Persistence of lactase activity among Northern Europeans: A weighing of evidence for the calcium absorption hypothesis

Considered in this paper is a broad range of evidence bearing on the calcium absorption hypothesis that has been advanced to explain high frequencies of the gene for persistence of lactase activity (PLA) among adults in northern Europe. According to that hypothesis, lactase‐sufficient individuals in early northern Europe enjoyed a selective advantage over lactase‐deficient ones that led to high incidences of PLA in adults of the region. Northern Europeans, the hypothesis goes, suffered from a dietary shortage of vitamin D and, in addition, were unable to synthesize adequate vitamin D from the sun's ultraviolet radiation because of northern Europe's cloudiness and its location in higher latitudes. This led to chronic vitamin D deficiency along with a reduced ability to absorb calcium from milk and lactose‐rich dairy products. As a result, the deficiency diseases rickets—which affects infants and children and can leave a child with bowlegs and other bone defects—and osteomalacia—which weakens and deforms the bones of adults—were common in early northern Europe, and represented powerful selective forces that contributed to development of the highly depigmented skin that is typical of the region's peoples. In addition, the hypothesis goes, calcium absorption was enhanced by a process independent of vitamin D. Such enhancement, found especially or solely among lactase‐sufficient individuals, was brought on by ingestion of lactose in milk and milk products. Thus, persons who enjoyed high lactase activity through life were favored in the struggle for survival, which ultimately led northern European peoples to have among the highest incidences of PLA in the world.

In this article, evidence, much of it recent, is presented to show that lactase‐deficient humans are able to absorb calcium from milk as readily, or nearly as readily, as lactase‐sufficient humans. Evidence is also presented that rickets and osteomalacia occur in parts of the world that have an abundance of sunshine, whether originating from customs that limit exposure to sunshine or otherwise; that heavy cloud cover and high latitude need not result in vitamin D deficiency, rickets, and osteomalacia; that, indeed, osteological evidence from archeological sites in northern Europe indicates that rickets and osteomalacia were quite rare in antiquity; that those conditions appear to have become common in northern Europe only with the advent of the Industrial Revolution, too short a time to have been a significant factor in bringing on the high incidences of PLA that prevail today; and that, indeed, the calcium absorption hypothesis is not confirmed by historical, osteoarcheological, or bio‐medical evidence.     

Mucus as a barrier to lipophilic drugs

Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once secreted, mucin forms a barrier to protect the underlying tissues against the extracellular environment. Mucus can therefore adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. Solubility and lipophilicity are key factors determining drug absorption, as a drug has to be soluble in the body fluids at the site of absorption and must also possess enough lipophilicity to permeate the biological membrane. Evidence has accumulated over the past 40 years indicating that poorly soluble drugs will interact with mucus glycoprotein. Studies of the permeability of native or purified mucous gels are important when it comes to understanding the relative importance of hindered diffusion versus drug binding in mucous layers. This review highlights the current understanding of the drug–mucin interaction and also examines briefly the interaction of polymers and particles with the mucus matrix. While the concept of mucoadhesion was thought to provide an intensified and prolonged contact to mucosal absorption sites, mucopenetrating properties are nowadays being discussed for (nano)particulate carriers to overcome the mucus as a barrier and enhance drug delivery through mucus.     

Development of Conductive Boron-Doped Diamond Electrode: A microscopic,Spectroscopic, and Voltammetric Study

Building on diamond characteristics such as hardness, chemical inertness and low electron emission threshold voltage, the current microscopic, spectroscopic and voltammetric investigations are directed towards improving the properties of electrode coating materials for their future use in clinical studies of deep brain stimulation via fast-scan cyclic voltammetry (FSCV). In this study we combine the capabilities of confocal Raman mapping in providing detailed and accurate analysis of local distributions of material constituents in a series of boron-doped polycrystalline diamond films grown by chemical vapor deposition, with information from the more conventional techniques of scanning electron microscopy (SEM) and infrared absorption spectroscopy. Although SEM images show a uniform distribution of film crystallites, they have the limitation of being unable to differentiate the distribution of boron in the diamond. Values of 10¹⁸–10²¹ atoms/cm³ of boron content have been estimated from the absorption coefficient of the 1290 cm⁻¹ infrared absorption band and from the 500 cm⁻¹ Raman vibration. The observed accumulation of boron atoms and carbon sp² impurities at the grain boundaries suggests that very high doping levels do not necessarily contribute to improvement of the material’s conductivity, corroborating with voltammetric data. FSCV results also indicate an enhanced stability of analyte detection.     

火焰原子吸收光谱法测定柏树叶中Zn Mn的含量

目的:测定柏树叶中Zn、Mn元素的含量。方法:HNO3∶HClO4(4+1)分解样品,火焰原子吸收光谱法测定柏树叶中微量元素Zn、Mn的含量。结果:柏树叶中含有丰富的微量元素Zn、Mn,含量分别为37.25μg/g,21.75μg/g,RSD<2.2%,加标回收率88.90%～108.00%。结论:柏树叶中含有丰富的微量元素且Zn的含量大于Mn。     

Lipid and lipoprotein changes after long-term weight reduction: the influence of gender and body fat distribution.

This study was designed: 1) to evaluate the effect of weight loss on body fat distribution, 2) to determine whether indices of body fat distribution can be considered as a prognostic indicator for the ability to lose weight and 3) to evaluate whether a change of body fat distribution is associated with changes in plasma glucose, lipids and lipoproteins in both sexes in order to evaluate a gender difference.

63 obese subjects (41 women and 22 men) were treated on an outpatient basis with an energy-reduced, protein-enriched low calorie diet (3150-4200 kJ/day) for a 6-month period. They were divided in different groups according to gender and body fat distribution using the waist-to-hip circumference ratio.

Body fat topography can be altered by dieting, but not by more than it increases when a person gains weight. Body fat distribution seems to be a significant prognostic indicator for the ability to lose weight in women but not in men. Although body weight and the waist-to-hip circumference decreased significantly, no relationships were found between percent decrease in these parameters and percent changes in plasma glucose, lipids and lipoproteins.

We conclude that an important caloric deficit may lead to a series of metabolic improvements but that gender and the type of fat distribution are important confounding factors in the prediction of metabolic success.     

Progress in absorption enhancers based on tight junction

Absorption enhancers have been investigated since the 1960s, in order to assist the transfer of drugs across the paracellular space in the intestinal epithelium. However, few absorption enhancers are presently used clinically, due to the difficulty of developing enhancers with high specificity and low toxicity. Using high-throughput genomic techniques, new drug candidates such as, non-Lipinski molecules, peptides, antibodies and nucleic acids, are being discovered, so the need for oral drug delivery strategies using absorption enhancers is gaining importance. The key to addressing this issue is to understand the molecular mechanism of the paracellular route in epithelial cell sheets. Towards this end, basic research in cell biology has revealed the components that regulate the paracellular route, and how the transport of substances is regulated. Based on these findings, novel strategies for enhancing drug absorption have been proposed. In this article, the authors first survey the development of absorption enhancers, then outline recent progress in the cell biology of tight junctions, and finally discuss novel approaches for absorption enhancers based on these advances.     

Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET™

One of the most important and challenging goals in drug delivery is overcoming the poor oral absorption of high-value therapeutics that include peptides. Gastrointestinal Permeation Enhancement Technology (GIPET?) attempts to address this question by safely delivering drugs across the small intestine in therapeutically relevant concentrations. GIPET is based primarily on promoting drug absorption through the use of medium-chain fatty acids, medium-chain fatty acid derivatives and microemulsion systems based on medium-chain fatty acid glycerides formulated in enteric-coated tablets or capsules. Importantly, these excipients are generally regarded as safe and the systems are formulated in such a way that there is no change in chemical composition of the active ingredient. More than 300 volunteers have been administered GIPET formulations in 16 Phase I studies of 6 separate drugs comprising both single- and repeat-dosing regimes. Oral bioavailability of alendronate, desmopressin and low-molecular-weight heparin in humans was increased using GIPET formulations compared with unformulated controls. GIPET was well tolerated by human subjects. Using fluxes of markers of epithelial permeability, the effects of GIPET on the human intestine were shown to be rapid, short-lived and reversible in vivo. These data suggest that GIPET formulations have genuine potential as a platform technology for safe and effective oral drug delivery of a wide range of poorly permeable drugs.     

Idiopathic Bile Acid Diarrhoea Reconsidered

Two new cases of a rare entity provisionally coined ‘idiopathic bile acid diarrhoea’ are reported and compared with previous cases. The diarrhoeal syndrome has been identified as a cholegenic enteropathy. In the absence of conventional ileopathy the cause of the bile acid loss is obscure, but it is hypothesized that it may be due to a relative deficiency in ileal absorptive sites for bile acid anions. So far the diagnosis has partly been based on measurements of faecal bile acid losses. It is suggested that a carefully conducted therapeutic trial with cholestyramine may be almost equally helpful.     

Passive absorption of fentanyl from the fentanyl HCl iontophoretic transdermal system

ABSTRACT

Background: The fentanyl HCl iontophoretic transdermal system (ITS) is a patient-controlled analgesic delivery system that actively administers bolus doses of fentanyl transdermally upon patient activation.

Objective: To determine the amount of fentanyl absorbed from fentanyl ITS via passive absorption over a 24.5-h period.

Methods: Serial blood samples for pharmacokinetic analyses were obtained from healthy adults who received fentanyl ITS for 24?h.

?Findings: The average absorption rate was 2.3?µg/h. An average total of 57.4?µg fentanyl was absorbed during the study. The mean maximum observed serum fentanyl concentration was 0.06?ng/mL.

Conclusions: Results indicate that the average amount of fentanyl absorbed passively or via passive delivery from fentanyl ITS is minimal. Maximum serum fentanyl concentrations fell below the range associated with analgesia and respiratory depression. The variability in fentanyl exposure was likely exaggerated by the low amounts of drug absorption resulting in overall fairly low fentanyl concentrations.     

Physiological conditions controlling the activity of an orally administered parasympatholytic drug: Hyoscine-N-butylbromide

Summary

The author reviews the experimental evidence relating to the activity of orally administered parasympatholytic drugs and comments that the effectiveness, especially of those with spasmolytic activity, can only be judged if allowance is made for the physiological and pharmacodynamic conditions at the target site.

Using hyoscine-N-butylbromide as an example it has been shown that, apart from a local effect on the gut wall, therapeutic effects on muscular organs are possible and even at very low blood levels, below the limit of detection in the systemic circulation, if the site of action has a special affinity for the drug. The absence of anticholinergic side-effects and low rates of absorption into the blood cannot disprove the effects of drugs which are accumulated at the site of action. The combination of specific binding capacity and reactivity of the smooth musculature to hyoscine-N-butylbromide is to be regarded as the optimum condition for a specific therapeutic action. Opposite conclusions are drawn whenever either the experimental design fails to take account of the muscular activity or when the absorption rate is overestimated and, simultaneously, the accumulation of the drug in the target organ is not considered