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Journal of Pharmaceutical Sciences Oct 2003Pyrimethamine, an antimalarial drug, was found to be able to inhibit both enzymes (DHFR-TS and PTR1) of the leishmanial folate pathway, although this effect in vivo...
Pyrimethamine, an antimalarial drug, was found to be able to inhibit both enzymes (DHFR-TS and PTR1) of the leishmanial folate pathway, although this effect in vivo appears only in relatively high concentrations. To reach the parasites inside macrophage cells, where they are sheltered, targeted drugs of pyrimethamine, carboxymethyldextran-thiomannopyranoside-pyrimethamine (CMD-P), and succinyldextran-thiomannopyranoside-pyrimethamine (SD-P), were synthesized and assayed against L.(L.) amazonensis amastigotes. CMD-P has 2.43% and SD-P has 2.58% of pyrimethamine attached. At a CMD-P dose of 200 microg/mL (4.86 microg/mL pyrimethamine), the results were very promising, with a destruction of approximately 50% of the intracellular amastigotes, with no detectable toxicity to macrophage cells. SD-P in similar doses did not show good results, probably due to different patterns of drug release. These results open the possibility of treating leishmaniasis with a safe targeted drug of pyrimethamine released directly inside the macrophage cells, reducing the host systemic toxicity.
Topics: Animals; Cells, Cultured; Dextrans; Female; Folic Acid; Leishmania mexicana; Macrophages; Male; Mice; Mice, Inbred BALB C; Prodrugs; Pyrimethamine; Trypanocidal Agents
PubMed: 14502550
DOI: 10.1002/jps.10476 -
European Journal of Clinical... Nov 1993A prospective study was conducted to evaluate azithromycin in combination with pyrimethamine for treatment of acute Toxoplasma encephalitis in patients with AIDS. Of the... (Clinical Trial)
Clinical Trial
A prospective study was conducted to evaluate azithromycin in combination with pyrimethamine for treatment of acute Toxoplasma encephalitis in patients with AIDS. Of the 14 patients given 75 mg pyrimethamine and 500 mg azithromycin daily for four weeks, eight were evaluable for clinical response. Five responded favorably, one had an intermediate response and two an unfavorable response. Of the nine patients evaluable for radiological response, six responded favorably, and three had an intermediate response. Eleven adverse events occurred in nine patients: rash (n = 5), abnormal liver function (n = 2), vomiting (n = 3) and hypoacousia (n = 1). This pilot study suggests that the combination of pyrimethamine and azithromycin may be further investigated and that the optimal dosage of azithromycin has yet to be determined.
Topics: AIDS-Related Opportunistic Infections; Acute Disease; Adult; Azithromycin; Drug Administration Schedule; Drug Therapy, Combination; Encephalitis; Female; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrimethamine; Sulfadiazine; Toxoplasmosis, Cerebral
PubMed: 8112357
DOI: 10.1007/BF02000407 -
Transactions of the Royal Society of... 1972
Topics: Acute Disease; Chloroquine; Drug Resistance, Microbial; Humans; Malaria; Male; Military Medicine; Plasmodium falciparum; Pyrimethamine; Pyrimidines; Sulfonamides
PubMed: 4558823
DOI: 10.1016/0035-9203(72)90150-2 -
Archives de Pediatrie : Organe Officiel... Mar 1996
Topics: Anti-Infective Agents; Drug Overdose; Female; Humans; Infant; Pyrimethamine; Seizures
PubMed: 8785570
DOI: 10.1016/0929-693x(96)81310-8 -
European Journal of Drug Metabolism and... 1991The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.
Topics: Adult; Biological Availability; Chromatography, High Pressure Liquid; Female; Humans; Indicators and Reagents; Male; Pyrimethamine; Spectrophotometry, Ultraviolet; Tablets
PubMed: 1820893
DOI: No ID Found -
Cancer Treatment Reviews Jun 1980
Comparative Study Review
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Diarrhea; Drug Administration Schedule; Drug Evaluation; Head and Neck Neoplasms; Humans; Lethal Dose 50; Leukopenia; Lung Neoplasms; Melanoma; Mice; Neoplasms, Experimental; Pyrimethamine; Rats; Seizures
PubMed: 6996812
DOI: 10.1016/s0305-7372(80)80019-3 -
Biopharmaceutics & Drug Disposition 1986We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each... (Comparative Study)
Comparative Study
We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 +/- 0.05, 0.30 +/- 0.03, 0.26 +/- 0.05 ml min-1), elimination half-life (4.5 +/- 0.5, 4.8 +/- 0.8, 4.9 +/- 0.5 h) and AUC (19.4 +/- 4.4, 17.3 +/- 2.2, 21.1 +/- 4.4 micrograms.h ml-1). By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups. The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for. These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Antimalarials; Carbon Radioisotopes; Feces; Injections, Intraperitoneal; Injections, Subcutaneous; Kinetics; Male; Mice; Mice, Inbred Strains; Pyrimethamine; Structure-Activity Relationship; Time Factors
PubMed: 3708123
DOI: 10.1002/bdd.2510070208 -
The Southeast Asian Journal of Tropical... Sep 2005A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium...
A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium falciparum malaria. Sixteen patients (76%) were completely cured with PS without any reappearance of asexual stage parasitemia during the follow-up examination. On the other hand, 5 patients (24%) failed to respond to this trial medication, resulting in recrudescence of asexual stage P. falciparum malaria. PS resistance resulted in higher prevalence of post-treatment gametocytemia, 25% gametocyte carriers among PS sensitive cases versus 75% of the resistant cases. These findings suggest that although the level of PS resistance is still valid for treatment of malaria in the study area of Lao PDR, post-treatment induction of gametocytemia among resistant cases may result an increase in transmission rate of PS resistant falciparum malaria.
Topics: Adolescent; Adult; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Laos; Malaria, Falciparum; Male; Middle Aged; Pyrimethamine; Sulfadoxine; Treatment Outcome
PubMed: 16438130
DOI: No ID Found -
Bulletin of the World Health... 1974For the treatment of malaria, combinations of drugs with antifolic action have the great advantage, compared with other drug associations, of synergic action, which... (Review)
Review
For the treatment of malaria, combinations of drugs with antifolic action have the great advantage, compared with other drug associations, of synergic action, which increases the effectiveness of the preparation, limits its toxicity, and reduces the risk of resistance. The associations of a sulfonamide (sulfalene, S) with a diaminopyrimidine derivative (pyrimethamine, P, or trimethoprim, T) have given good immediate clinical results. An analysis of the pharmacodynamic and pharmacokinetic characteristics of the three components explains the relative ease with which relapse is encountered with the association ST. The association SP is, from this point of view, more logical and effective and its importance in prophylaxis is surveyed in the light of a critical discussion of the arguments that are at present throwing doubt on the usefulness of its wider employment.
Topics: Adolescent; Adult; Child; Child, Preschool; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Erythrocytes; Folic Acid Antagonists; Humans; Immunity; Infant; Infant, Newborn; Malaria; Middle Aged; Oxidoreductases; Plasmodium falciparum; Pyrimethamine; Sulfonamides; Trimethoprim
PubMed: 4613504
DOI: No ID Found -
Lancet (London, England) Oct 1989To evaluate the efficacy of pyrimethamine on the blood stage (suppressive prophylaxis) and liver stage (causal prophylaxis) of Plasmodium falciparum in pregnant women,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
To evaluate the efficacy of pyrimethamine on the blood stage (suppressive prophylaxis) and liver stage (causal prophylaxis) of Plasmodium falciparum in pregnant women, in vivo and in vitro field studies were conducted in Ilorin, Nigeria, from Jan 1 to June 30, 1988. For pregnant women with P falciparum infections who received 25 mg of pyrimethamine weekly for suppressive prophylaxis, 67% (59/88) of in vivo and 60% (6/10) of in vitro tests showed pyrimethamine resistance. A second group of parasitaemic and parasite-free pregnant women was enrolled to evaluate the efficacy of pyrimethamine as a primary tissue schizonticide; after receiving a curative dose of chloroquine (25 mg/kg), half the women were given 25 mg of pyrimethamine weekly and half received no prophylaxis. Parasitologic failure rates did not differ between the pyrimethamine-treated (8/34) and the control (11/37) groups during the 16-week follow-up. Thus, pyrimethamine is not effective for suppressive or causal prophylaxis in pregnant women in Ilorin.
Topics: Adolescent; Adult; Animals; Chloroquine; Drug Evaluation; Drug Resistance; Female; Follow-Up Studies; Gestational Age; Humans; Malaria; Nigeria; Parity; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Infectious; Pyrimethamine; Randomized Controlled Trials as Topic; Tablets
PubMed: 2571759
DOI: 10.1016/s0140-6736(89)92998-x