Benzoyl peroxide stability in pharmaceutical gel preparations

The storage stability of benzoyl peroxide in the presence of both individual and combined pharmaceutical gel ingredients was investigated. Benzoyl peroxide was quite unstable in the presence of nucleophilic agents and certain acidic substances. At both 30 and 40 degrees storage temperatures, benzoyl peroxide was destroyed rapidly (within 1 month) in the presence of ethanol and acidic chelating agents. The substitution of acetone for ethanol, the elimination of chelating agents, and the addition of sodium hydroxide to gel preparations markedly reduced degradation.     

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.     

Josamycin and rosamicin: in vitro comparisons with erythromycin and clindamycin

The macrolide antibiotics josamycin and rosamicin were compared in vitro with erythromycin for activity against Staphylococcus aureus, S. epidermidis, and enterococci and with clindamycin for activity against a variety of anaerobic organisms. Rosamicin and erythromycin were similar in activity and superior to josamycin against aerobic cocci. Most isolates of S. aureus (96%), S. epidermidis (79%), and the enterococci (87%) were inhibited by 1.56 mug of either of the new macrolide compounds per ml. Clindamycin was the most active compound against the anaerobic organisms.     

Influence of methylprednisolone on the intracellular antimicrobial activity of erythromycin and clindamycin against Legionella pneumophila

We have investigated the effect of methylprednisolone on the intracellular activity of erythromycin and clindamycin in vitro. An assay system was developed for the determination of intracellular activity of antibiotics against Legionella pneumophila using guinea pig resident alveolar macrophages. Erythromycin at a concentration of 0.625 mg/L (5 x MIC) and clindamycin at a concentration of 8 mg/L (MIC) inhibited the growth of a single strain of L. pneumophila in macrophages, whilst ceftizoxime at a concentration of 0.625 mg/L (5 x MIC) did not. Methylprednisolone at therapeutic concentrations did not affect the intracellular antibacterial activity of either erythromycin or clindamycin against L. pneumophila. We found no direct effect of methylprednisolone on the intracellular antibacterial activity of either erythromycin or clindamycin.     

Treatment of rosacea: topical clindamycin versus oral tetracycline

BACKGROUND: A new topical antibiotic preparation, clindamycin in a lotion base, was compared with oral tetracycline in the treatment of rosacea. Forty-three patients clinically diagnosed as having rosacea were examined in an investigator-blinded study. METHODS: Patients used topical clindamycin lotion applied twice daily or the usual oral dose of tetracycline hydrochloride (250 mg four times a day for 3 weeks, then 250 mg twice a day for the remaining 9 weeks). Patients' lesions were examined clinically at 3-week intervals over a period of 12 weeks. RESULTS: Topical clindamycin treatment produced similar clinical results to oral tetracycline and was superior in the eradication of pustules. CONCLUSIONS: These results show topical clindamycin in a lotion base to be a safe and effective alternative to oral tetracycline therapy in the treatment of rosacea.     

Depression of the N-demethylation of erythromycin, azithromycin, clarithromycin and clindamycin in murine Toxoplasma infection

The N-demethylation of macrolides was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii (20 or 40 cysts/mouse) and microsomes were prepared from liver homogenates and jejunum villus tip enterocytes on day 10 post-infection. The rate of N-demethylation of the anti-Toxoplasma macrolides azithromycin, clarithromycin and clindamycin was investigated and compared to that of the macrolide erythromycin, a marker of activity of the cytochrome P-450 3A (CYP3A) mono-oxygenases. In infected mice (20 cysts/mouse), the rate of N-demethylation fell in the liver and jejunum for erythromycin (-25% and -35%, respectively), azithromycin (-12% and -10%, respectively), clarithromycin (-23% and -21%, respectively) and clindamycin (-20% and -28%, respectively). The degree of hepatic depression was more marked in mice receiving a 40-cysts burden: for erythromycin (-54%), azithromycin (-29%), clarithromycin (-49%) and clindamycin (-47%).     

In vitro activity of josamycin and rosamicin against Bacteroides fragilis compared with clindamycin, erythromycin, and metronidazole

The inhibitory and bactericidal activities of josamycin and rosamicin against 29 clinical isolates of Bacteroides fragilis were compared with those of clindamycin, erythromycin, and metronidazole by a broth dilution technique. Josamycin and rosamicin had similar inhibitory activity to metronidazole and clindamycin. Rosamicin had similar bactericidal activity to clindamycin but was less bactericidal than metronidazole (the most bactericidal agent tested). Josamycin was slightly more bactericidal than erythromycin (the least bactericidal agent tested), but less so than rosamicin and clindamycin.     

Efficacy and safety of azelaic acid and glycolic acid combination therapy compared with tretinoin therapy for acne

We conducted a 12-week, multicenter, randomized, double-masked, parallel-group study of the efficacy, safety, and tolerability of azelaic acid 20% cream and glycolic acid lotion compared with tretinoin 0.025% cream and a vehicle lotion to treat mild-to-moderate facial acne vulgaris. Patients treated with azelaic/glycolic acid experienced a significantly greater reduction in the number of papules, as well as a greater reduction in the number of inflammatory lesions, than those treated with tretinoin. Overall global improvement was approximately 25% in both groups. In the physician evaluations, treatment with azelaic/glycolic acid was found to cause significantly less dryness, scaling, and erythema than tretinoin. Patients also reported significantly less dryness, redness, and peeling with azelaic/glycolic acid. Significantly more patients in the azelaic/glycolic acid group than the tretinoin group reported that they felt attractive. The combination of azelaic acid and glycolic acid is a useful alternative to tretinoin, being at least as efficacious as the latter, while offering a superior tolerability and patient approval profile.     

Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study

BACKGROUND: The addition of polyolprepolymer-2 in tretinoin formulations may reduce tretinoin-induced cutaneous irritation. OBJECTIVE: This study compared the efficacy and safety of a new 0.025% tretinoin gel containing polyolprepolymer-2, its vehicle, and a commercially-available 0.025% tretinoin gel in patients with mild to moderate acne vulgaris. METHODS: In this 12-week multicenter, double-blind, parallel group study, efficacy was evaluated by objective lesion counts and the investigators' global evaluations. Subjective assessment of cutaneous irritation by the investigators and patients evaluated safety. RESULTS: The efficacy of the two active treatments in this 215 patient study was comparable, and both treatments were statistically significantly more effective than vehicle. When compared with the commercially-available tretinoin gel, the formulation containing polyolprepolymer-2 demonstrated statistically significantly less peeling at days 28, 56, and 84, statistically significantly less dryness by day 84, and statistically significantly less itching at day 14. Irritation scores for the formulation containing polyolprepolymer-2 were numerically lower but not statistically different from those of the commercially-available gel for erythema and burning. The number of cutaneous and noncutaneous adverse events were similar for both active medications. CONCLUSION: The two 0.025% gels studied demonstrated comparable efficacy. However, the gel formulation containing polyolprepolymer-2 caused significantly less peeling and drying than the commercially-available formulation by day 84 of the study.     

Copper ion-mediated modification of bases in DNA in vitro by benzoyl peroxide

The mouse skin tumor promoter benzoyl peroxide (BzPO), in conjunction with Cu(I), causes promutagenic damage in DNA. Because free radical intermediates are produced by the reaction of BzPO with Cu(I), we sought to determine whether BzPO plus Cu(I) caused DNA base damage typical of that caused by the hydroxyl radical. A broad range of modified DNA bases were measured by GC-MS with selected-ion monitoring after exposure of purified plasmid pCMV beta gal DNA to BzPO +/- Cu(I). Exposure to BzPO/Cu(I) caused up to 20-fold increases in the levels of adenine-derived modified bases, up to 4-fold increases in guanine- and cytosine-derived modified bases, and only a < 2-fold increase in thymine-derived modified bases. The guanine-derived modified base 8-hydroxyguanine was elevated to the highest net amount, approximately 160 molecules/10(5) DNA bases. Exposure to BzPO alone or Cu(I) alone induced only minor (< < 2-fold) DNA base modification. Also, benzoic acid, the major non-radical metabolite of BzPO, or BzPO plus Fe(II) were ineffective at inducing DNA base modification. The hydroxyl radical scavenger dimethyl sulfoxide inhibited BzPO/Cu(I)-induced base modification by 10-50%. These data suggest that the reaction of BzPO with Cu(I) generates hydroxyl radical or a similarly reactive intermediate which causes DNA base damage. This damage may be responsible for BzPO/Cu(I)-mediated mutagenesis.     

Activity of fleroxacin alone and in combination with clindamycin or metronidazole in experimental intra-abdominal abscesses

To assess the potential efficacy of fleroxacin in combination with clindamycin or metronidazole in mixed aerobic and anaerobic infections, we used a rat model of intra-abdominal abscesses in which the inoculum consisted of pooled rat feces mixed with BaSO4. Two hours after bacterial challenge, antimicrobial therapy was begun intravenously with regimens designed to stimulate human pharmacokinetics. A combination of clindamycin and gentamicin was included as an established treatment regimen. After 8.5 days of therapy, final bacterial counts in abscesses showed that fleroxacin alone or combined with metronidazole or clindamycin effectively eradicated Escherichia coli, with bacterial densities of < or = 2.84 +/- 0.1, < or = 2.9 +/- 0.1, and < or = 2.9 +/- 0.1 (mean +/- standard error of the mean) log10 CFU/g, respectively. The addition of either clindamycin or metronidazole to fleroxacin substantially enhanced the effectiveness of the regimens against Bacteroides fragilis, with bacterial counts of < or = 3.0 +/- 0.1 or < or = 2.9 +/- 0.1 log10 CFU/g, respectively, versus 9.2 +/- 0.2 log10 CFU/g for fleroxacin alone. The combination of metronidazole and fleroxacin also resulted in a significantly greater reduction of peptostreptococci and Bacteroides thetaiotaomicron than fleroxacin alone (< or = 2.9 +/- 0.1 versus 6.1 +/- 0.9 log10 CFU/g and 3.3 +/- 0.4 versus 8.3 +/- 0.1 log10 CFU/g, respectively). Except for those of B. fragilis, counts of other anaerobes were reduced to a greater extent by metronidazole plus fleroxacin than by clindamycin plus fleroxacin, although differences were not always significant. Metronidazole plus fleroxacin was at least as active a clindamycin plus gentamicin against all species and was significantly more active against Clostridium spp. No regimen effectively eradicated enterococci from the abscesses. These results suggest that the addition of either metronidazole or clindamycin would effectively enhance the spectrum of fleroxacin for treatment of mixed aerobic and anaerobic infections.     

High-performance liquid chromatographic determination of clindamycin in human plasma or serum: application to the bioequivalency study of clindamycin phosphate injections

This paper presents an assay of clindamycin phosphate injection in human plasma or serum. A 0.5-ml volume of plasma was used with the internal standard, propranolol. The sample was loaded onto a silica extraction column. The column was washed with deionized water and then eluted with methanol. The eluates were evaporated under nitrogen gas. The residue was reconstituted with the mobile phase and injected onto the high-performance liquid chromatographic system: a 5-micron, 25 cm X 4.6 mm I.D. ODS2 column was used with acetonitrile, tetrahydrofuran and 0.05 M phosphate buffer as the mobile phase and with ultraviolet detection at 204 nm. A limit of quantitation of 0.05 microgram/ml was found, with a coefficient of variation of 11.6% (n = 6). The linear range is between 0.05 and 20.00 micrograms/ml and gives a coefficient of determination (r2) or 0.9992. The method has been successfully applied to the bioavailability study of two commercial preparations of clindamycin phosphate injection (300 mg each) in twelve healthy adult male volunteers.     

Ocular contact time of a carbomer gel (GelTears) in humans

BACKGROUND/AIMS: Carbomers are widely used in products for the treatment of dry eye; however, the polymer gel thins on addition of probes (for example, fluorescein salt) confounding the comparison of products by objective clinical tests such as spectrophotofluorimetry or scintigraphy. A novel method of radiolabelling carbomer gels, with minimum change to their rheology, has permitted the non-invasive evaluation of precorneal residence of the gel in volunteers using gamma scintigraphy. The technique was used to evaluate the precorneal clearance of the liquid phase and of a suspended particulate in GelTears. METHODS: Low sodium technetium-99m labelled diethylenetriaminepentacetic acid (99mTc-DTPA) was used to label carbomer 940 gel, either adsorbed onto sterile charcoal to model an entrapped drug, or added directly to the gel to a final activity of 1 MBq per 25 microliters dose. The clearance of the labelled gels was then compared with 99mTc-DTPA labelled saline in 12 volunteers. RESULTS: The addition of the low sodium radiopharmaceutical produced insignificant rheological changes in the gel compared with conventional 99mTc-DTPA labelling. The residence times on the eye of the gel formulations were significantly greater than that of the saline control. At 8 minutes postdosing, the label levels retained (mean (SD)) on the ocular surface were: saline, 7% (7%); 99mTc-DTPA gel, 42% (27%); and 99mTc-carbon gel, 42% (20%) of administered dose. There was no difference observed in the precorneal distribution between 99mTc-DTPA solution and particulate markers. CONCLUSIONS: These data demonstrate that carbomer based gels significantly extend contact of solutes or suspended solids with the corneal surface. The method of labelling does not significantly change the initial viscosity and is superior to previous methods which have used sodium salts (for example, sodium fluorescein) and therefore underestimate contact time.     

A comparison of antibody responses to veterinary vaccine antigens potentiated by different adjuvants

Six adjuvant formulations were compared for their ability to potentiate the primary and memory antibody responses in mice to three companion animal vaccine immunogens--feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), and a recombinantly-derived heartworm antigen. The combination of a novel bacterial immunostimulator, gliding bacterial adjuvant (GBA), either adsorbed onto an aluminum hydroxide gel (Rehydragel HPA), or emulsified with a vehicle of polyalcohol and detergent, elicited the strongest memory responses to both virus preparations. Both forms of aluminum hydroxide gels administered without GBA gave similar levels of adjuvant effects, on par with or greater than those generated by incomplete Freund's adjuvant (IFA). The Acemannan immunostimulant was not effective in increasing the responses to the virus antigens, but increased the primary response to the heart-worm antigen over tenfold from control levels. All preparations appeared to be well tolerated, with no detectable adverse reactions observed in any of the 250 mice used. The proven safety of aluminum hydroxide adjuvants and the apparent absence of adverse reactions seen with GBA make this vehicle/adjuvant formulation worthy of additional study.     

Studies on development of pharmaceutical preparation with the purpose of improving controlled-release and bioavailability

During the past fifteen years, the experiments based on three main propositions were proceeded to carry out in our laboratory, that is, (1) Microencapsulation: The method of solvent evaporation in water or oily phases was adopted because of its comparative simplicity in the procedure and its high reproducibility. The application of pharmacokinetic consideration to in vivo evaluation of microencapsulated drugs using beagle dogs intended for obtaining controlled-release by oral administration. The pullulan acetate phthalate microcapsules containing cefadroxil were prepared by the solvent evaporation method in liquid paraffin and showed a zero-order dissolution pattern in pH 6-7.4. (2) Rectal gel preparation: The hydrogels and xerogels were prepared by Eudispert hv. These gels have excellent staying properties in the lower part of the rectum, over a fairly long period. Eudispert hv hydrogels or xerogels containing propentfylline were tested for avoidance of the first-pass metabolism. The absolute bioavailability of propentofylline from gel preparations was almost 100%. (3) Binary vehicle for transdermal delivery: The effects of glycerides, short-chain alcohols and their binary vehicles as donor components on the skin permeation of ketoprofen across the excised hairless mouse skin were evaluated with the diffusion cell. Among single vehicles, Panasate 800 as lipophilic vehicle and ethanol as hydrophilic vehicle showed the effective permeation flux of ketoprofen. The greatest enhancement was observed in an ethanol/Panasate 800 (40/60) binary vehicle. The relationship between lipophilicity and skin permeability of 16 drugs from the ethanol/Panasate 800 (40/60) binary vehicle showed a parabolic shape with a peak at a more hydrophilic range compared with other past references.     

Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa

BACKGROUND: Antibiotics are often used to treat hidradenitis, but only topical clindamycin has been shown to be effective in a randomized controlled trial. The paucity of these trials may be the result of difficulties in disease assessment. OBJECTIVE: We compare topical clindamycin with systemic tetracycline in the treatment of hidradenitis suppurativa, and study clinical disease assessment. METHODS: A total of 46 patients with stage 1 or 2 hidradenitis suppurativa were treated in a double-blind, double dummy controlled trial. RESULTS: No significant difference was found between the two types of treatment. Patients' global assessment of disease was significantly worse than physician's assessment in 3 of 5 evaluations (P = .0096 to .015), but the correlation between patients' and physicians' assessments was satisfactory after only one visit (rs = .761 to .895). Soreness was the key factor in patients' overall assessment of the disease. CONCLUSION: Systemic therapy with tetracyclines did not show better results than topical therapy with clindamycin. Subjective factors, particularly soreness, appear to be a key factor in patients' assessment of the disease and should, therefore, be included as an outcome variable in future therapy studies.     

Curing of chloroquine-resistant malaria with clindamycin

A randomized comparative trial for treating adult patients with Plasmodium falciparum malaria was performed in Lambarene, Gabon. Forty-two patients received chloroquine (25 mg/kg for 48 hr) and 38 patients received clindamycin (5 mg/kg twice a day, for five days). Chloroquine treatment cured 15 patients (36%). Twenty patients (48%) showed recrudescent malaria by day 28 of follow-up (RI resistance) and seven patients (17%) showed persistent parasitemia after chloroquine treatment (RII/III resistance). In contrast, clindamycin treatment cured 37 of 38 patients (97%) and only one (3%) showed a recrudescence by day 28 (P < 0.001). Although the parasite clearance time was significantly longer after clindamycin treatment (median five days, range 3-6) than after chloroquine treatment (median four days, range 2-8) (P < 0.01), no differences were seen in the duration of symptoms after chemotherapy. In both treatment groups, no severe side effects occurred. Clindamycin can be used as a safe alternative to achieve radical cure in semi-immune adult patients with chloroquine-resistant P. falciparum malaria in Central Africa.     

Treatment with interleukin 12 in combination with atovaquone or clindamycin significantly increases survival of mice with acute toxoplasmosis

The capacity of interleukin 12 (IL-12) to potentiate drugs in the treatment of murine toxoplasmosis was examined. IL-12 (100 ng/injection), atovaquone (10 mg/kg of body weight/day), or clindamycin (5 mg/kg/day) administered alone caused delayed time to death or minimal survival rates. In contrast, significant survival rates resulted when the same dose of IL-12 was used in combination the same doses of atovaquone (P=0.01) or clindamycin (P=0.001). Infected mice treated with IL-12 plus drug produced significantly higher levels of gamma interferon than controls. Although IL-12 was effective only when administered before infection, these results suggest that this cytokine may be a useful adjunct in the therapy of human toxoplasmosis in situations when cysts reactivate and tachyzoites start multiplying in immunocompromised patients.     

Renal failure following gentamicin in combination with clindamycin

Acute renal failure (ARF) occurred concomitantly with the administration of gentamicin in combination with clindamycin in three patients in whom no other known predisposing cause of ARF could be demonstrated. The evidence for combined nephrotoxicity consisted of the temporal relationship between administration of the antibiotics and the development of ARF, and the prompt improvement in renal function upon cessation of therapy. Complete or partial recovery of renal function occured in all patients. Renal function should be carefully monitored in patients receiving this antibiotic combination.     

A comparative study on the efficacy of the new quinolone alatrofloxacin in the treatment of experimental legionellosis in guinea pigs

The in vivo efficacy of trovafloxacin, intraperitoneally administered as alatrofloxacin (CP-116,517), was assessed and compared with that of erythromycin, alone or in combination with rifampicin, in a model of Legionella pneumophila pneumonia in guinea pigs. Trovafloxacin (5 mg/kg administered as alatrofloxacin once daily for 7 days) gave a survival rate of 100% in infected animals. Clearance of bacteria and of bacteria-induced lesions from lungs was achieved by day 6 post-inoculation. The lungs of trovafloxacin-treated animals remained free of bacteria at day 28 post-challenge. Trovafloxacin proved as effective as erythromycin administered intraperitoneally, but was superior to erythromycin alone. or in combination with rifampicin, when given orally.