Interspecies scaling: predicting oral clearance in humans.

The objective of this study was to test the interspecies scaling approach for a wide variety of drugs to predict oral clearance in humans from animal data. This study is an attempt to evaluate whether the rule of exponents of Mahmood and Balian for the prediction of systemic clearance can also be applied for the prediction of oral clearance in humans. Three different methods were used to generate log-log plots to scale up the clearance values: (1) clearance versus body weight (simple allometric equation), (2) the product of clearance and maximum life-span potential (MLP) versus body weight, and (3) the product of clearance and brain weight versus body weight. Data from 32 drugs were analyzed, and it was concluded that the oral clearance of drugs could be best predicted using one of the allometric equations.     

Misconceptions and issues regarding allometric scaling during the drug development process

Introduction: Allometry is the study of size and its consequences. The simple hypothesis of allometric scaling is that all physiological parameters are proportional to body size or body mass. This review examines the development of theory-based allometry or fixed exponents (0.75 and 1.0 for basal metabolic rate and volume, respectively) and the evidence for or against the theory. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the concept of theory-based allometry in biology, physiology, and pharmacokinetics.

Areas covered: In this review, the history of the development of theoretical allometry and the strong evidence against theory-based allometry demonstrated by experimental data is provided. During drug development, allometry is applied to both inter-species (from animals to humans) and intra-species (adults to children) scaling. These two forms of allometric scaling in the context of theory-based allometry are discussed and provide insight on scientific progress that refute theory-based allometry.

Expert opinion: Theory-based allometry is a mere theory and experimental data and real-life observations strongly negate the existence of such a theory. Pharmacostatistical and physiological models based on theory-based allometry can be misleading and incorrect because the theory-based allometric exponent 0.75 is not universal. The exponents of allometry are data dependent and are not fixed in the universe.     

Prediction of clearance in humans from in vitro human liver microsomes and allometric scaling. A comparative study of the two approaches

The objective of this study was to evaluate whether the predicted clearance of a drug in humans from in vitro human liver microsomes was comparable with the predicted clearance in humans obtained by allometric scaling. Sixteen drugs were randomly selected from the literature and their hepatic clearances were predicted using human liver microsomes. For allometric scaling at least three animal species were used and three methods were utilized to generate allometric equations to predict the clearance in humans: (i) clearance vs body weight (simple allometry); (ii) product of the clearance and maximum life-span potential (MLP) vs body weight; and (iii) the product of clearance and brain weight vs body weight. The choice of one of the methods was based on the 'rule of exponents' as described by Mahmood and Balian /2,3/. The results of this study indicated that the use of human liver microsomes to predict hepatic clearance in humans may not provide reliable predictions. On the other hand, the prediction of clearance in humans using allometric scaling combined with the 'rule of exponents' can provide comparatively better prediction of clearance in humans.     

Use of autologous cultured limbal and conjunctival epithelium in a patient with severe bilateral ocular surface disease induced by acid injury: a case report of unique application

PURPOSE: Reconstruction of the ocular surface in a case of severe bilateral partial limbal stem cell deficiency (LSCD) with extensive symblephara using autologous cultured conjunctival and limbal epithelium. CASE REPORT: A 31-year-old woman presented with severe bilateral ocular surface disease with partial limbal stem cell deficiency, symblephara, lid and facial scarring, with a vision of 20/400 and counting fingers at 1 m in both eyes. Limbal and conjunctival tissue was harvested from the healthy-appearing left eye and used to generate two sheets of composite epithelium consisting of central limbal and peripheral conjunctival cells. The limbal tissues were explanted in the central region while the conjunctival tissues were explanted on the periphery of the deepithelialized human amniotic membrane (HAM) and nurtured using human corneal epithelial cell medium. After successful generation of a monolayer from both tissues had been confirmed, the composite of cultivated limbal and conjunctival epithelium with HAM was transplanted in each eye after excision of fibrous tissue and release of symblephara. One year postoperatively, the patient had a best spectacle-corrected visual acuity of 20/40 in the right eye (preoperative acuity 20/400) and counting fingers at 1 m in the left eye (same as preoperative) with a stable ocular surface. CONCLUSIONS: Autologous cultured epithelial transplantation is as an excellent option in selected patients with bilateral partial LSCD with small area(s) of healthy limbus in either eye and avoids the attendant risk of rejection and cost and potential toxicity of immunosuppression in allogeneic tissue transplantation. This case also highlights the feasibility of generating a composite culture of limbal and conjunctival epithelium using a single amniotic membrane.     

Selection of the first-time dose in humans: comparison of different approaches based on interspecies scaling of clearance

The authors describe four approaches to selecting a safe starting dose for humans in clinical drug trials based on interspecies scaling of clearance. Human clearance was predicted by scaling for 10 example drugs for which animal clearance values were available in the literature. The predicted human clearance values were then used to select the estimated starting dose in humans. These doses were then compared with the actual doses given to humans during clinical trials. All four approaches used to estimate the first-time dose in humans provided values that were within the dose range given to humans from Phases I to III. This work demonstrates that animal pharmacokinetic data can be used to estimate a suitable human starting dose, provided the data have been obtained from a dose that produces no adverse effects.     

Association of HLA-DR5 with recurrent spontaneous abortion in women treated with paternal leukocytes. Possible subclinical autoimmune disease

The incidence of pregnancy loss is higher in patients with various autoimmune diseases than in the general population. The causes of recurrent spontaneous abortions (RSA) are unknown; however, the presence of antinuclear antibodies and other antibodies in some women with RSA who are otherwise healthy suggests the possibility of underlying autoimmune disease. Because autoimmune diseases are often associated with an increased incidence of certain histocompatibility antigens, we examined the occurrence of specific HLA antigens in patients who had been treated for RSA. We found HLA-DR5 to be significantly overrepresented in the patients with RSA who aborted again after treatment with paternal mononuclear cell immunotherapy, compared with the incidence of this phenotype in a control population. Neither antinuclear antibodies nor antilymphocyte antibodies segregated with DR5. However, DR5+ patients who developed antilymphocyte antibodies after immunotherapy were more likely than all other treated patients to experience subsequent abortion (P less than 0.01). Our findings suggest the possibility of an underlying autoimmune disease in these women.     

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N₁–C₅-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis.