Biomedical subjects

M T Dzimianski

Publications and source records attributed to M T Dzimianski.

10 recordsLinked to original sources

PubMed2000

Anticancer agents suppressive for adult parasites of filariasis in Mongolian jirds.

Eight chemical structures not previously reported to possess antifilarial activity have been identified. A total of 79 compounds with anticancer properties were evaluated for possible macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones unguiculatus). All eight active compounds were suppressive for the onchocerciasis type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the lymphatic form (Brugia pahangi). These new structures may represent a nucleus around which effective drugs can be synthesized.

Animals↗

PubMed2000

Pharmacokinetics of UMF-078, a candidate antifilarial drug, in infected dogs.

The pharmacokinetics of the filaricidal benzimidazole compounds UMF-078 and UMF-289 were evaluated in beagle dogs experimentally infected with Brugia pahangi. Twenty-four infected microfilaremic beagles were selected and randomly allocated into 4 treatment groups of 6 dogs each: oral (PO) UMF-078, PO UMF-289 (the HCl salt form of UMF-078), intramuscular (IM) UMF-078, and untreated controls. Equivalent doses of 50 mg/kg of the free base were given twice a day for 3 days to the 3 groups of treated dogs. Oral absorption is rapid compared with IM dosing; the absorption half-life (K01-HL) for the IM treatment is approximately 14 hr compared with 1 and 2 hr for the PO regimen of salt and free base forms, respectively. The elimination half-lives (K10-HL) for the PO regimens are 13 and 15 hr for the salt and free base forms, respectively. Because of sustained absorption following IM dosing, the K10-HL is prolonged. In contrast to oral administration, IM dosing of UMF-078 provides sustained, relatively low plasma drug levels, with good tolerance and efficacy.

Administration, Oral↗

PubMed1999

Polyamines: agents with macrofilaricidal activity.

There is a need for effective macrofilaricidal drugs. The polyamine metabolism of filarial worms has been recognized as a possible target for effective drug action. In an attempt to identify agents that might provide leads in developing an effective macrofilaricide, 78 polyamine compounds were selected from among > 250,000 structures that have been amassed by the Walter Reed Army Institute of Research, in the U.S.A. These thousands of agents have been chosen principally for drug-development programmes for other parasitic diseases. The 78 prospective drugs selected were evaluated for their macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae, in male Mongolian jirds (Meriones unguiculatus). The animal models using these two parasites were designed to mimic, in so far as possible, human lymphatic filariasis and onchocerciasis, respectively. Thirteen of the compounds were found to be active although none of these has been previously reported to be macrofilaricidal. Two were suppressive for B. pahangi and 11 for A. viteae. These active agents may represent a nucleus around which highly effective drugs can be synthesised.

Animals↗

PubMed1998

Bis-cationic heteroaromatics as macrofilaricides: synthesis of bis-amidine and bis-guanylhydrazone derivatives of substituted imidazo[1,2-a]pyridines.

A series of guanylhydrazone, amidine, and hydrazone derivatives of 2-phenylimidazo[1,2-a]pyridine have been prepared and evaluated for macrofilarial activity against Acanthocheilonema viteae and Brugia pahangi in jirds. Compounds with 4',6-bis-substitution by cyclic guanylhydrazone groups show activity. 4',6-Bis-amidines show some activity but are more toxic; 4'- or 6-monosubstituted compounds are inactive. 2,6-Bis-substituted compounds lacking the phenyl ring are inactive. 4',6-Bis-substituted compounds having additional double bonds inserted between the heterocyclic ring and the phenyl ring or between the substituent and the ring system show reduced activity.

Amidines↗

PubMed1997

Pharmacokinetic and local tissue disposition studies of naproxen-following topical and systemic administration in dogs and rats.

The pharmacokinetic profiles of naproxen in blood and synovial fluid (SF) following topical and i.v. bolus administration in dogs, and the local tissue disposition of the drug following topical and oral administration in rats, were investigated to assess the feasibility of topical delivery of naproxen for local and systemic effects. The naproxen gel in poloxamer 407 (PF-127) was applied on the stifle joint of dogs, and serum and synovial fluid samples were collected. For local tissue disposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin. Steady state serum concentrations occurred at approximately 20 h after topical doses and lasted for the next approximately 30 h in dogs. Similar SF-serum concentration ratios of naproxen were found between i.v. (0.61 +/- 0.16) and topical (0.55 +/- 0.14) routes of administration. Following the i.v. dose, the half-life of naproxen in SF (approximately 60 h) was significantly longer than that in serum (approximately 40 h). The bioavailability of naproxen in the topical gel was approximately 2% of the applied dose in dogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as well as the concentrations of naproxen in the underlying dermis and muscle tissues, but exerted little effect on the disposition of naproxen in the epidermis.

Administration, Oral↗

PubMed1995

Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus and topical routes of administration in dogs.

PURPOSE: The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus i.v. and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. METHODS: A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. RESULTS: Peak MTX concentrations in SF occurred at 38 +/- 5 min following bolus i.v. dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 +/- 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 +/- 1.2 hr) and SF (12.7 +/- 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 +/- 0.21 hr) was longer than that in plasma (2.56 +/- 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at approximately 4 hr, lasting for approximately 20 hr. The bioavailability of MTX from the gel was 11.8 +/- 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. CONCLUSIONS: Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.

Administration, Topical↗

PubMed1994

Clinical prophylactic activity of melarsomine dihydrochloride (RM 340) against Dirofilaria immitis in heartworm-naive beagles exposed to natural infection in three southeastern states.

Melarsomine dihydrochloride (RM 340), a drug being developed as an adulticide for treatment of heartworm (Dirofilaria immitis) infection in dogs, was safe and highly effective as a clinical prophylactic agent against naturally acquired infections using Strategic and Tactical Treatment Programs. The Strategic Program involved treatment every 4 months (three series of treatments per year), disregarding the mosquito season (MS), to clear the existing infection at each treatment. The Tactical Program consisted of two series of treatments per year, 4 months apart, with the first one given about the middle of the MS (August) and the second one given after the end of the MS (December). Melarsomine was administered as two i.m. injections (lumbar muscles) of 2.2 mg kg-1 given 3 h apart. A total of 90 heartworm-naive beagles and a number of microfilaremic 'seed' dogs were used. Three similar experiments (30 beagles per experiment) were conducted at selected areas (Georgia, Florida, Louisiana) known to be enzootic for heartworm. At each site, 30 beagles were allocated to six groups of five dogs each, and four of these groups were placed outdoors in April of 1988. Two groups (control and treated) were exposed for 12 months, and the treated group was given melarsomine at 4, 8, and 12 months after exposure was started (Strategic Program). Another group was exposed for 8 months and treated with melarsomine at 4 and 8 months (Tactical Program). One group of tracer (sentinel) beagles was exposed from April to August 1988, one group from August to December 1988, and another from December 1988 to April 1989. April-August and August-December tracers served as controls for the tactically treated dogs. After exposure, all dogs were held indoors for 5 months before necropsy. Blood was collected at 4-5 month intervals and examined for microfilariae (MF) and adult heartworm antigen (enzyme-linked immunosorbent assay, ELISA). Treatment by the Strategic Program was 99% effective, with only one of the total of 15 treated dogs harboring any worms (a single female) at necropsy. Thirteen of the 14 control dogs (93%) exposed for 12 months became infected, with average worm recoveries of 6.8, 5.4, and 25.2 (range 1-45) for the Georgia, Florida, and Louisiana sites, respectively. All of the 13 heartworm-infected control dogs were antigen-positive, and 12 of these were also MF-positive, while none of the strategically treated dogs was either antigen- or MF-positive at necropsy. Tactical treatment of the total of 14 dogs twice per year was 100% effective.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Use of melarsomine dihydrochloride (RM 340) for adulticidal treatment of dogs with naturally acquired infections of Dirofilaria immitis and for clinical prophylaxis during reexposure for 1 year.

Heartworm-infected dogs were treated therapeutically with a new heartworm adulticide (melarsomine dihydrochloride, RM 340) and then put on a Strategic Program with treatment every 4 months for clinical prophylaxis to take advantage of the drug's potent activity against 4-month-old immature as well as adult Dirofilaria immitis. Ten random-source dogs with naturally acquired heartworm infections (microfilariae- and antigen-positive) were given melarsomine (2.2 mg kg-1 twice 3 h apart) by i.m. injection in the lumbar muscles to clear their existing infections. They were then placed outdoors (August 1988) in a high-risk area in Georgia (USA) for heartworm transmission and given melarsomine at the same posology every 4 months (Strategic Program) for 12 months as a clinical prophylactic measure. Five nontreated heartworm-naive beagles placed at this site during the same period served as 'controls' to monitor heartworm transmission. After exposure for 12 months, the ten treated and five 'control' dogs were taken indoors and held for 5 months. Microfilaremia and antigenemia levels were monitored in both groups by testing at 4-5 month intervals throughout the study and the intensity of infection was determined at necropsy. Microfilaremia levels in treated dogs dropped dramatically following the initial therapeutic treatment and remained either negative or low. Only two of the five 'control' dogs became microfilaremic, and this occurred near the end of the study. Nine of the ten treated dogs were antigen-negative 4 months after the initial therapeutic treatment, and all of them were antigen-negative at all bleedings thereafter. Four of the five 'control' dogs were antigen-positive at necropsy, and only one of these was positive 4 months earlier. Based on these antigen data, the initial treatment cleared 90% of the dogs of worms, and no worms were detected in any of the treated dogs thereafter. However, it is possible that undetectable immature heartworms were present. Although all of the treated dogs were antigen-negative at necropsy, three of them had a total of eight heartworms, seven of which were clearly immature, as determined by worm length measurements, and the remaining worm was a young adult female that was probably too young to be detected. All of the five 'control' dogs had heartworms (average 7.4; range 1-16), and about half of these worms were clearly immatures. Therapeutic treatment followed by strategic treatment with melarsomine every 4 months during reexposure was at least 89.2% effective overall.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Filariasis testing in a jird model: new drug leads from some old standbys.

A total of 65 compounds, most of which were from chemical classes having members known to be active against one or more parasitic organisms, were evaluated against Brugia pahangi and Acanthocheilonema viteae for macrofilaricidal activity in male Mongolian jirds (Meriones unguiculatus). Sixteen of the 65 compounds tested suppressed the number of parasites. Of these 16, three were suppressive for B. pahangi, 10 for A. viteae, and three for both parasites. The antibiotic nigericin and the antihistaminic isothipendyl were found to be most active.

Animals↗

PubMed1994

A new class of anti-filariasis compounds: a preliminary look.

Parasitic nematode worms which produce filariasis in humans place approximately one billion people at risk in more than 75 countries. More than 100 million people are infected with these diseases and are recognized as being of significant military importance. During World War II, filariasis was among the leading causes of medical evacuation from the entire South Pacific area. Agents available to treat the diseases exhibit significant toxicity. Better drugs are urgently needed. Data are reported from work using a Mongolian jird animal model on a new class of potential drugs, thiosemicarbazones. These compounds exhibit activity against the parasites which cause both lymphatic filariasis and the "onchocerciasis type" of the disease.

Animals↗