Some biological actions of alkylglycerols from shark liver oil.

Shark liver oil has been used for over 40 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkylglycerols. Initial clinical use was for treating leukemias, and later to prevent radiation sickness from cancer x-ray therapy. Studies over the last 30 years have shown that alkylglycerols are multifunctional. The level of natural alkylglycerols rises within tumor cells, apparently in an effort to control cell growth. Recent studies indicate that the activation of protein kinase C, an essential step in cell proliferation, can be inhibited by alkylglycerols. This action suggests a competitive inhibition of 1.2-diacylglycerol by alkylglycerols. Further studies on the immunostimulatory action of alkylglycerols suggest a primary action on the macrophage. The process of macrophage activation has been demonstrated with both synthetic and natural alkylglycerols. While the exact mechanism has not been found, both an autocrine and paracrine system have been suggested. Shark liver is a major natural source of alkylglycerols, which have no known side effects in dosages of 100 mg three times a day. The information presented in this article suggests that alkylglycerols may be used both as an adjunct therapy in the treatment of neoplastic disorders and as an immune booster in infectious diseases.

1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine--a methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism.

Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1-100 microM 1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH3) induced platelet aggregation but 1-O-hexadecyl-sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH3 (0.1 microM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [3H]WEB 2086 showed that Et-16-OCH3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 microM Et-16-OCH3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 microM. Thus, this study shows that Et-16-OCH3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.

Interactions between alkylglycerols and human neutrophil granulocytes.

We evaluated whether various alkylglycerols would initiate a functional response of human neutrophils or modify responses induced by a formyl peptide (fMLP) in vitro. We found that platelet activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response (assessed by cytochrome c reduction and/or chemiluminescence), followed by ET-16-OCH3. Lyso-PAF, ET-18-OCH3, batyl- and chimyl alcohols exhibited only a weak activity. PAF was also the most efficient lipid conferring a rise of intracellular calcium concentrations ([Ca2+]i). ET-16-OCH3, ET-18-OCH3 and lysoPAF were less potent, although maximal [Ca2+]i levels were similar to that of 0.1 mumol/l fMLP. The kinetics of the calcium responses were highly specific for each ether lipid. When neutrophils had been treated with PAF or ET-18-OCH3 and were subsequently stimulated by fMLP, enhancement of the oxidative response was noted. Thus, this study shows that there was an association between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure-activity relationships for these lipids.

Haemorrhagic and thromboembolic complications versus intensity of treatment of venous thromboembolism with oral anticoagulants.

In order to assess the recommended therapeutic interval with the prothrombin complex analysis, using Stago Prothrombin-complex Assay (SPA) as the reagent, a retrospective multicentre study was performed to obtain clinical documentation. All thromboembolic and haemorrhagic complications during secondary prophylaxis after venous thromboembolism in 272 patients were recorded and related to the intensity of the oral anticoagulation. Six thromboembolic complications in patients without a malignant disease occurred at SPA levels greater than or equal to 28%, confirming that the limit of the therapeutic range, determined by the risk of thromboembolic recurrences, should be set at an SPA level of 25% (international normalized ratio, INR = 2.0), at least in venous disease. Major haemorrhages occurred mainly at SPA levels less than 10% (INR greater than 4.0), unless underlying risk factors were present, thus setting the other limit of the therapeutic range. However, an adjustment of this limit to SPA = 15% (INR approximately 3.0) is suggested, since it would lead to further reduction of haemorrhage and is advisable in most patients with venous thromboembolism.

Monthly antimalarial chemotherapy to children in a holoendemic area of Liberia.

Two hundred and eighty-two children, two to nine years old, were included in a prospective three-year study in four villages with holoendemic malaria. In three villages the children received monthly doses of either chloroquine, pyrimethamine or chlorproguanil respectively for two years. In the fourth, vitamin tablets were used as placebo. Presumptive treatment with chloroquine (10 mg base kg-1) was given to all children with fever of suspected malarial origin. The two-year drug distribution was satisfactorily fulfilled to 168 children. Surveys, including physical and laboratory examinations were performed every six months, four weeks after medication. A fifth village was only visited at the start of the study and after two years. The mean crude parasite rate was initially 92%. Plasmodium falciparum was the main species. Splenomegaly was recorded in all children. In the chloroquine-treated children, the parasite rates varied between 30% and 50% during the study. By the end of the second year the spleen rate was reduced from 100% to 50%. Reported episodes of fever were reduced to half and mean haematocrit levels increased by 6% in comparison with children receiving the placebo. Total IgG concentrations were reduced from 36.7 g l-1 to 25.9 g l-1, whereas no significant decrease was observed in malarial seropositivity as measured by indirect immunofluorescence. Chlorproguanil had a weaker impact on parasitaemia with parasite rates between 50% and 90%. However, the spleen rate was reduced to 67% and there was a significant reduction of reported fever episodes. Mean haematocrits increased by 4%. Total IgG decreased from 31.8 g l-1 to 23.8 g l-1. In contrast, in the pyrimethamine group, the placebo group and the untreated group from the fifth village, the malariometric indices after two years were comparable to each other and to the initial values. During the third year only presumptive chloroquine treatment was given, and by the end of the study all malariometric indices were again comparable. From clinical observations there was no apparent impairment of protective immunity to malaria from the two years of regular distribution of the drugs. We conclude that a certain degree of malaria control could be achieved in Liberian children by the administration of monthly doses of chloroquine 10 mg base kg-1. The administration of chlorproguanil (1.5 mg kg-1) represents an alternative regimen.

Sensitivity in vivo of Plasmodium falciparum to chloroquine and pyrimethamine/sulfadoxine in a coastal area of Tanzania.

The in vivo response of Plasmodium falciparum to chloroquine and to pyrimethamine/sulfadoxine was studied for seven days in schoolchildren from two villages 30 to 40 km north of Dar es Salaam. Standard therapeutic regimen of chloroquine (25 mg base kg-1) failed to clear parasitaemia in 17 of 62 (27%) treated subjects. In contrast, standard treatment with pyrimethamine/sulfadoxine cleared the parasitaemia in all 44 treated subjects within five days. Hence, in the studied area, the therapeutic effect of sulfadoxine/pyrimethamine was superior to that of chloroquine.

Reduced mortality in cancer patients after administration of alkoxyglycerols.

A regression of tumor growth is observed when alkoxyglycerols are administered prior to radiation treatment of patients suffering from cancer of the uterine cervix. This regression is remarkably higher for patients below the age of 60 years than for those over 60. The regression has been demonstrated by a change in the quotient between the incidence of early and advanced stages.

Malaria control by chlorproguanil. I. Clinical effects and susceptibility of Plasmodium falciparum in vivo after seven years of monthly chlorproguanil administration to children in a Liberian village.

For seven years, chlorproguanil (1.0 to 2.0 mg kg-1) was administered monthly to the children below 15 years of age in a village with holoendemic malaria. Malariometric indices were recorded every six months. Susceptibility in vivo was monitored by the clearance of Plasmodium falciparum parasitaemia after drug intake. Three parasite species were found initially: P. falciparum (52%), P. malariae (8%) and P. ovale (4%). The parasites found during the study were mainly P. falciparum, and parasite rates ranged from 37 to 87% at the different surveys one month after respective drug intake. A fifty-fold decrease of mean parasite density was generally observed seven days after drug intake. Splenomegaly was initially recorded in all two to nine year old children, with a mean size of 2.64 according to Hackett's index. From 18 months onwards as the mean spleen index was 1.15 in the same age group. Chlorproguanil may represent an important alternative drug to groups at risk in malaria control schemes.

Different malaria control activities in an area of Liberia--effects on malariometric parameters.

The epidemiology of malaria was studied in a West African mining town (Yekepa) and three surrounding zones defined as Close, Middle and Far areas. Malariometric parameters were investigated in children two to nine years of age at the end of the rainy season. In Yekepa, vector control measures and intense suppression of malaria with drugs had created an almost hypoendemic situation with a spleen rate of 11%. In Close area, vector control was applied to some extent and malaria drugs were frequently used for treatment; the spleen rate was 40%. In Middle area, a mobile clinic provided sporadic malaria treatment to small children, but the clinic did not reach out to Far area. The spleen rates were 95 and 99%, respectively. Three species of Plasmodium were found in all areas. The prevalences in Far area were P. falciparum 82%, P. malariae 39% and P. ovale 9%. The crude parasite rates increased from 13% in Yekepa to 92% in Far area, whereas haematocrit levels decreased from 37.6 to 35.2, respectively. Plasmodium falciparum seropositivity, as measured by indirect immunofluorescence, was 74% in Yekepa and 99% in Middle and Far areas. Total IgG concentrations ranged from 18 g1(-1) in Yekepa to 33 g1(-1) in Far area. Three main anopheline species were found in the zones outside Yekepa. Their relative frequencies in Far area were Anopheles funestus 45%, A. hancocki 37%, and A. gambiae 18%. The local inoculation rates gradually increased outwards from Yekepa from less than 0.01 to 0.17 inoculations per man and night at the beginning of the dry season.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of persistent malarial infections on haemoglobin A2 levels in Liberian children.

Children two to nine years old from an area of holoendemic malaria in northern Liberia had mean HbA2 and haematocrit values significantly (P less than 0.001) lower than others from a neighbouring town where malaria is hypoendemic. After regular administration of chloroquine over two years to 38 children living in a holoendemic village, their mean HbA2 rose from 2.1%, SE +/- 0.04, to 2.6%, SE +/- 0.08 (P less than 0.001) and their mean haematocrit from 0.348, SEM +/- 0.004, to 0.382, SE +/- 0.004 (P less than 0.001), values similar to those of children from the neighbouring town. In another village where chloroquine was not given regularly, mean HbA2, haematocrit and malariometric indices were little changed at the end of the two-year period. We conclude that persistent malarial parasitaemia was the main factor in the relatively low values of the village children. Although it is not clear how malaria depresses HbA, the findings were consistent with the hypothesis that chronic malaria induces iron-deficiency.

Is the working capacity of Liberian industrial workers increased by regular malaria prophylaxis?

In a study of the impact of malaria prophylaxis upon the physical working capacity of Liberian industrial workers, two groups of men, one with and the other without malaria prophylaxis, were compared over a period of one year. At the beginning and at the end of the study, the haemoglobin concentration, haematocrit, blood volume and physical performance--measured by bicycle ergometry and expressed as work load at heart rate 170--were compared. No significant differences were found, either within or between the two groups. Routinely distributed malaria prophylaxis thus seems to be of little importance with respect to working capacity in this type of community, where malaria is meso-endemic.

Falciparum malaria and beta-thalassaemia trait in northern Liberia.

In a study in northern Liberia of the malaria and beta-thalassaemia hypothesis, the frequencies of beta-thalassaemia and HbS traits were 9.1 and 3.4% in the Mano and 9.5 and 1.7% in the Gio tribal samples. HbC and HbN were present at low frequency. G6PD deficiency was found in 16% of males. An observed increase with age of beta-thalassaemia trait frequencies was consistent with the selection hypothesis. However, we could not entirely exclude that associated iron deficiency influenced the results in the six to 11 month age group. Malaria was holoendemic; Plasmodium falciparum predominated, P. malariae and P. ovale were also identified. Plasmodium falciparum prevalence rates were similar in normal and beta-thalassaemia trait children but parasite densities were consistently lower in the latter. Using the criterion of a falciparum parasite density of 1 x 10(9) 1(-1) or greater to indicate a potentially important infection, the relative risk in beta-thalassaemia traits one to four years old from the cross-sectional study was 0.45 (upper 95% confidence interval 0.79) and 0.41 (0.61) in two to nine year trait carriers from a longitudinal study. Plasmodium falciparum gametocyte rates were lower in beta-thalassaemia trait children (P less than 0.005). The geometric mean titre of P. falciparum antibodies was lower in beta-thalassaemia trait children from the one to four year group (P less than 0.05). Otherwise immunological studies showed little difference between the different Hb types. Parasitological findings were consistent with relative resistance of HbS trait carriers towards P. falciparum infection. We found no evidence for relative resistance of beta-thalassaemia traits towards P. malariae infection nor that G6PD deficient males were more resistant to P. falciparum than those with normal activity. We conclude that the results are consistent with relative resistance of beta-thalassaemia trait carriers to P. falciparum malaria.

A case-control study in northern Liberia of Plasmodium falciparum malaria in haemoglobin S and beta-thalassaemia traits.

A case-control study was carried out on 558 patients with malaria attending a hospital in Yekepa, northern Liberia; 94 patients (16.8%) were aged at least ten years, probably because of a low level of protective immunity in town dwellers due to malaria control. The proportion of sickle cell traits (1.8%) among the patient group was lower than in the population (7.2%) served by the hospital (chi 2, 21.455, 1 df, P less than 0.001). A stratified analysis showed the relative risk for Plasmodium falciparum malaria in sickle cell trait over normal homozygotes, as 0.29 (upper 95%) confidence interval, 0.56). For beta-thalassaemia trait, the proportion among patients was 5.5% as against 9.0% in the general population (chi 2, 6.158, 1 df, 0.025 greater than P greater than 0.010). Stratified analysis gave a weighted relative risk for beta-thalassaemia heterozygotes of 0.49 (upper 95% confidence interval, 0.74). Although there were four beta-thalassaemia traits in the 10-14 year stratum with moderate to high parasitaemias, we consider that the overall results are consistent with relative resistance against P. falciparum malaria of both sickle cell and beta-thalassaemia heterozygotes in this population. No conclusions were possible from this investigation with regard to HbC and the malaria hypothesis. We found no evidence that P. falciparum malaria elevates HbA2 concentrations into the beta-thalassaemia range.