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Biomedical subjects

D P Waller

Publications and source records attributed to D P Waller.

At least 19 recordsLinked to original sources
PubMed2002

Mandelic acid condensation polymer: novel candidate microbicide for prevention of human immunodeficiency virus and herpes simplex virus entry.

Presently marketed vaginal barrier methods are cytotoxic and damaging to the vaginal epithelium and natural vaginal flora when used frequently. Novel noncytotoxic agents are needed to protect men and women from sexually transmitted diseases. One novel candidate is a mandelic acid condensation polymer, designated SAMMA. The spectrum and mechanism of antiviral activity were explored using clinical isolates and laboratory-adapted strains of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). SAMMA is highly effective against all CCR5 and CXCR4 isolates of HIV in primary human macrophages and peripheral blood mononuclear cells. SAMMA also inhibits infection of cervical epithelial cells by HSV. Moreover, it exhibits little or no cytotoxicity and has an excellent selectivity index. SAMMA, although not a sulfonated or sulfated polymer, blocks the binding of HIV and HSV to cells by targeting the envelope glycoproteins gp120 and gB-2, respectively, and also inhibits HSV entry postattachment. SAMMA is an excellent, structurally novel candidate microbicide that warrants further preclinical evaluation.

Antiviral Agents↗
PubMed2001

Properties of a new acid-buffering bioadhesive vaginal formulation (ACIDFORM).

Vaginal prophylactic methodology may prevent heterosexual transmission of the HIV and other sexually transmitted disease-causing organisms as well as unplanned pregnancies. A new delivery system (ACIDFORM) was designed with acid-buffering, bioadhesive, and viscosity-retaining properties to (1) maintain the acidic vaginal milieu (the low pH inactivates many pathogens and spermatozoa), (2) form a protective layer over the vaginal/cervical epithelium (minimizing contact with pathogenic organisms), and (3) provide long-term vaginal retention. A Phase I clinical study with ACIDFORM provided initial information about its safety and showed the formation of a layer over the vaginal/cervical epithelium [1; Amaral et al., Contraception 1999;60:361-6]. To study the properties of the gel (without active ingredient) in more detail, ACIDFORM's acid-buffering, bioadhesive, viscosity-retaining, and spermicidal properties were compared in vitro to marketed formulations, and its long-term stability was assessed. ACIDFORM, either when titrated with NaOH or when mixed directly with semen, is highly acid buffering and much more effective than Aci-Jel, a commercial acid-buffering vaginal product. ACIDFORM adheres well to two model membranes (excised sheep vagina and cellophane) and is more bioadhesive than Conceptrol, Advantage S, Replens, Aci-Jel, and K-Y jelly. On dilution, ACIDFORM also retains its viscosity better than these marketed products. ACIDFORM is spermicidal and is stable for at least 2 years. These results suggest that ACIDFORM has advantages over presently marketed vaginal delivery systems. The gel may either be useful by itself as an antimicrobial contraceptive product or as a formulation vehicle for an active ingredient with antimicrobial and/or contraceptive properties.

Acrylic Resins↗
PubMed2000

A new vaginal antimicrobial contraceptive formulation: phase I clinical pilot studies.

Pilot clinical trials were performed with a new vaginal suppository called "Long Acting, Sustained Release of Spermicide" ("LASRS"). No visual or colposcopic lesions or patient complaints occurred as a result of using LASRS with increasing doses of nonoxynol-9 (up to 20%) for 5 days or of applying the highest dose of nonoxynol-9 (20%; total 400 mg) for 8 h. Colposcopic or visual lesions were also not induced when LASRS with 20% nonoxynol-9 was used for 7 consecutive days by the study participants except for those who developed symptomatic monilia vaginitis. Symptoms were reported although these were mostly minor. A long-lasting, bioadhesive, translucent layer (film) of formulation formed over the vaginal and cervical surfaces. Postcoital spermicidal studies showed LASRS to be highly effective for prolonged periods of time. Although intercourse was delayed for 5 to 8.5 h after insertion of the formulation, an average of only 0. 2 motile sperm/HPF could be found in cervical mucus. These studies suggest LASRS to possess advantages over presently marketed formulations by having long-term efficacy and by forming a bioadhesive, presumably protective layer over the genital tract epithelium. The results also suggest the formulation to decrease the vaginal irritation caused by nonoxynol-9 as noted by colposcopy. These pilot data support a more extensive study with the LASRS suppository.

Adult↗
PubMed2000

Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases.

Presently marketed vaginal barrier agents are cytotoxic and damage the vaginal epithelium and natural vaginal flora with frequent use. Novel noncytotoxic agents are needed to protect women from sexually transmitted diseases. One candidate compound is a high-molecular-mass form of soluble poly(sodium 4-styrene sulfonate) (T-PSS). The antimicrobial activity of T-PSS was evaluated in primary culture systems and in a genital herpes murine model. Results obtained indicate that T-PSS is highly effective against herpes simplex viruses, Neisseria gonorrhoeae, and Chlamydia trachomatis in vitro. A 5% T-PSS gel protected 15 of 16 mice from vaginal herpes, compared with 2 of 16 mice treated with a placebo gel. Moreover, T-PSS exhibited little or no cytotoxicity and has an excellent selectivity index. T-PSS is an excellent candidate topical antimicrobial that blocks adherence of herpes simplex virus at low concentrations, inactivates virus at higher concentrations, and exhibits a broad spectrum of antimicrobial activity.

Animals↗
PubMed1994

Theobromine toxicity on Sertoli cells and comparison with cocoa extract in male rats.

The target cell(s) of theobromine toxicity on rat testes and reproductive toxicity induced by pure theobromine and cocoa extract are evaluated in the present studies. Theobromine (500 mg/kg x 7 days) inhibited body weight gain in treated rats. Decreased cauda epididymal sperm reserve (38%), seminiferous tubule fluid (STF) volume (33%), lactate concentration in STF (22%), inhibition of binding activity of androgen binding protein (ABP, 21%) and reduced ABP content in STF were also observed in theobromine-treated animals. Cocoa extract containing an equivalent amount of theobromine did not produce significant toxicity in treated rats. Theobromine concentrations in serum and testes from pure theobromine-treated rats were 1.8- and 1.6-fold higher, respectively, than that in rats treated with cocoa extract. The results support Sertoli cells as the primary target cells of theobromine toxicity. The lower theobromine concentrations in serum and testes of cocoa extract-treated rats could account for the lower toxicity in these animals.

Animals↗
PubMed1993

Methods in ethnopharmacology.

A variety of pharmacological models are utilized in the evaluation of ethnomedicine. Most investigations are focused on developing new leads for therapeutic agents. However, there should be more efforts focused on the development of ethnomedicines because of their accessibility and acceptability in areas where modern medicine is not readily available. Testing methods to identify the active agents must be carefully selected utilizing information from ethnoanthropology, ethnobotany, phytochemistry, toxicology and pharmacology. New pharmacological models focused on cellular and molecular mechanisms can be used for ethnomedical evaluations but with great caution since they are based on known mechanisms of actions and limited by knowledge of the disease state.

Animals↗
PubMed1992

Reproductive toxicity of theobromine and cocoa extract in male rats.

The toxicities of theobromine and cocoa extract on the reproductive tract of male rats were compared in the present study. A cocoa powder extract containing 117 mg theobromine/g extract was prepared using 85% boiling methanol. Sprague-Dawley rats were weighed and dosed daily for 31 days with vehicle, 250 mg/kg theobromine, 2.14 g/kg cocoa extract (117 mg theobromine/g extract), or 0.43 g/kg cocoa extract by oral gavage. The animals were sacrificed on day 32. One testis and epididymis were removed and weighed. The epididymis was saved for the determination of epididymal sperm reserves. The remaining testis was fixed by whole body glutaraldehyde perfusion and processed for morphologic examination. A decrease in body weight gain and epididymal weights were observed in theobromine and high-dose cocoa-extract-treated groups. Theobromine and high-dose cocoa extract caused vacuolation within the Sertoli cell, abnormally shaped spermatids, and failed release of late spermatids in treated animals. Most of the vacuolations were found in the earlier and middle stage seminiferous tubules (stages I to VIII). However, the frequency of some parameters of testis alterations were significantly lower in the high-dose cocoa-extract-treated group compared to the theobromine-treated group. These data demonstrate the ability of a cocoa extract containing theobromine to alter testis structure in a similar pattern but with reduced intensity compared to that observed after oral exposure to pure theobromine.

Animals↗
PubMed1990

The effect of ketoconazole on fertility of male rats.

The effect of ketoconazole on the fertility of male rats was evaluated. Three days of oral dosing with ketoconazole at 200 mg/kg reduced fertility compared to controls. A complete loss of fertility was observed after doses of 400 mg/kg. There was no change in the testicular weight, epididymal sperm concentration or epididymal weight between the control and treatment groups. Motility was reduced in the high-dose group and forward progression was reduced in both dosing groups compared to control. These data support previous observations in the dog and primate that orally administered ketoconazole alters sperm viability. Although ketoconazole is too toxic for contraceptive application, its derivatives may be useful for this purpose.

Administration, Oral↗
PubMed1990

The lack of mutagenicity of aryl 4-guanidinobenzoates in the transplacental micronucleus assay in mice.

Two acrosin inhibitors, 4'-methylumbelliferyl 4-guanidinobenzoate and 2'-carbomethoxyphenyl 4-guanidinobenzoate, were tested for mutagenicity in the transplacental micronucleus assay and the mouse bone marrow micronucleus assay. The compounds were administered intraperitoneally at doses of 125 mg/kg and 250 mg/kg to pregnant mice. Fetal peripheral blood and maternal bone marrow cells were examined at 36 h for the frequency of micronucleated polychromatic erythrocytes. Neither compound induced micronuclei in maternal or fetal tissues. The ratio of polychromatic erythrocytes to normochromatic erythrocytes was not affected by the drug treatments indicating that the compounds had no effect on the cell cycle or mitosis in these tissues and that they were not cytotoxic. Both compounds, which show promise as vaginal contraceptives, were not mutagenic in this study.

Animals↗
PubMed1989

Nonhormonal mediation of male reproductive tract damage: data from contraceptive drug research.

Chemicals can interfere with hormonal control of the male reproductive tract and/or directly alter male reproductive tract function. A review is presented of those chemicals developed and tested as male contraceptive agents which have a direct effect on the male reproductive tract with minimal disturbance of the hormonal milieu. Such chemicals can have one or more sites of action: 1) the testis, disturbing spermatogenesis; 2) the epididymis, altering sperm maturation; 3) the vas deferens, affecting sperm transport; and 4) the accessory sex glands, entering the ejaculate and changing the functional activity of the spermatozoa. Examples of each mode of action are presented.

Animals↗
PubMed1988

Identification of senecionine and senecionine N-oxide as antifertility constituents in Senecio vulgaris.

The MeOH extract of Senecio vulgaris L., administered po to rats on Days 1-10 postcoitum, significantly decreased the number of normal fetuses per pregnant rat found at autopsy on Day 16. Additional experiments showed a similar activity for its hepatotoxic constituents senecionine and senecionine N-oxide, suggesting that the latter two compounds were probably responsible for the effect seen with the extract. No antifertility effects were seen in MeOH extract-treated hamsters.

Animals↗
PubMed1987

Inhibition of lactate dehydrogenase-X by imino-derivatives of gossypol:structure activity relationship.

Six imino-derivatives (II, III, IV, V, VI, VII) of gossypol (I) have been synthesized, and their effects were evaluated on the purified mouse lactate dehydrogenase-X. Three of these derivatives (V, VI, VII) with aldehyde groups substituted with hydrophobic functionalities showed equivalent or more inhibitory effects on lactate dehydrogenase-X than gossypol, whereas three other derivatives (II, III, IV) with aldehyde groups substituted with hydrophilic functional groups lost the ability to inhibit lactate dehydrogenase-X. It is suggested that two aldehyde groups of gossypol are not essential to inhibit lactate dehydrogenase-X. Furthermore, the hydrophobic property of the gossypol molecule seems to play a more important role in inhibiting lactate dehydrogenase-X. Therefore, lactate dehydrogenase-X inhibition by gossypol may not be associated with its antifertility mechanism, because the aldehyde group of gossypol is known to be required for its antifertility effect.

Animals↗
PubMed1987

Studies on zoapatle. V. Correlation between in vitro uterine and in vivo pregnancy interruption effects in guinea pigs.

The zoapatle plant, Montanoa tomentosa, has an extensive ethnomedical history of use in fertility regulation. Several fractions and isolates of this plant were evaulated in in vitro and in vivo tests to identify and characterize active constituents which may be responsible for its antifertility effects. The guinea pig was the animal model. Two types of in vitro activity were observed, a uterotonic type effect and an inhibition of spontaneous contractions of the uterine muscle. The in vivo effects appear to correlate with the ability of a fraction/isolate to inhibit the spontaneous contractions in in vitro testing. The non-polar fractions/isolates accounted for the inhibition of spontaneous contraction effects and the in vivo activity. The more polar fractions/isolates accounted for the uterine stimulant activity.

Abortifacient Agents↗
PubMed1986

Comparison of the spermicidal activity and acute toxicity of nonoxynol-9 and agent 741 [alkylphenoxy polyethoxy ethanol(10)].

A spermicidal agent called "741" is used in the People's Republic of China as a substitute for nonoxynol-9 in vaginal contraceptive preparations. The relative spermicidal activity of these two agents was evaluated using dog, rabbit, monkey and human semen. Acute LD50 determinations in mice were also performed. The spermicidal activity and acute toxicity of both agents were either identical or very similar in all species. Since agent 741 is less expensive than nonoxynol-9 to manufacture and equally as potent in vitro, it is an alternative spermicide for vaginal contraceptive formulations.

Animals↗
PubMed1986

Synthesis and inhibition of human acrosin and trypsin and acute toxicity of aryl 4-guanidinobenzoates.

The aryl 4-guanidinobenzoate, 4'-nitrophenyl 4-guanidinobenzoate (NPGB), is a potent inhibitor of sperm acrosin, an enzyme with an essential function in the fertilization process. NPGB prevents fertilization in a number of animal species and is a good lead compound for the development of contraceptive agents. In order to assess the efficacy of other aryl 4-guanidinobenzoates as acrosin inhibitors, 24 of these compounds were synthesized. Their inhibitory activity toward human acrosin was determined and compared with their activity toward human pancreatic trypsin in order to assess whether inhibitor sensitivity differed between these similar enzymes. Nine of the inhibitors were synthesized from phenols approved by the FDA for therapeutic use. The acute toxicity of these inhibitors in mice was determined and compared to that of nonoxynol-9, the most commonly used active ingredient in today's vaginal contraceptive preparations. All of the compounds proved to be potent inhibitors of human acrosin although 3 orders of magnitude difference were observed between the most and least effective inhibitors. Little specificity was present in regard to their inhibition of acrosin and trypsin. All the aryl 4-guanidinobenzoates synthesized from FDA-approved phenols were less toxic than nonoxynol-9, and it is concluded that these 4-guanidinobenzoates are of interest for further development and testing as nonhormonal contraceptive agents.

Acrosin↗
PubMed1985

Vaginal contraceptive activity of aryl 4-guanidinobenzoates (acrosin inhibitors) in rabbits.

Nine aryl 4-guanidinobenzoates were synthesized as inhibitors of the sperm enzyme acrosin. These esters were prepared from 4-guanidinobenzoic acid and a number of phenols which had been approved by the FDA for clinical use. The vaginal contraceptive activity of the inhibitors was evaluated in the rabbit at nonspermicidal concentrations (0.1 mg/ml). All the inhibitors except the 2'-carboxamidophenyl and the 2'-isopropyl-5'-methylphenyl 4-guanidinobenzoates caused significant reductions in fertilization compared to the controls. Several of the aryl 4-guanidinobenzoates appeared to be particularly effective. Nonoxynol-9, under the same conditions but at 10- and 100-fold higher concentrations, also showed an antifertility effect. However, even at these increased dose levels, the contraceptive efficacy of nonoxynol-9 was no higher than that of most of the inhibitors and was less consistent than that of the most active aryl 4-guanidinobenzoates. The relatively high in vivo antifertility activity exhibited by several of the aryl 4-guanidinobenzoates encourages their further evaluation as vaginal contraceptive agents.

Acrosin↗