PROF. JUMA FRANCIS D

Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future

A chemical investigation of the chloroform extract of the roots of Uvaria ludida Benth. (Annonaceae), an important African traditional medicine, led to the isolation of six new compounds; three pyrenes, 2-hydroxy-1,8-dimethoxypyrene (1), 8-methoxy-1,2-methylenedioxypyrene (2), and 7-hydroxy-8-methoxy-1,2-methylenedioxypyrene (3), two pyrenediones, 2-hydroxy-1,8-pyrenedione (4) and 2-methoxy-1,8-pyrenedione (5), and a sesquiterpene, (-)-10-oxo-isodauc-3-en-15-oic acid (6), together with eight known compounds (7-14). The structural elucidation by spectroscopic studies of the compounds isolated is described. While pyrenes did not exhibit strong cytotoxicity against human promyelocytic leukemia HL-60 cells, pyrenediones showed strong cytotoxicity. The IC(50) of 4 was 70 ng mL(-1), which was close to that of etoposide (IC(50) = 60 ng mL(-1)).

A chemical investigation of the petroleum ether extract and chloroform extract of the root of Uvaria scheffleri Diels (Annonaceae) led to the isolation of two new compounds, named hydroxyespintanol (1) and schefflerichalcone (2), together with eight known compounds (3-10). The structural elucidation of compounds 1 and 2 by spectroscopic studies is described. The cytotoxicity of the isolated compounds against human promyelocytic leukemia HL-60 cells was studied. Among these, 2'-hydroxy-3',4',6'-trimethoxychalcone (5) exhibited cytotoxicity (IC(50) 12 microM), and espintanol (3), which was the main ingredient, also showed some cytotoxicity (IC(50) 44 microM)

From the secondary and tertiary alkaloidal fractions of the root and the bark of Xylopia parviflora (Annonaceae), the isoquinoline alkaloids, 10,11-dihydroxy-1,2-dimethoxynoraporphine and parvinine were isolated, along with 39 known alkaloids. Their structures were determined on the basis of analysis of spectroscopic data.

The antinociceptive effects of highly selective mu (DAMGO), delta (DPDPE) and kappa (U-50488 and U-69593) opioid agonists were evaluated following intraperitoneal (i.p.) administration in the naked mole-rat. A hot plate test set at 60 degrees C was used as a nociceptive test and the latency to the stamping of the right hind paw (response latency) was used as the end-point. DAMGO (5-10 mg/kg) and DPDPE (2.5-5 mg/kg) caused a naloxone-reversible significant decrease in the mean response latency. Subcutaneous injection of naloxonazine (20 mg/kg) 24h prior to the administration of DAMGO (5 mg/kg) also blocked the reduction in the response latency observed when DAMGO was injected alone. On the contrary, U-50488 (2.5-5 mg/kg) or U-69593 (0.08 or 0.1 mg/kg) caused a naloxone-reversible significant increase in the mean response latency. These results showed that activation of mu or delta receptors caused hyperalgesia, whereas activation of kappa receptors caused antinociception in the hot plate test in naked mole-rat. This suggests that mu and delta receptors modulate thermal pain in a different way than kappa receptors in the naked mole-rat. It is not possible at the moment to point out how they modulate thermal pain as little is known about the neuropharmacology of the naked mole-rat.

Two new C-benzylated dihydrochalcones, isochamuvaritin (1) and acumitin (2), have been isolated from the African medicinal plant Uvaria acuminata, together with the previously reported benzylbenzoate (3), uvaretin (4), isouvaretin (5), diuvaretin (6), and uvangoletin (7). The structural elucidation of compounds 1 and 2 in spectroscopic studies is described. C-Benzylated dihydrochalcones, especially 1, 2, 4, and 6, showed considerable cytotoxicity toward human promyelocytic leukemia HL-60 cells.

From the quaternary alkaloidal fraction of the bark and the root of Xylopia parviflora (Annonaceae), four isoquinoline alkaloids, xylopinidine, dehydrocoreximine, N, N-dimethylanomurine and N-methylphoebine were isolated along with the known compounds, pycnarrhine, lotusine, 6,7-dimethoxy-2-methyl-isoquinolinium salt, 1,2-dehydroreticuline, (-)-phellodendrine, (+)-tembetarine, (-)-litcubine, (+)-magnoflorine, tetradehydroreticuline, (-)-oblongine, (+)-menisperine, (+)-N-methylcorydine, stepharanine, (+)-xanthoplanine, dehydrodiscretine, jatrorrhizine and palmatine. 3,4-Dihydro-6,7-dimethoxy-2-methyl-isoquinolinium and N-methylpurpuerine were isolated as natural products for the first time. Their structures were determined on the basis of spectroscopic evidence.

The absolute configurations of two acyclic triterpenoids 1 and 2, previously isolated from the bark of Ekebergia capensis (Meliaceae) have been determined by the modified Mosher's method.

Four new prenylated flavanones, abyssinone-V 4'-methyl ether (1) and abyssinoflavanones IV (2), V (3), and VI (4), have been isolated as minor flavanones from the African medicinal plant, Erythrina abyssinica, together with a known flavanone, sigmoidin D. The structure elucidation of compounds 1-4 by spectroscopic studies is described.

African medicinal plants Uvaria acuminata and Uvaria lucida were examined for their alkaloidal constituents. Three alkaloids, (-)-anolobine, (-)-anonaine, and (+)-reticuline were isolated from U. acuminata, and four alkaloids, (-)-anolobine, (+)-reticuline, (-)-asimilobine, and (-)-discretamine from U. lucida. Furthermore, HPLC profiles of the alkaloidal fractions of both plants were studied.

From the dried bark of Ekebergia capensis, two novel acyclic triterpenoids, 2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene and 2-hydroxymethyl-2,3,22,23-tetrahydroxy-6,10,15,19,23-pentamethyl-6,10,14,18-tetracosatetraene were isolated, along with known cyclic triterpenoids. The structures of these two new triterpenoids were determined by spectroscopic and chemical methods.

Quaternary alkaloids of two Kenyan medicinal plant belonging to the genus Zanthoxylum, Z. usambarense and Z_ chalybeum, were examined using ion-pair HPLC. Both plants contained similar alkaloids, but colored protoberberines were found only in Z. chalybeum. From the stems of Z. usambareni e a new alkaloid named usambanoline (I) was isolated and characterized,

Sixty newly diagnosed adult patients with mild to moderate essential hypertension were assessed to determine their cardiovascular risk factor profiles. Detailed history and physical examinations were done. Resting 12-lead ECG was done and serum levels of uric acid, fasting cholesterol, and fasting glucose were determined. Twenty nine patients had hypertension and two or more cardiovascular risk factors. The most prevalent cardiovascular risk factors other than hypertension were electro-cardiovascular left ventricular hypertrophy (31.7%), obesity (28.3%) and hypercholesterolaemia (28.3%). About a half of these patients (48.3%) can be classified as high risk hypertensives. This calls for aggressive management of cardiovascular risk factors as a whole and not just hypertension alone if we are to reduce incidence of hypertensive complications.

Mitogenic activities in African traditional herbal medicines were examined using protein fractions obtained from their extracts by precipitation with ammonium sulfate. Potent mitogenic activities for human and mouse lymphocytes were found in the three plants: Croton macrostachyus, Croton megalocarpus (Euphorbiaceae), and Phytolacca dodecandra (Phytolaccaceae). All the gel chromatographic patterns of these protein fractions progressed toward the smaller molecule site with pronase treatment, while their mitogenic activities decreased significantly. Protein fractions from these three plants induced mitogenesis both in human and mouse isolated T cells, but not in lymphocytes from athymic nude mice. By testing further fractionated protein fractions with gel filtration chromatography, it was found that all three plants contained several mitogens having different molecule sizes.

In this study, the investigation of hydralazine acetylator phenotype was undertaken for the first time in African hypertensives at Kenyatta National Hospital. A total of 25 randomly selected patients with moderate to severe hypertension (diastolic pressure 105-130 mmHg), participated in the phenotyping study. The phenotyping was done by administering oral standard hydralazine dose of 150 mg/day in three divided doses. The 24 hour urinary MTP/hydralazine ratio was used to categorize patients into slow and fast acetylators. Of the patients studied 69.9% were slow acetylators while 30.4% were fast acetylators. The mean 24 hour urinary MTP/hydralazine ratio for slow acetylators was 1.01 +/- 0.95. This was significantly different from the fast acetylators where the mean 24 hour urinary MTP/hydralazine ratio was 10.6 +/- 4.4 (P < 0.001). The acetylator phenotyping divided the patients into two distinct populations and no further arbitrary method was required to divide the patients into either group.

In the current re earch, the inland genus Ca sipourea of Rhizophoraceae in Kenya was pinpointed as a target for developing new medicinal resources. The field work on four species of Cassipourea, i.e. Cassipourea malosana, C. gummiflua, C. euryoides, and C. celastroides was carried out during three months in 1987, which all are grown in different habitats each other. It was proved with detective indicator (PdcI) at field work that the barks of these trees contain some sulfur compounds as we had expected. The plant materials transfered from field to laboratory provided some sulfur compounds as result of chemical studies such as isolation of compounds and determination of their structures. These compounds were such various alkaloid a pyrrolidine and pyrrolizidine posessing 1,2-dithiolane ring and bisdi¬sulphide bridge systern respectively. Among the alkaloid two new pyrrolidine alkaloids named guinesine-D and euryoidine have been isolated from Cassipourea euryoides.Guinesine¬D has als0 been found in C. celastroides. Another new pyrrolizidine alkaloid named is ocassi¬pourine have been isolated from C. malosana and C. gummiflua, For these three compounds, structure 1. 8 and were Proposed respectively on toe basis of spectro copic evidence

In this study, the investigation of hydralazine acetylator phenotype was undertaken for the first time in African hypertensives at Kenyatta National Hospital. A total of 25 randomly selected patients with moderate to severe hypertension (diastolic pressure 105-130 mmHg), participated in the phenotyping study. The phenotyping was done by administering oral standard hydralazine dose of 150 mg/day in three divided doses. The 24 hour urinary MTP/hydralazine ratio was used to categorize patients into slow and fast acetylators. Of the patients studied 69.9% were slow acetylators while 30.4% were fast acetylators. The mean 24 hour urinary MTP/hydralazine ratio for slow acetylators was 1.01 +/- 0.95. This was significantly different from the fast acetylators where the mean 24 hour urinary MTP/hydralazine ratio was 10.6 +/- 4.4 (P < 0.001). The acetylator phenotyping divided the patients into two distinct populations and no further arbitrary method was required to divide the patients into either group.

Eight brands of antacid tablets commonly available in the private market in Kenya were subjected to in-vitro tests for neutralizing capacity. The neutralizing capacity per gram and per tablet of the products was compared. The neutralizing capacity in millilitres of 0.1 M HC1 per gram ranged from 103.10 for Gelusil to 225.13 for Maalox, with others ranging between +/- 18.1% and -12% about the average. The neutralizing capacity per tablet ranged from 64.90 ml for Magnesium trisilicate Co tablets B.P. to 263.15 ml for Maalox, with the others ranging between +/- 24.9% and -33.1% about the average. This shows high variation in the neutralizing capacities of the different brands available especially in relations to the neutralizing capacities per tablet due to the high variation in the tablet weight.

Mefloquine pharmacokinetics were studied in Kenyan African normal volunteers and in patients with severe acute attack of Plasmodium falciparum malaria. Peak concentrations were achieved in both groups at 20-24 hours. The mean half-life of elimination was 385 +/- 150 hours (mean +/- SD) in normal subjects while in severe malaria it was 493 +/- 215 hours which was significantly longer (P less than or equal to 0.001). The volume of distribution was significantly smaller in severe malaria where it was 30.76 +/- 10.50 l/kg (mean +/- SD) while in the normal subjects it was 40.90 +/- 20.70 l/kg (mean +/- SD) (P less than or equal to 0.001). The total body clearance in severe malaria was 3.75 +/- 1.51 l/h (mean +/- SD). This was significantly lower than in the normal subjects where it was 5.15 +/- 1.50 l/h (mean +/- SD) (P less than or equal to 0.001).

Eight brands of antacid tablets commonly available in the private market in Kenya were subjected to in-vitro tests for neutralizing capacity. The neutralizing capacity per gram and per tablet of the products was compared. The neutralizing capacity in millilitres of 0.1 M HC1 per gram ranged from 103.10 for Gelusil to 225.13 for Maalox, with others ranging between +/- 18.1% and -12% about the average. The neutralizing capacity per tablet ranged from 64.90 ml for Magnesium trisilicate Co tablets B.P. to 263.15 ml for Maalox, with the others ranging between +/- 24.9% and -33.1% about the average. This shows high variation in the neutralizing capacities of the different brands available especially in relations to the neutralizing capacities per tablet due to the high variation in the tablet weight.

Eight brands of antacid tablets commonly available in the private market in Kenya were subjected to in-vitro tests for neutralizing capacity. The neutralizing capacity per gram and per tablet of the products was compared. The neutralizing capacity in millilitres of 0.1 M HC1 per gram ranged from 103.10 for Gelusil to 225.13 for Maalox, with others ranging between +/- 18.1% and -12% about the average. The neutralizing capacity per tablet ranged from 64.90 ml for Magnesium trisilicate Co tablets B.P. to 263.15 ml for Maalox, with the others ranging between +/- 24.9% and -33.1% about the average. This shows high variation in the neutralizing capacities of the different brands available especially in relations to the neutralizing capacities per tablet due to the high variation in the tablet weight.

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5 +/- 1.0 h (m +/- SD), which was significantly longer than in the normal controls in whom it was 7.6 +/- 1.4 h (p less than 0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8 + 8.61 X kg-1 than in the controls in whom it was 63.0 +/- 7.61 X kg-1 (p less than 0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5 +/- 1.0 h (m +/- SD), which was significantly longer than in the normal controls in whom it was 7.6 +/- 1.4 h (p less than 0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8 + 8.61 X kg-1 than in the controls in whom it was 63.0 +/- 7.61 X kg-1 (p less than 0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 +/- 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/- 0.11 l kg-1 (mean +/- s.d.) and the total body clearance was 40.7 +/- 3.2 ml kg-1 h-1 (mean +/- s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 +/- 2.7 h (mean +/- s.d.). The apparent volume of distribution was 0.72 +/- 0.14 l kg-1 (mean +/- s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/- 9.4 ml kg-1 h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/- 1.3 h (mean +/- s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/- 0.07 l kg-1 (mean +/- s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/- 5.5 ml kg-1 h-1 (mean +/- s.d.) (P less than 0.01).

The pharmacokinetics of cyclophosphamide was studied in 10 Kenyan Africans with Hodgkins lymphoma. The mean +/- s.d. elimination half-life (t1/2) was 7.5 +/- 1.38 h. The mean +/- s.d. volume of the central compartment (V1) was 0.35 +/- 0.12 l/kg and the apparent volume of distribution (V) was 0.64 +/- 0.06 l/kg. The microconstants k21, k12 and k10 were 1.81 +/- 0.84 h-1, 1.90 +/- 1.080 h-1 and 2.05 +/- 0.86 h-1 respectively (mean +/- s.d.).

The pharmacokinetics of pindolol was studied in 8 normal Africans following administration of a single oral 10 mg dose. The mean peak concentration was 30.2 +/- 5.0 ng X ml-1, the mean half-life (t1/2) of the elimination phase was 3.4 +/- 1.1 h, and the total body clearance was 628 +/- 13 ml X min-1. The apparent volume of distribution was 3.0 +/- 1.31 X kg-1. The values are the same as those reported in Europeans.

The pharmacokinetics of pindolol was studied in 8 normal Africans following administration of a single oral 10 mg dose. The mean peak concentration was 30.2 +/- 5.0 ng X ml-1, the mean half-life (t1/2) of the elimination phase was 3.4 +/- 1.1 h, and the total body clearance was 628 +/- 13 ml X min-1. The apparent volume of distribution was 3.0 +/- 1.31 X kg-1. The values are the same as those reported in Europeans.

Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0-51 ml . min-1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21 +/- 2.33 (SD) h whilst that in renal failure was 10.15 +/- 1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6 +/- 10.9 ml . kg-1h-1 which was significantly larger than in renal failure where it was 48.8 +/- 10.9 ml . kg-1h-1. Vd beta, Vdss and Vc were not significantly different between the two groups. A linear relationship exists between beta, the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t1/2 in normal patients was 8.33 +/- 2.0 h, whilst in the renal failure group it was 13.37 +/- 4.23 h. Total alkylating activity as measured by the nitrobenzyl-pyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.

The pharmacokinetics of pindolol was studied in 8 normal Africans following administration of a single oral 10 mg dose. The mean peak concentration was 30.2 +/- 5.0 ng X ml-1, the mean half-life (t1/2) of the elimination phase was 3.4 +/- 1.1 h, and the total body clearance was 628 +/- 13 ml X min-1. The apparent volume of distribution was 3.0 +/- 1.31 X kg-1. The values are the same as those reported in Europeans.

Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0-51 ml . min-1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21 +/- 2.33 (SD) h whilst that in renal failure was 10.15 +/- 1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6 +/- 10.9 ml . kg-1h-1 which was significantly larger than in renal failure where it was 48.8 +/- 10.9 ml . kg-1h-1. Vd beta, Vdss and Vc were not significantly different between the two groups. A linear relationship exists between beta, the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t1/2 in normal patients was 8.33 +/- 2.0 h, whilst in the renal failure group it was 13.37 +/- 4.23 h. Total alkylating activity as measured by the nitrobenzyl-pyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.

A simple gas chromatographic assay utilising alkali flame ionisation detection is described for the estimation of cyclophosphamide as its trifluoroacetate derivative from plasma. Examination of five patients following intravenous cyclophosphamide gave values of 8.9 h (SD 2.7) for the half-life and 0.061 liters/h/kg (SD 0.011) for whole-body clearance of the drug.