First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification.

AIMS: SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. METHODS: This is a first-time-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. RESULTS: Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg-1 and the dose ascended to 12.5 mg kg-1 . The dose selected for HD patients was 9 mg kg-1 . Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment-emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg-1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3-84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, -32.4 to 49.7). CONCLUSION: The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end-stage renal disease and calciphylaxis warranting further human studies.

Host status of commercial mango cultivars to Thaumatotibia leucotreta (Lepidoptera: Tortricidae) in South Africa.

The objective of this study was to determine the host status of commercially cultivated mango fruit, Mangifera indica L. (Anacardiaceae) to Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) in South Africa. T. leucotreta was monitored with parapheromone traps in mango orchards in Limpopo and Mpumalanga from 2007 to 2010. Fruit were inspected for the presence of T leucotreta eggs in mango orchards. Mango fruit of the cultivars 'Tommy Atkins', 'Kent', 'Keitt', and 'Sensation' were artificially infested with T. leucotreta eggs on the tree to determine if the larvae were able to develop in fruit. Mature fruit of these cultivars were harvested and were then exposed to T leucotreta eggs and the larval development monitored. Before harvest, fruit were inspected for natural infestations and a packhouse survey was conducted during the 2009-2010 season to determine if any infested fruit were present. T. leucotreta was present in all mango orchards where monitoring was done with traps but no eggs were found on the fruit, which suggests the presence of antixenosis. Development occurred in mature harvested fruit of all cultivars that had been exposed to T. leucotreta eggs. Depending on the cultivar, between 0 and 5.05% of immature fruit on the tree supported development and demonstrate antibiosis. No naturally infested fruit were found in the orchards or during the packhouse survey. Mango in South Africa is not a natural host for T. leucotreta. Mature mango fruit is an acceptable host for T. leucotreta larval development under artificial conditions. The latex plays an important role in the resistance mechanism of mango fruit to T. leucotreta.

Developing a systems approach for Thaumatotibia leucotreta (Lepidoptera: Tortricidae) on 'Hass' avocado in South Africa.

Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) is pest of the avocado, Persea americana (Mill.) (Lauraceae), in South Africa and is regarded as a phytosanitary threat. The objective of this study was to develop a systems approach for T. leucotreta on 'Hass' avocado that will mitigate the pest risk. T. leucotreta males were monitored with pheromone traps, and numbers declined during the winter. Field studies indicated that most of eggs were laid during January in the Deerpark area, and during harvest, only 0.029 lesions produced live larvae. Survival of larvae in fruit infested on the tree and left to develop after harvest varied and depended on the time of infestation before harvest. Fruit firmness was measured and fifth instars were only present in soft fruit. Fenpropathrin and a granulovirus were effective in reducing the infestation levels. Bags used to cover fruit also reduced infestation levels. Lesions caused by T. leucotreta were visible from two weeks after infestation and fruit with lesions can be sorted. The mean infestation rate per orchard was 0.003 lesions per fruit which makes T. leucotreta on Hass amenable to the alternative treatment efficacy approach and maximum pest limit. In the case of T. leucotreta on Hass, poor host status, production, preharvest and postharvest measures were studied and low infestation levels were observed; all these elements would make a systems approach an option. Furthermore, inspection and certification as well as shipping and distribution measures could be added.

Local and systemic effects of Na+/K+ATPase inhibition.

The positive inotropic and electrophysiological effects of cardiac glycosides on cardiac muscle are mediated through inhibition of Na+/K+ ATPase by binding to a specific extracytoplasmic site of the a-subunit of this enzyme. The inhibition of Na+/K+ ATPase affects ionic flux and produces direct local effects on cardiac contractility, electrical excitability and conduction, but also profound systemic effects mainly as a result of haemodynamic changes. These effects are responsible for beneficial therapeutic as well as toxic effects. Inhibition of Na+/K+ ATPase results in potentiation of K+ loss from cells and Na+ entry into cells, so consequently affects action potential generation and propagation. This also underlines the potentiation of certain effects of cardiac glycosides by hypokalemia and hypomagnesaemia, and the effects of changes in calcium homeostasis on the cardiac glycoside pharmacodynamics. Furthermore, inhibition of Na+/Ca++ exchange enhances Ca++ mobilization and promotes contractility. These effects (locally and systemically) differ greatly, depending on the haemodynamic status and myocardial oxygen supply. Cardiac glycosides have less affinity for Na+/K+ ATPases at other sites (e.g. skeletal muscle), but some extracardiac effects (vascular effects, effects on colour vision, CNS and autonomic effects, renal effects) may be related to Na+/K+ ATPase inhibition.

Opportunities and strategies for introducing pharmacogenetics into early drug development.

Following the publication of the first draft of the human genome, this is a good time to re-analyse the potential contribution of genomics to drug development. Pharma, biotech and academia are already queuing up to deliver novel data impinging on every aspect of medicine and we can foresee a five-year scenario in which every new drug with a known mode of action will have a target gene sequence in the public domain. As such, current development strategies must ultimately be capable of anticipating and addressing genetic issues. This article attempts to position recent developments in genomics from an industrial perspective.

A new mixed micellar preparation for oral vitamin K prophylaxis: randomised controlled comparison with an intramuscular formulation in breast fed infants.

OBJECTIVE: To compare a new oral preparation of vitamin K1 (Konakion MM) containing lecithin and glycocholic acid with a standard intramuscular (IM) preparation during the first 8 weeks of life in exclusively breast fed infants. METHODS: Infants were randomised at birth to the IM group (1 mg vitamin K) or the oral group (2 mg given at birth and repeated at 7 and 30 days of life). Prothrombin time (INR), plasma vitamin K1, and PIVKA II (undercarboxylated prothrombin) were monitored at 14, 30, and 56 days of age. RESULTS: Seventy nine infants were randomised to the oral group and 77 to the IM group. Sixty seven infants in each group completed eight weeks of the study. Prothrombin times did not differ between the two groups. Mean (SD) plasma vitamin K1 values (in ng/ml) decreased in both groups over time, but were higher in the oral group at 14 and 56 days: 2.0 (1.6) v 1.3 (1.1) at 14 days; 0.5 (0.3) v 0.5 (0.7) at 30 days; and 0.5 (0.8) v 0.2 (0.2) at 56 days of life. PIVKA II was raised (> or = 0.1 AU/ml) in cord blood in 47% of the infants. By 14 days, only one infant in each group had a raised PIVKA II value and both of these initially had high concentrations of PIVKA II in cord blood. At 30 days, there were no raised PIVKA II values. At 56 days, there were no raised PIVKA II values in the oral group, although three infants in the IM group had raised values. CONCLUSIONS: Plasma vitamin K concentrations were at least equal or significantly higher in babies given oral vitamin K supplements compared with IM treated babies at the time points measured. Through the first 8 weeks of life, multiple doses of the new oral preparation maintain haemostasis and vitamin K status in breast fed infants at least equal to that of the intramuscular preparation.

Epidemiology and control of schistosomiasis mansoni in communities living on the Cuando River floodplain of East Caprivi, Namibia.

The Cuando River area of eastern Caprivi, Namibia, is highly endemic for Schistosoma mansoni whereas S. haematobium transmission, due to the scarcity of its intermediate host snail, Bulinus africanus, does not occur. Chemotherapy (6-monthly blanket treatments with praziquantel) combined with focal mollusciciding (monthly application of niclosamide) was used in a project in the area to control the disease. Although as many adults and pre-school children as possible were tested and treated, the project concentrated largely on school-age children. It took 3 years for prevalence to decline from > 80% to 20% because of a lack of proper sanitary facilities and piped water supplies and high rates of absenteeism and re-infection. However, intensity of infection decreased more rapidly, from an arithmetic mean of > 200 to < 5 eggs/g faeces. Hepatomegaly was common among school children when the project started but could be seen in only a small percentage of them after 3 years of control. Neither the bovine schistosome, S. mattheei, nor the lechwe schistosomes, S. margrebowiei and S. leiperi, were observed in the excreta of humans living in the area.

Cardiac glycoside poisoning involved in deaths from traditional medicines.

Autopsy cases (from all areas of South Africa except the Cape Province) are referred for chemical investigation to the Johannesburg Forensic Chemistry Laboratory of the State Health Department. Over a 1-year period in 41 autopsies where death was presumed to have been caused by a herbal medicine, the presence of cardiac glycosides was sought and was found in 44%. Most of the cases were from the Transvaal, followed by Natal. Clinical histories of the patients revealed that gastrointestinal irritation was the most common syndrome experienced after traditional medicine administration (54%). It is concluded that in patients presenting with gastro-intestinal symptoms, presumably due to poisoning by traditional medicines, cardiac glycoside poisoning should be suspected.

Laboratory evaluation of B-2 as a molluscicide in the control of the snail intermediate hosts of schistosomiasis in South Africa.

There is a continuous need for the development and evaluation of new, inexpensive but highly effective molluscides for the control of freshwater snails acting as intermediate hosts of schistomiasis. For this reason B-2 (Hokko Chemical Industry Co. Ltd, Japan), also called Phebrol (sodium 2,5-dichloro-4-bromophenol), was evaluated in our laboratory as a candidate molluscicide for the control of freshwater snails in South Africa. Bulinus africanus and Biomphalaria pfeifferi, intermediate hosts of Schistosoma haematobium and Schistosoma mansoni respectively, were exposed to different B-2 concentrations for 24 and 48 hours. An indigenous fish species, Oreochromis mossambicus, which is common in local schistosomiasis endemic areas, was also exposed to the molluscicide. The calculated values obtained from a probit analysis (LC50, 24 hours: B. africanus = 2.6 mg 1(-1) and B. pfeifferi = 2.9 mg 1(-1), indicated that these species from southern Africa are less sensitive to B-2 than are B. truncatus and B. pfeifferi from northern Africa, which in turn are less sensitive than the Oncomelania spp. from Japan, China and the Philippines. It is expected that molluscicidal levels of B-2 would be harmful to O. mossambicus populations. Although B-2 has a marked potential for snail control in South Africa, niclosamide (Bayluscide) remains the molluscicide of choice.

The molluscicidal properties of Apodytes dimidiata subsp. dimidiata (Icacinaceae).

The molluscicidal and piscicidal activity of extracts from the leaves, berries and bark of the tree Apodytes dimidiata were evaluated experimentally. The leaves were highly toxic to both Bulinus africanus and Biomphalaria pfeifferi, the intermediate host snails of Schistosoma spp. B. pfeifferi profusely exuded mucus which appeared to render some protection against the toxic substance(s) of the plant but did not prevent their eventual demise. The LC10 after one-hour exposures of fish (Oreochromis mossambicus) was within molluscicidal levels.

Compliance in black patients with non-insulin-dependent diabetes mellitus receiving oral hypoglycaemic therapy.

Poor compliance with drug therapy is an important cause of therapeutic failure. Sixty-eight black patients with non-insulin-dependent diabetes mellitus receiving oral hypoglycaemic agents were interviewed and various factors, such as age, sex, degree of control and type of therapy, were recorded by means of a questionnaire. Compliance was determined by qualitatively assessing urine for the presence of the drugs. An alarmingly high incidence of non-compliance of 65% was found, which could still be an under-estimation because of the long half-life of one of the drugs involved--chlorpropamide. Although interesting trends were noted, no statistically significant differences between compliant and non-compliant patients were found. In the light of the high incidence of non-compliance, a larger and more detailed study seems to be warranted to identify problem areas and to plan appropriate interventions.

Further studies on the susceptibility of Bulinus africanus to infection with Schistosoma haematobium.

Genetic manipulation of the intermediate host snails of schistosomiasis has been proposed as a possible method of reducing the rate at which the parasite is transmitted to the final host. This technique is based on the finding that snail-schistosome compatibility is variable, and that refractory snails could be introduced into natural habitats in an attempt to change existing highly-susceptible populations into non-susceptible ones. In our search for such a refractory snail population, offspring from eight different Bulinus africanus populations were infected with Schistosoma haematobium, isolated from school children in the Nelspruit district. A great variation in minimum prepatent period was recorded (33-55 days), while the infected snails surviving that period ranged from 22-89%. A significant difference was found between the infection rates of B. africanus from Newlands in Natal and those of the other seven populations from the Eastern Transvaal Lowveld. The former population could be regarded as partially refractory, and none of the other populations proved to be completely refractory, to infection.

A comparison of the effects of digoxin and digitoxin on systolic time intervals and colour vision.

Animal studies suggest that for the same inotropism hydrophilic cardiac glycosides produce greater depression of atrioventricular (AV) conduction than lipophilic ones. This has been explained on the basis of a greater vagomimetic effect with hydrophilic agents and a greater sympathomimetic effect with lipophilic agents. In this randomized, cross-over study we investigated the effects of placebo, digoxin (relatively hydrophilic), and digitoxin (relatively lipophilic) in twelve healthy volunteers. For both drugs steady-state serum concentrations in the mid-therapeutic range were achieved. Both drugs produced the same positive inotropic effect as measured by systolic time intervals (QS2c). There was a trend for digoxin to have a greater effect on AV conduction than digitoxin. After atropine or propranolol there was no difference between the effect of the two cardiac glycosides on AV conduction. No significant effects on colour vision were seen. We conclude that, there do not seem to be pharmacodynamic differences between digoxin and digitoxin at mid-therapeutic serum concentrations.

Adherence of blood platelets and leucocytes to hybrid schistosomes.

The bovine parasite, Schistosoma mattheei was crossed with the human schistosome, S. haematobium. The F1 hybrids resulting from this cross were viable in both snails and rodents. However, F1 x F1 (F2) crosses were less viable in snails and a proportion of them seemed to be changed structurally when viewed by scanning electron microscopy. Certain of the schistosomes were covered with a dense mass of interconnected blood platelets resembling a temporary haemostatic plug but not a blood clot. Interspersed between the platelets were a small number of leucocytes. We suggest that the platelets may have responded to the presence of an antigen which is masked in normal schistosomes but which is exposed in certain F2 hybrids.

Scanning electron microscopical observations on the shedding of the tegument of adult Schistosoma mattheei.

In search of indications of membrane turnover the teguments of male Schistosoma mattheei from cattle and laboratory rodents were studied by means of scanning electron microscopy. A number of slightly elevated circular patches of tegument which appeared to peel off on the edges were seen on the outer membrane of a limited number of specimens from both rodents and cattle. It is suggested that this phenomenon may represent limited rapid turnover of the outer layer in response to host immunological action.

The effect of miglitol and acarbose after an oral glucose load: a novel hypoglycaemic mechanism?

1. Alpha-glucosidase inhibitors such as miglitol and acarbose lower blood glucose after a starch load in healthy volunteers and diabetic patients by interfering with the conversion of disaccharide to monosaccharide in the gastrointestinal tract. 2. The effect of placebo, 100 mg miglitol and 100 mg acarbose given 30 min prior to a 75 g oral glucose load was investigated in nine healthy Caucasian volunteers. 3. Miglitol produced a statistically significant fall in post-peak blood glucose levels when compared with placebo and acarbose. Serum insulin did not change significantly. 4. As miglitol is well absorbed and acarbose is not, it is suggested that miglitol has a systemic hypoglycaemic effect, probably related to its close structural similarity to glucose, which warrants further investigation.