Simultaneous Quantification of 3'- and 6'-Sialyllactose in Rat Plasma Using Liquid Chromatography-Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Study.

Sialyllactose (SL), an acidic oligosaccharide, has immune-protective effects against pathogens and helps with the development of the immune system and intestinal microorganisms. To elucidate the pharmacokinetic characterization after oral administration to rats, the simultaneous quantification method for 3'-SL and 6'-SL in rat plasma was validated, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in an electrospray ionization (ESI) mode. Several types of columns [C18, amide, and hydrophilic interaction liquid chromatography (HILIC) phase] were used to separate the peaks of 3'-SL and 6'-SL, which improved chromatographic selectivity. Ultimately, the HILIC phase column had a good peak shape and quick resolution, with a mobile phase comprising ammonium acetate buffer and acetonitrile obtained by gradient elution. In addition, the simultaneous quantification of 3'-SL and 6'-SL in rat plasma samples were adequately applied to pharmacokinetic study.

Lactose monohydrate flow characterization using shear cell method.

The flow properties of pharmaceutical powders have a great importance in the manufacturing of solid dosage forms. In order to ensure the performance in the production line this parameter must be determined. There are several methods described in European Pharmacopeia that are used to measure these properties. Some of them were used in this study and the results obtained from conventional methods (Conv) and shear cell using the powder flow tester (PFT) showed differences that were more evident in fractions with smaller particle size (F < 63) and for bulk powder (FTotal). The various powder behaviors showed to be related with the size of the particles. An increase of the ffc (Flow Index) was observed with the increase of the particle size. It was also found for the different fractions that the ffc always increases with increasing major principal consolidation stress (σ1). This study shown to be predictive because it also allowed the behavior profiles of other LactMN fractions to be known by interpolation of the median size (Dv50) or σ1 values ranged between the studied intervals. Furthermore, it was also observed that ffc of the FTotal was similar to the F < 63, showing the same behavior under σ1. The occurrence of caking was not observed.

Spray-Dried PulmoSphere™ Formulations for Inhalation Comprising Crystalline Drug Particles.

Over the past 20 years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100 ng to 100 mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their in vitro drug release.

Drug release from hydroxypropyl methylcellulose (HPMC) hydrophilic matrix tablets is controlled by drug diffusion through the gel layer of the matrix-forming polymer upon hydration, matrix erosion or combination of diffusion and erosion mechanisms. In this study, the relationship between viscoelastic properties of the gel layer of swollen intact matrix tablets and drug release was investigated. Two sets of quetiapine fumarate (QF) matrix tablets were prepared using the high viscosity grade HPMC K4M at low (70 mg/tablet) and high (170 mg/tablet) polymer concentrations. Viscoelastic studies using a controlled stress rheometer were performed on swollen matrices following hydration in the dissolution medium for predetermined time intervals. The gel layer of swollen tablets exhibited predominantly elastic behavior. Results from the in vitro release study showed that drug release was strongly influenced by the viscoelastic properties of the gel layer of K4M tablets, which was further corroborated by results from water uptake studies conducted on intact tablets. The results provide evidence that the viscoelastic properties of the gel layer can be exploited to guide the selection of an appropriate matrix-forming polymer, to better understand the rate of drug release from matrix tablets in vitro and to develop hydrophilic controlled-release formulations.

Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure.

OBJECTIVE: To test the hypothesis that feeding and antibiotic exposures affect intestinal barrier maturation in preterm infants, we serially measured intestinal permeability (IP) biomarkers in infants <33 weeks gestation (gestational age [GA]) during the first 2 weeks of life. STUDY DESIGN: Eligible infants <33 weeks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the nonmetabolized sugars lactulose/rhamnose enterally on study days 1, 8, and 15 and lactulose/rhamnose were measured in urine by high-performance liquid chromatography. Serum zonulin and fecal alpha-1-anti-trypsin, 2 other IP markers, were measured by semiquantitative Western blot and ELISA, respectively. RESULTS: In a cohort of 43 subjects, the lactulose/rhamnose ratio was increased on day 1 and decreased over 2 weeks, but remained higher in infants born at ≤28 weeks of gestation compared with IP in infants born at >28 weeks of gestation. Exclusive breastmilk feeding was associated with more rapid maturation in intestinal barrier function. A cluster analysis of 35 subjects who had urine samples from all time points revealed 3 IP patterns (cluster 1, normal maturation: n = 20 [57%]); cluster 2, decreased IP during the first week and subsequent substantial increase: n = 5 [14%]); and cluster 3, delayed maturation: n = 10 [29%]). There were trends toward more prolonged antibiotic exposure (P = .092) and delayed initiation of feeding ≥4 days (P = .064) in infants with abnormal IP patterns. CONCLUSIONS: Intestinal barrier maturation in preterm infants is GA and postnatal age dependent, and is influenced by feeding with a maturational effect of breastmilk feeding and possibly by antibiotic exposures. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01756040.

Major human milk oligosaccharides are absorbed into the systemic circulation after oral administration in rats.

Human milk oligosaccharides (HMO) are involved in many biological functions influencing infant health. Although HMO act locally at the intestine, recent evidence has demonstrated that HMO are partially incorporated into the systemic circulation of breast-fed infants. In the last few years, a large amount of research has been conducted using preclinical models to uncover new biological functions of HMO. The aim of this study was to evaluate the absorption and urine excretion of HMO in rats. We administered a single oral dose of the following HMO: 2'-fucosyllactose (2'-FL), 6'-sialyllactose and lacto-N-neotetraose at different concentrations to adult rats. The time course of absorption of HMO into the bloodstream and their appearance in urine was studied. Our results showed that rats, similar to human infants, are able to effectively absorb a portion of HMO from the intestine into plasma and to excrete them in urine. On the basis of this, we also conducted a specific kinetic absorption study with 2'-FL, the most predominant HMO in human milk, in 9-11-d-old rat pups. Our results confirmed that a significant amount of 2'-FL was absorbed into the systemic circulation and subsequently excreted in urine during lactation in rats in a dose-depended manner. We also found basal levels of these HMO in plasma and urine of adult rats as well as rat pups as a natural result of nursing. Our data suggest that the rat may be a useful preclinical model that provides new insights into the metabolism and functions of HMO.

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles.

PURPOSE: This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations. METHODS: Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (Ra) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor. RESULTS: Fluid-bed processing resulted in a modest increase in the Ra from 562 to 907 nm while roller compaction led to significant increases in Ra > 1300 nm. The roller compacted carriers exhibited FPF > 35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60-200% whereas only < 30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air. CONCLUSIONS: The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice.

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6'-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6'-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6'-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6'-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6'-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6'-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.

The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets.

The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5-4 mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45-125 µm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125-355 µm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125-355 µm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.

Delivery of a lactose derivative of endomorphin 1 to the brain via the olfactory epithelial pathway.

The rapid and direct delivery of a neuroactive endomorphin 1 derivative to the brain via nasal delivery is reported. A synthetic derivative of the native opioid peptide, endomorphin 1 bearing a lactose unit on the N-terminus of the peptide has been previously reported to exhibit antinoceceptive activity similar to morphine after both intravenous and oral administration. This compound has been administered nasally to rats and appeared in the olfactory bulb within 10 min of administration with negligible levels appearing in the circulating blood or in the rest of the brain. These results indicate that the peptide is absorbed into the brain via the olfactory epithelial pathway suggesting nasal delivery may be a viable alternative route of delivery in clinical applications.

Further constituents of Galianthe thalictroides (Rubiaceae) and inhibition of DNA topoisomerases I and IIα by its cytotoxic ß-carboline alkaloids.

A new cytotoxic ß-carboline alkaloid, 1-methyl-3-(2-hydroxypropan-2-yl)-2-(5-methoxy-9H-ß-carbolin-1-yl)-cyclopentanol (1), was isolated from roots of Galianthe thalictroides, together with the alkaloid 1-(hydroxymethyl)-3-(2-hydroxypropan-2-yl)-2-(5-methoxy-9H-ß-carbolin-1-yl)-cyclopentanol (2), the anthraquinones 1-methyl-alizarin and morindaparvin-A, the coumarin scopoletin, homovanillic alcohol, (-)-epicatechin, and the steroids stigmast-4-en-3-one, 4,22-stigmastadien-3-one, campest-4-en-3-one, stigmast-4-en-3,6-dione, 6-ß-hydroxy-stigmast-4-en-3-one, stigmasterol, campesterol, ß-sitosterol, and ß-sitosterol-3-O-ß-D-glucopyranoside. Among the previously known compounds, homovanillic alcohol is a novel finding in Rubiaceae, while 1-methyl-alizarin, morindaparvin-A, scopoletin, stigmast-4-en-3-one, 4,22-stigmastadien-3-one, campest-4-en-3-one, stigmast-4-en-3,6-dione, and 6-ß-hydroxy-stigmast-4-en-3-one is reported for the first time in the genus Galianthe. The cytotoxic ß-carboline alkaloids 1 and 2 exhibited potent antitopoisomerase I and IIα activities and strong evidence is provided for their action as topoisomerase IIα poisons and redox-independent inhibitors.

Carbohydrate-conjugated porphyrin dimers: synthesis and photobiological evaluation for a potential application in one-photon and two-photon photodynamic therapy.

We report the synthesis of bioconjugated zinc porphyrin dimers 1a-e designed as photosensitizers for one-photon and two-photon excited photodynamic therapy. These macrocycles are substituted with carbohydrate units (glucose, mannose, lactose) in order to target tumor cells over-expressing lectin membrane receptors. Polarity, singlet oxygen production and in vitro photocytotoxicity are studied to determine their photodynamic therapy potentiality.

Semiquantitative assessment of breath hydrogen testing.

BACKGROUND AND AIM: A major use of breath hydrogen testing is to assess absorptive capacity for sugars to assist dietary design for management of gut symptoms. Qualitative reporting takes no account of the vigor of hydrogen response and provides little insight into degrees of malabsorption. This study aimed to describe a semiquantitative reporting method and to compare results with those reported qualitatively. METHODS: In consecutive Caucasian patients with Crohn's disease (n = 87), ulcerative colitis (59), functional gastrointestinal disorders (FGID) (162), and healthy controls (76), area under the curve was calculated for lactulose (15 g). This was compared with that for lactose (50 g) and fructose (35 g). Degree of malabsorption was categorized into arbitrary groups. RESULTS: Semiquantitative results for ≥ 30% (designated "convincing") malabsorption was most similar to those using a qualitative cutoff value of 20 ppm, but in 38% and 21% of patients, the classification of malabsorption (nil or clinically significant) changed for fructose and lactose, respectively. Using a cutoff of 10 ppm, 49% and 5% were classified differently. Crohn's disease had a higher prevalence (42%) of convincing fructose malabsorption than controls (24%) or patients with FGID (33%) (P < 0.02). Highest prevalence of convincing lactose malabsorption (38%) was in ulcerative colitis, greater than controls (18%) and FGID (18%) (P < 0.02). CONCLUSIONS: Semiquantitative assessment provides different results with different clinical implications in more than one third of patients, but disease-related alterations in prevalence are similar to those defined qualitatively. This method may be preferable because it lessens the confounding influence of the vigor of the hydrogen response.

The low FODMAP diet improves gastrointestinal symptoms in patients with irritable bowel syndrome: a prospective study.

BACKGROUND AND AIM: Current treatment for irritable bowel syndrome (IBS) is suboptimal. Fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may trigger gastrointestinal symptoms in IBS patients. Our aim was to determine whether a low FODMAP diet improves symptoms in IBS patients. METHODS: Irritable bowel syndrome patients, who had performed hydrogen/methane breath testing for fructose and lactose malabsorption and had received dietary advice regarding the low FODMAP diet, were included. The effect of low FODMAP diet was prospectively evaluated using a symptom questionnaire. Furthermore, questions about adherence and satisfaction with symptom improvement, dietary advice and diet were assessed. RESULTS: Ninety patients with a mean follow up of 15.7 months were studied. Most symptoms including abdominal pain, bloating, flatulence and diarrhoea significantly improved (p < 0.001 for all). 75.6%, 37.8% and 13.3% of patients had fructose, lactose malabsorption or small intestinal bacterial overgrowth respectively. Fructose malabsorption was significantly associated with symptom improvement (abdominal pain odds ratio (OR) 7.09 [95% confidence interval (CI) 2.01-25.0], bloating OR 8.71 (95% CI 2.76-27.5), flatulence OR 7.64 (95% CI 2.53-23.0) and diarrhoea OR 3.39 (95% CI 1.17-9.78), p < 0.029 for all). Most patients (75.6%) were adherent to the diet, which was associated with symptom improvement (abdominal pain, bloating, flatulence and diarrhoea all significantly associated with adherence, r > 0.27, p < 0.011). Most patients (72.1%) were satisfied with their symptoms. CONCLUSIONS: The low FODMAP diet shows efficacy for IBS patients. The current strategy of breath testing and dietary advice provides a good basis to understand and adhere to the diet.

Lactose, Maltose, and Sucrose in Health and Disease.

SCOPE: This review represents a focus on the structure and properties of the common nutritional disaccharides (lactose, maltose, and sucrose) in health and disease. The aim is to provide a comprehensive reference source related to the role of disaccharides in human nutrition. METHODS AND RESULTS: Key reference sources are searched, including Web of Science, PubMed, Science Direct, and Wiley Online, and key reference works are selected to support the factual basis of the text where interpretations and relevance of the works are discussed in the review. There are key nutritional health benefits of receiving dietary energy in the form of sugars, but equally life-threatening issues exist associated with constant/excess consumption. These issues are discussed together with genetic disorders, which impact upon health associated with consumption of the disaccharides (e.g., specific disaccharide intolerance due to deficiency of relevant digestive enzymes). CONCLUSIONS: As the three common dietary disaccharides (lactose, maltose, and sucrose) are consumed on a very regular basis in the human diet, it is critical to understand insofar as possible their role in health and disease. This review provides an insight into the structure and properties of these molecules in health and disease.

Development of M10, myricetin-3-O-ß-d-lactose sodium salt, a derivative of myricetin as a potent agent of anti-chronic colonic inflammation.

Myricetin is a natural dietary flavonoid compound with multiple activities, such as anti-oxidant, anti-inflammatory, anti-carcinogenic and anti-proliferative effects. However, myricetin exhibited substantial limitations, such as poor water-solubility, and low stability in body when it was administrated by oral. To solve these problems, we designed and synthesized a series of derivatives based on the structure of myricetin. M10 was produced by adding a hydrophilic glycosylation group and then forming a sodium salt derivative, which exhibited excellent water-solubility (>100 mg/mL), and better stability in Wistar rat plasma and liver microsomes. In vivo study, M10 exhibited higher efficacy than myricetin and mesalazine in a dextran sulfate sodium (DSS) induced mice model with ulcerative colitis. In addition, M10 also exhibited high safety (LD50 > 5 g/kg) in mice. Based on these results, M10 could be developed as a potential therapeutic agent for treatment of ulcerative colitis.

Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems.

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Cellobiose is extensively digested in the small intestine by beta-galactosidase in rats.

OBJECTIVE: The bioavailability of cellobiose (CEB) was investigated with respect to small intestinal digestibility and cecal fermentation in rats. Further, whether small intestinal beta-galactosidase is responsible for the hydrolysis of CEB was examined. METHODS: Ileorectostomized rats were fed diets including 6% CEB or fructo-oligosaccharide with or without 0.1% neomycin in drinking water for 7 d. The fecal excretion of the respective oligosaccharides was determined. In vitro digestion of CEB and lactose was characterized using mucosal enzymes of the small intestine from suckling and adult rats. Cecal fermentation in normal rats fed a control diet or a diet including 3% or 6% CEB for 14 d was examined. RESULTS: The small intestinal digestibility of CEB was 64%, irrespective of the presence of neomycin in drinking water, whereas the digestibility of fructo-oligosaccharide differed significantly between groups administered (26%) or not administered (35%) neomycin. The in vitro digestibility of lactose (62%) and CEB (36%) was three times greater with the enzymes from the suckling rats than with those from the adult rats. Michaelis constant (K(m)) and maximum velocity (V(max)) values for CEB were 25 and 7 times lower, respectively, than those for lactose. Normal rats fed the 6% CEB diet showed a greater cecal organic acid than those fed the control diet, but no differences were observed between those fed the control and 3% CEB diets. CONCLUSION: Our results indicate that dietary CEB was extensively digested in the small intestine by beta-galactosidase in rats, leading to complete digestion of CEB when dietary supplementation was limited.

Hydrogen breath test for the diagnosis of lactose intolerance, is the routine sugar load the best one?

AIM: To evaluate the prevalence of lactose intolerance (LI) following a load of 12.5 g in patients diagnosed as high-grade malabsorbers using the hydrogen breath test (HBT)-25. METHODS: Ninety patients showing high-grade malabsorption at HBT-25 were submitted to a second HBT with a lactose load of 12.5 g. Peak hydrogen production, area under the curve of hydrogen excretion and occurrence of symptoms were recorded. RESULTS: Only 16 patients (17.77%) with positive HBT-25 proved positive at HBT-12.5. Hydrogen production was lower as compared to HBT-25 (peak value 21.55 parts per million (ppm) +/- 29.54 SD vs 99.43 ppm +/- 40.01 SD; P < 0.001). Symptoms were present in only 13 patients. The absence of symptoms during the high-dose test has a high negative predictive value (0.84) for a negative low-dose test. The presence of symptoms during the first test was not useful for predicting a positive low-dose test (positive predictive value 0.06-0.31). CONCLUSION: Most patients with a positive HBT-25 normally absorb a lower dose of lactose and a strict lactose restriction on the basis of a "standard" HBT is, in most instances, unnecessary. Thus, the 25 g lactose tolerance test should probably be substituted by the 12.5 g test in the diagnosis of LI, and in providing dietary guidelines to patients with suspected lactose malabsorption/intolerance.

Studies on effects of lactose on experimental Trypanosoma vivax infection in Zebu cattle. 1. Plasma kinetics of intravenously administered lactose at onset of infection and pathology.

Lactose in normal saline was administered intravenously to a group of Zebu cattle infected with Trypanosoma vivax to determine the blood plasma kinetics at onset of an experimental infection and its ability to protect tissues against damage as part of preliminary studies to determine its suitability for use in the treatment of trypanosomosis. Significantly (P < 0.01) higher lactose concentrations were observed in the T. vivax-infected bulls at 30 min and 1 h (P < 0.05) post-infection (p.i.) and by 4 h p.i. the plasma lactose remained above the level prior to infusion, after which it fell slightly below the pre-infusion level in the uninfected group. Calculated pharmacokinetic parameters revealed delayed excretion of lactose in the T. vivax-infected group soon after infection. The total body clearance (Cl(B)) was significantly (P < 0.05) reduced. The biological half-life (t1/2), elimination rate constant (k(el)) and apparent volume of distribution (V(d)) were relatively decreased (P > 0.05) as a result of the T. vivax infection. Retention of lactose in the plasma was attributed to decreased plasma clearance. It is suggested that the presence of trypanosomes in circulation rather than organic lesions could have been responsible for the delay observed in the excretion of lactose. At 12 weeks p.i., when the experiment was terminated, the group infected and given lactose infusion (despite higher parasitaemia) had no gross or histopathological lesions in the brain, spleen, lymph nodes, heart, kidneys, liver and testes. However, the group infected but not infused with lactose were emaciated, had pale mucosae, watery blood, general muscular atrophy, serous atrophy of coronary fat and other adipose tissue, hepatomegaly, splenomegaly, swollen and oedematous lymph nodes, all of which are suggestive of trypanosomosis. Histopathological lesions included narrowing of Bowman's space and hypercellularity of glomerular tufts in the kidneys with the mean glomerular tuft nuclear indices (GTNs) in the group significantly higher (P < 0.01) than the mean GTNs of the lactose-infused and control bulls. Degenerative changes occurred in the myocardium, spleen, testes and epididymides. The tesicular and epididymal lesions are indicative of male reproductive dysfunction.