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.

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.

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.

Penbutolol in the treatment of mild to moderate essential hypertension in black South Africans.

The antihypertensive effects of penbutolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, was assessed in nonobese black South Africans aged 25 to 65 years with uncomplicated mild to moderate essential hypertension. After a 4-week placebo run-in period 50 patients entered a randomized placebo-controlled study with a crossover design. For 8 weeks they received a once daily dose of 40 mg penbutolol (or placebo) which was increased to 80 mg per day for the next 4 weeks in poor responders. This was followed by a 4-week placebo washout period after which a crossover of treatment was achieved and a second 12-week period of treatment initiated. Thirty-five patients completed the whole study and in 15 patients diastolic blood pressure was reduced below 95 mm Hg. The mean systolic pressures of these patients decreased by 21 mm Hg and their mean diastolic pressure decreased by 11 mm Hg during treatment with penbutolol. These results suggest that penbutolol monotherapy is an alternative therapeutic approach to hypertension in black South Africans.

Effects of essential fatty acids on mild to moderate essential hypertension.

A double-blind placebo-controlled study with a crossover design was conducted on 25 non-obese black patients with mild-moderate uncomplicated essential hypertension. They were randomly assigned into two groups. After having received placebo capsules for 4 weeks, they received dietary supplementation with either Efamol-marine (containing desaturated n-6 and n3 essential fatty acids), or sunflower seed and linseed oil capsules for 12 weeks. Thereafter a second 4 weeks placebo phase and a subsequent second 12-week active phase were entered into during which a crossover of the dietary supplementation of the groups was brought about. The mean systolic blood pressure of patients receiving Efamol-marine was significantly lowered after 8 and 12 weeks, while those receiving sunflower/linseed oil supplementation had no significant reduction of blood pressure. This observation may indicate that defective desaturation of the essential fatty acids by the enzyme delta-6-desaturase, could play an important role in the etiology of essential hypertension.

A laboratory study on the possible use of Helisoma duryi in the biological control of Bulinus africanus, intermediate host of Schistosoma haematobium.

In order to evaluate the possible use of Helisoma duryi as biological competitor of Bulinus africanus, life-tables were compiled for these two snail species maintained either in the presence of each other, or separately. Population parameters were calculated from these life-tables and it was found that H. duryi had a higher innate capacity of increase, net reproduction rate and growth rate as well as a longer lifespan and reproductive period than Bu. africanus. Furthermore, the biological potential of Bu. africanus was found to be adversely affected in the presence of H. duryi. It was concluded that the latter might be capable of replacing Bu. africanus in certain freshwater habitats and that field trials ought to be undertaken in South Africa.

Susceptibility of South African Bulinus africanus populations to infection with Schistosoma haematobium.

The use of intermediate host snails of Schistosoma spp. which are insusceptible to infection has been proposed as a possible method of controlling schistosomiasis. The objective of this approach is to change the susceptibility of natural snail populations from being predominantly susceptible to a non-susceptible state, through the release of refractory snails into natural habitats. In an attempt to determine whether or not such refractory Bulinus africanus populations occur in eastern South Africa, F1 generation snails of populations from 8 different areas were exposed to miracidia hatched from eggs excreted in the urine of schoolchildren infected with Schistosoma haematobium in the Nelspruit district. The proportion of snails successfully infected ranged from 27 to 100%, which revealed considerable genetic heterogeneity amongst populations of the same snail species. One population from Natal could be regarded as partially refractory, while a laboratory population from Durban proved to be 100% susceptible. A completely refractory strain of B. africanus has not yet been identified.

Aspects of poisoning with traditional medicines in southern Africa.

During 1981-1985, 1306 patients were admitted to Ga-Rankuwa Hospital due to acute poisoning. The major causes were paraffin (59.0%) and traditional medicines (15.8%). The mortality from paraffin was low (2.1%), but poisoning from traditional medicine resulted in a high mortality (15.2%) and accounted for 51.7% of all deaths. The traditional healer was the main source (83.4%), of traditional medicines, while 11.6% was bought from African medicine shops. The rest was acquired from other sources. In 82.5% of cases traditional medicines were taken orally, and in 10.5% of cases they were administered as an enema. Poisoning by traditional medicines was always accidental and probably due to overdosage. Vomiting, diarrhea, and abdominal pain were the most frequently encountered symptoms while the lungs, liver, and central nervous system were commonly affected. Treatment consisted of ventilation, intravenous fluids, and other palliative measures. A great deal of secrecy still surrounds traditional medicine, hampering rational therapy. Questioning of patients and interviews with traditional healers facilitated the identification of a number of major etiological agents. This elucidated the problem and should promote effective treatment.

The occurrence of Schistosoma mattheei in the south-western Transvaal.

To determine whether Schistosoma mattheei is present in the south-western Transvaal, sixty habitats were searched for the intermediate host snail, Bulinus africanus. Ten populations of this snail were located, 2 of which were infected with S. mattheei. Eggs of one of these isolates, originating from a spring in the Mooi River, were examined with an optical microscope. Scanning electron micrographs of the teguments of adult male worms and the terebratorial membranes of miracidia are described. These parasites are morphologically similar to some previously described from another habitat in the same geographical area and both populations can be regarded as typical S. mattheei.

Geographical distribution and habitat preferences of the invader freshwater snail species Lymnaea columella (Mollusca: Gastropoda) in South Africa.

The present geographical distribution of Lymnaea columella, as recorded in the National Freshwater Snail Collection, is described and discussed. It appears that L. columella is the most successful colonist of all the freshwater snail species in South Africa, and, together with Bulinus tropicus and Lymnaea natalensis, it forms the most widely distributed freshwater snail species in the region. Data regarding the 2,341 discovery sites of L. columella recorded by collectors during surveys are analysed. L. columella cluster mainly in rivers or streams with perennial, slow flowing, or stagnant freshwater with many plants and a mud substrate. L. columella is regarded as a more effective intermediate host for the transmission of fascioliasis than the indigenous snail species. The economical implications of this are discussed briefly in the light of its success as an invader species.

The tegument of Schistosoma hippopotami from Hippopotamus amphibius in the Kruger National Park.

Schistosoma hippopotami were collected from the right heart chambers and pulmonary arteries of Hippopotamus amphibius culled in the Kruger National Park. The schistosomes were subjected to scanning electron microscopy as well as optical microscopy. The results indicate that S. hippopotami is not conspecific to S. mansoni as suggested in the literature. On account of the morphology of certain tegumental structures of both male and female parasites, it is suggested that S. hippopotami is adapted to the pulmonary arterial circulation of its host.

Notes on the occurrence of tubercular spines in Schistosoma margrebowiei and Schistosoma mattheei.

Scanning electron microscopical (SEM) studies on the tegument of the bovid schistosomes, Schistosoma margrebowiei and Schistosoma mattheei have yielded conflicting results; certain authors observed the tubercles on the tegument of these species to be spined, while others reported that they are spineless. The present study indicates that the protrusion of tubercular spines is subject to phenotypic plasticity regulated by external factors such as the identity of the host species and whether or not the schistosome is paired.

Toxicology units in developing countries: different priorities?

The Toxicology Service at the Medical University of Southern Africa (MEDUNSA) deals with a predominantly developing Black patient population. To determine priorities, a retrospective comparative epidemiological study for the period 1970-1976 was made of Black and White patients admitted to the teaching hospitals of the University of the Orange Free State. The study revealed that among Whites the pattern of poisoning was very similar to that reported from developed countries. Drug poisonings predominated, there were more deliberate than accidental poisonings, and the majority of patients were females. Among the developing Black community, the picture differed markedly. Drug overdoses were responsible for very few poisonings, most poisonings were accidental, and males predominated. In addition, the vast majority of poisonings occurred in childhood. Accordingly, the toxicology service at MEDUNSA regards drug identification and psychiatric help for attempted suicides as low priorities and is geared toward establishing epidemiological trends and dealing with problems such as the treatment and prevention of organophosphate poisoning, paraffin poisoning, carbon monoxide poisoning, and poisoning with traditional African medicines.

Poisoning admissions of black South Africans.

During the period 1981-1985, 1306 patients with acute poisoning were admitted to Ga-Rankuwa Hospital. Of these 60% were males and 40% females. The majority (80%) were children aged 10 years or less. Sixty patients (4.6%) died. Most poisonings were accidental and only 4.0% were due to deliberate self-poisoning. The most important causes of acute poisoning were kerosene (59%) and traditional medicines (15.8%). The major causes of mortality were traditional medicines responsible for 51.7% and kerosene responsible for 26.7% of the deaths that occurred. The prevention and treatment of kerosene poisoning and poisoning by traditional medicines merits high priority in the health care of the indigenous population of South Africa.

Digitalis in clinical practice.

Rational use of digitalis requires adequate knowledge of the drug, the disease and the patient, and an ability to integrate these factors. The pharmacology of digitalis is reviewed and the pathophysiology of cardiac failure and supraventricular arrhythmias, as well as aspects of toxicity and the use of serum levels, is discussed. Emphasis is placed on individualisation of therapy and on careful clinical observation.

Chorea and psychiatric changes in organophosphate poisoning. A report of 2 further cases.

The acute muscarinic and nicotinic side-effects of organophosphate poisoning are well known. Less commonly encountered are neurological symptoms such as chorea and psychiatric disturbances such as psychoses and depression. Two patients with organophosphate poisoning are described, both exhibiting marked choreiform dyskinesias and one experiencing severe depression and emotional lability. Both responded well to the appropriate treatment. Because of the widespread use of organophosphate insecticides in agriculture, the neurological and psychiatric effects of chronic low-dose exposure to organophosphates in farmers and their employees deserves attention.

Attitudes of private medical practitioners towards package inserts and other drug information sources.

One thousand questionnaires were distributed to private medical practitioners by representatives of a pharmaceutical company. The 221 respondents were predominantly male (91%) and most were trained at the Universities of Pretoria (37%), the Witwatersrand (22%) and Cape Town (19%) during 1960 - 1969 (24%) and 1970 - 1979 (45%). The majority (72%) found package inserts useful or extremely useful and 70% had consulted one during the previous week or on the day that they completed the questionnaire. Reasons for consulting the package insert, in order of frequency, were for information on untoward effects (64%), indications (33%) and mechanism of action (33%). Most respondents (71%) used the Monthly Index of Specialities (MIMS) more often than package inserts and 53% used the MIMS desk reference more often than package inserts. As regards additional regular information on drugs, 67% preferred a regular book to a loose-leaf system and 69% were prepared to pay for it. We are of the opinion that there is a need for information on drugs that would be complementary to current information systems, and that this should be a joint venture between Government and private enterprise, with the consumer being prepared to share the cost.