Metformin lowers blood glucose and glycosylated hemoglobin significantly, compared with placebo. Metformin and sulfonylurea have an equal effect on fasting blood glucose and glycosylated hemoglobin, but the body weight is significantly lower after metformin compared with sulfonylurea treatment because of an increase in body weight after sulfonylurea treatment.

Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

Protamine sulphate is an effective inhibitor of heparin and is used clinically to neutralise both low molecular weight heparins (LMWH) and unfractionated heparin (UFH). However, protamine sulphate does not fully counter the anti-Xa effect of LMWH, even in excess (>40 μg to 1 IU/ml). To investigate the molecular basis for this observation, the residual potencies in the presence and absence of plasma as well as the molecular weight profiles of commercial LMWH neutralised with increasing amounts of protamine were measured. Materials over 5000 Da are preferentially neutralised by protamine. To further investigate this molecular weight dependence, monodisperse oligosaccharides were prepared from three commercial LMWHs. The specific anti-Xa activity for the fractions increased with molecular weight, and was found to vary between the three preparations for oligosaccharides of the same molecular weight. Our results indicate that protamine sulphate neutralisation is largely dependent on molecular weight, leading to the implication that LMWHs containing a larger proportion of small oligosaccharides will not be as effectively neutralised. Protamine sulphate neutralisation of any given LMWH is also affected by the specific anticoagulant activities of its low molecular weight components, which varies between LMWH products, presumably with the method of manufacture.

The fatty acid composition of microsamples from 10 AGA term, 8 SGA term, 7 AGA preterm and 4 SGA preterm, 2-4 day old infants and their mothers were analyzed. In AGA preterm newborns the mean percent of palmitic and stearic acid was lower and the mean percent of linoleic acid was higher than in AGA term infants indicating that there is an increase in fatty acids derived by synthesis from glucose throughout gestation. SGA infants had relative amounts of palmitic and stearic acid similar to what was found in AGA term infants. This indicates that the enzymes involved in synthesis of fatty acids from glucose are intact in intrauterine growth retardation (IUGR). The absolute amount of adipose tissue and fatty acids, however, is smaller in SGA infants due to a reduced availability of glucose in IUGR gestation. No differences were found in the fatty acid composition of subcutaneous adipose tissue from the mothers in the 4 groups. All mothers had a lower mean percent of palmitic and stearic acid and a higher mean percent of oleic and linoleic acid than their infants, ensuring a transplacental gradient to the fetus of this latter essential fatty acid. The fatty acid composition of plasma free fatty acids generally reflected the composition of the subcutaneous adipose tissue in the infants.

Low density lipoprotein (LDL) receptor activity was measured in lymphocytes from pre-term and term infants in order to elucidate if the hypercholesterolemia found in pre-term infants might be secondary to a block in cholesterol transport across the cell membrane, analogous to that seen in familial hypercholesterolemia (FH). LDL receptor activity was found to be fully developed in pre-term infants and no different from that of term infants and of a normal adult control.

The fatty acid composition of the major plasma lipids and blood lymphocyte phospholipids was studied in four patients before and after 1 month of parenteral nutrition including 2 to 3 g/kg/day of Intralipid fat and in four matched controls before and after 1 month of breast-feeding. After treatment with Intralipid the concentration of polyunsaturated fatty acids including linoleic acid increased in all plasma lipids. The total concentration of polyunsaturated fatty acids in lymphocyte phospholipids did not change. The increase of linoleic acid and decrease of arachidonic acid in lymphocyte phospholipids were not statistically significant. In control infants the concentration of polyunsaturated fatty acids including linoleic and arachidonic acid in lymphocyte phospholipids increased after 1 month of breast-feeding to almost the same values as in the patients. The study indicates that at least in lymphocytes the incorporation of polyunsaturated fatty acids is actively regulated. The present way of administering Intralipid does not seem to cause any abnormal fatty acid pattern of the plasma and lymphocyte lipids. The use of intravenous fat emulsion with high content of linoleic acid in term newborns should thus not be expected to result in changes of the physical-chemical properties of membranes and membrane dysfunction.

The biochemical effect of vitamin E supplementation to mothers with threatened premature delivery and to premature infants after birth has been studied. Although a weak correlation was found between maternal and cord blood vitamin E levels at birth, cord blood levels were not significantly higher in the infants from supplemented mothers than those from unsupplemented mothers. Furthermore, maternal vitamin E treatment did not prevent either erythrocyte hemolysis or lipid peroxide formation in the premature infants after birth. On the other hand, intramuscular vitamin E to infants after birth produced a marked biochemical effect, with both zero erythrocyte hemolysis and low lipid peroxide formation when serum vitamin E increased above 2 mg/100 ml. We conclude that intramuscular vitamin E immediately after birth is necessary to achieve a biochemical effect of vitamin E in the early neonatal period. (No cases of retrolental fibroplasia occurred in the present study.)