase the sensitivity. Only 20 microliter or less of plasma was required for analysis. The coefficient of variation was 4.6%, which was better than the conventional gas-liquid chromatographic methods. These latter methods require 20 to 50 times larger samples, as compared with the present assay. This method is suitable for the measurement of both total free fatty acids and individual fatty acid patterns in small plasma samples.

Fetal and neonatal responses to maternal canine starvation: circulating fuels and neonatal glucose production.

Pregnant dogs were starved for 72 hr while controls were fasted overnight. Maternal starvation significantly reduced fetal birth weight (269 +/- 7.2 versus 294 +/- 4.4 g). Total caloric deprivation had no effect on maternal or fetal blood glucose concentration at the time of delivery; however, fasting neonatal blood glucose levels were depressed during the first 9 hr of life. Starvation produced a large elevation of maternal free fatty acids (1.68 +/- 0.39 versus 0.74 +/- 0.2 mM) and ketone bodies (2.99 +/- 0.70 versus 1.04 +/- 0.48). Although fetal free fatty acids increased minimally (0.39 +/- 0.03 versus 0.22 +/- 0.07), ketone body levels were markedly elevated (2.53 +/- 0.35 versus 1.01 +/- 0.32). After birth, plasma-free fatty acid and beta-hydroxybutyrate levels were lower in pups of starved mothers at 3 hr, and acetoacetate was lower at 6 and 9 hr. Other alternate fuels such as amino acids demonstrated lower levels of glutamine in pups of starved mothers throughout the day (except 3 hr), whereas alanine levels declined significantly only at 24 hr (114.9 +/- 15 versus 187.6 +/- 26 microM. Glucose production was significantly depressed in pups of starved mothers at 3 (13.7 +/- 1.4 versus 22.7 +/- 3) and 9 hr (17.5 +/- 2.2 versus 26.0 +/- 2.8 mumoles/kg/min), whereas glucose clearance rates were elevated at 3, 6 and 9 hr of age. Lactate carbon incorporation into glucose increased throughout the day but was not significantly affected by prior maternal starvation.

Fetal and neonatal cerebral metabolism following maternal canine starvation.

Pregnant dogs were starved for 72 hr before a term delivery. Maternal (1.68 +/- 0.39 versus 0.74 +/- 0.20 mM) and fetal (0.39 +/- 0.03 versus 0.22 +/- 0.07) circulating free fatty acids and maternal (2.99 +/- 0.79 versus 1.04 +/- 0.84) and fetal (2.53 +/- 0.35 versus 1.01 +/- 0.32) ketones were elevated whereas blood glucose values remained unchanged at the time of delivery. After birth, pups born to starved mothers had significantly lower blood glucose values during 3, 6, 9, and 24 hours of neonatal fasting. Intracerebral glucose concentrations paralleled those in the blood as they were depressed at 3, 6, and 9 hours of age. Cerebral glycogen content was lower in pups born to starved mothers at 6 (2.72 +/- 0.43 versus 4.32 +/- 0.56 mumoles/g) and 24 (2.31 +/- 0.17 versus 3.48 +/- 0.39 mumoles/g) hr, whereas UDP-glucose concentrations were significantly elevated in these pups during fetal, 3, 9, and 24 hr of age. Phosphoenolpyruvate was higher after maternal starvation in the fetus and at 6 and 9 hr, whereas cerebral pyruvate concentrations were elevated at 3, 6, and 9 hr of age. The elevation of pyruvate with no alteration of lactate concentration resulted in an elevated cytoplasmic NAD/NADH ratio at 3 hr of age (1381 +/- 194 versus 792 +/- 198). Cerebral alpha-ketoglutarate and calculated oxaloacetate concentrations were elevated throughout the day after maternal starvation whereas malate concentrations were depressed at 3 and 9 hr of age. Cerebral energy charge was unaffected, whereas the calculated energy reserve was lower at 3, 6, and 24 hours. Cerebral amino acids demonstrated elevated aspartate concentrations at 3 and 6 hr. Cerebral glutamine concentrations were lower during fetal stage (7.86 +/- 0.52 versus 10.01 +/- 0.41 mumoles/g) and 3, 6, and 9 hr of life.

Effect of maternal canine starvation on fetal and neonatal liver metabolism.

Heptic glycolytic and gluconeogenic intermediates from fasted newborns of five control and five 3-day starved canine mothers (MCS) were studied at 0, 3, 6, 9, and 24 h of age. MCS did not affect fetal hepatic glycogen concentration; however, a significant increase in uridine diphosphate glucose (UDPG) (0.186 vs. 0.106 mumol/g), fructose 6-phosphate (0.084 vs. 0.034), pyruvate (0.321 vs. 0.126), and citrate (0.190 vs. 0.140) concentrations occurred. At 3 h, the intrahepatic glucose concentration among the MCS newborns declined (3.09 vs. 6.34) and remained lower than the controls for up to 9 h. UDPG concentration, however, remained elevated throughout the 24 h. In addition intrahepatic pyruvate was significantly elevated in the MCS group. Elevated phosphoenolpyruvate concentrations were observed between 3 and 6 h. Malate levels were lower than controls between 6 and 9 h and alpha-ketoglutarate was significantly higher between 6 and 24 h. Calculated cytoplasmic NAD/NADH ratio was elevated throughout the 24 h. Hepatic triglycerides were higher than controls up to 9 h. A decline in hepatic triglycerides was observed between 9 and 24 h. The results suggest increased glycolysis and suppressed gluconeogenesis in the MCS puppies, probably because of increased triglyceride synthesis and decreased free fatty acid oxidation resulting in a lack of cytoplasmic NADH.

Substrate-turnover interrelationships in fasting neonatal dogs.

Substrate-turnover relationships were determined in unanesthetized healthy fasted neonatal dogs during the first day of life. Pups were born at term by cesarean section to starved or control mothers. Pups born to starved mothers developed significantly lower blood glucose concentrations during neonatal fasting. In all pups, blood glucose concentrations during neonatal fasting. In all pups, blood glucose concentrations correlated to glucose utilization (r = 0.462, P < 0.001). Blood lactate concentration was significantly related to its turnover. The relationship between lactate turnover and lactate carbon appearance into glucose was significantly correlated. However, the relationship between lactate concentration and its carbon incorporation into glucose was only significant at 24 h of age in pups born to starved mothers. These data suggest that the neonatal dog is capable of regulating its glucose and lactate utilization by the availability of substrate. Because peripheral insulin levels correlated poorly to fasting blood glucose and glucose turnover; it is doubtful whether insulin secretion plays a significant role in fasting neonatal canine glucose homeostasis.