text:
(60) Provisional application No. 61/843,540, filed on Jul. 8, 2013.
Provisional application No. 61/919,208, filed on Dec. 20, 2013.
Provisional application No. 61/927,717, filed on Jan. 15, 2014.
 This application is entitled to priority pursuant to 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61/843,540, filed Jul. 8, 2013, U.S. Provisional Patent Application No. 61/919,208 filed Dec. 20, 2013, and U.S. Provisional Patent Application No. 61/927,717, filed Jan. 15, 2014, the disclosure of each of which is hereby incorporated by reference herein in its entirety.
 Ivermectin is an anti-parasitic drug derivative from the macrocyclic lactones family approved for human use for treatment and chemoprophylaxis of onchocerciasis and strongyloidiasis since 1996 in the USA and since 1988 in France. In addition, it has been approved in France for the treatment of human scabies. Oral ivermectin in human and animal demodicidosis was effective in reducing Demodex folliculorum and improving demodicidosis. Moreover, when administered orally, ivermectin combined with a subsequent weekly application of topical permethrin showed treatment efficacy in a patient presenting chronic rosacea-like demodicidosis (14).
 U.S. Pat. No. 5,952,372 discloses a method of treating rosacea in humans involving orally or topically administering ivermectin. However, according to U.S. Pat. No. 5,952,372, because of the skin barrier effect, topical treatment with ivermectin would be anticipated to require once- or twice-daily applications for as long as four weeks to achieve sufficient follicle penetration and effective miticidal activity. It further describes that after ivermectin carries out its miticidal activity on skin Demodex folliculorum organisms, inflammatory responses to them begin to diminish but remnants of the dead mites still elicit some flushing and lesion formation until the cleanup processes of the body remove them, a process that requires six to eight weeks. It suggests to employ conventional anti-rosacea medications, such as oral tetracycline and topical metronidazole, to suppress early flareups and to give early clinical response during the initial phase of ivermectin administration. U.S. Pat. No. 5,952,372 contains no specific disclosure on topical treatment of PPR.
 U.S. Pat. No. 6,133,310 and U.S. Pat. No. 8,415,311 also disclose a method of treating acne rosacea by topical application of ivermectin. However, they contain no specific disclosure on treating inflammatory lesions of rosacea or PPR.
 Accordingly, treatments demonstrated to have a greater efficacy in treating PPR, particularly moderate to severe PPR, than the currently available compositions, such as metronidazole compositions, are still needed to provide greater, longer lasting, or more rapid relief to those in need of the treatment. There is a need for improved effective treatment of PPR, particularly moderate to severe PPR. Such need is met by the present invention.
 It is now demonstrated that topical administration of ivermectin provided more rapid relief of papulopustular rosacea as well as longer period of time that is free of relapse as compared to the currently available treatments, such as the topical treatment with 0.75% by weight of metronidazole.
 In one general aspect, embodiments of the present invention relate to a method of treating papulopustular rosacea in a subject in need thereof, comprising topically administering to a skin area affected by the papulopustular rosacea a therapeutically effective amount of a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier.
 Another general aspect of the present invention relates to a method of treating inflammatory lesions of papulopustular rosacea in a subject in need thereof, comprising topically administering to a skin area affected by the inflammatory lesions of papulopustular rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier. In a preferred embodiment of the present invention, the pharmaceutical composition comprises about 0.5% to 1.5% by weight ivermectin.
 In another preferred embodiment of the present invention, the subject has moderate to severe papulopustular rosacea before the treatment.
 In yet another preferred embodiment of the present invention, the subject has at least 10, preferably at least 12 and more preferably at least 15, inflammatory lesions of papulopustular rosacea, before the treatment.
 According to embodiments of the present invention, once daily topical treatment with ivermectin is significantly superior than twice-daily topical treatment with metronidazole in treating papulopustular rosacea.
 Other aspects, features and advantages of the invention will be apparent from the following disclosure, including the detailed description of the invention and its preferred embodiments and the appended claims.
 The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise embodiments shown in the drawings.
 FIG. 12 shows time to first relapse defined as first re-occurrence of IGA≧2 after the successful treatments with ivermectin and metronidazole.
 Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles, or the like which have been included in the present specification is for the purpose of providing context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.
 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.
 Ivermectin is a member of the avermectin class, which has been shown in immunopharmacological studies to exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines, such as tumor necrosis factor alpha and interleukin (IL)-1b, while upregulating the anti-inflammatory cytokine IL-1010. It is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis, that belongs to the avermectin family of macrocyclic lactones. Ivermectin is a mixture containing 5-O-demethyl-22,23-dihydroavermectin Ala plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin Ala, generally referred to as 22,23-dihydroavermectin B1a and B1b or H2B1a and H2B1b, respectively. The respective empirical formulas of H2B1a and H2B1b are C48H74O14 and C47H72O14 with molecular weights of 875.10 and 861.07 respectively.
 Ivermectin is a macrocyclic lactone derivative, its therapeutic effect is thought to be prominently due to its anti-inflammatory properties, similar to that of other macrolides.11-12 Avermectin has been reported to exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines. In addition to its anti-inflammatory mode of action, ivermectin possesses antiparasitic properties. Its predecessor, avermectin, is an antiparasitic agent of agricultural importance first isolated in 1974.13 Several studies support ivermectin's role in the effective oral treatment of cutaneous demodicidosis (in combination with topical permethrin cream) and scabies, as well as topical treatment of head lice.14-16 Ivermectin causes death of parasites, primarily through binding selectively and with high affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and muscle cells. This leads to the interruption of nerve impulses, causing paralysis and death of parasitic organisms. Ivermectin is known to act on Demodex mites in localized and generalized demodicidosis in animals and in humans.
 In the present invention, studies were conducted to evaluate the efficacy and safety of ivermectin in treating papulopustular rosacea (PPR). It was discovered that, as early as 2 weeks after the initial topical administration of a pharmaceutical composition comprising 0.5 to 1.5% (w/w) ivermectin to the subject, a significant reduction in inflammatory lesion count was observed. As used herein, a “significant reduction” refers to a reduction that is statistically significant, not due to chance alone, which has a p-value of 0.05 or less. A “significant reduction” can have a p-value of less than 0.05, 0.04, 0.03, 0.01, 0.005, 0.001, etc. As used herein, “inflammatory lesion count” refers to the number of inflammatory lesions associated with rosacea or PPR. Inflammatory lesions can be papules and/or pustules. A papule is a small, solid elevation less than one centimeter in diameter, and a pustule is a small, circumscribed elevation of the skin, which contains yellow-white exudates.
 The lesions can be, e.g., papules and/or pustules of any sizes (small or large). For example, at two weeks after the initial treatment, about 30% (p<0.001) and 27.3% (p<0.01) median reduction of the inflammatory lesion counts were observed from patients treated with ivermectin in two separate clinical studies using methods of the present invention. These reductions are statistically significant because they had p values less than 0.01 or even less than 0.001.
 This early onset of significant effectiveness is unexpected and surprising in comparison with the conventional treatments. For example, significant treatment differences were only observed from week 4 or week 8 forward in two phase III studies for the topical treatment of moderate PPR using twice-daily 15% azelaic acid (Thiboutot et al., 2003, J. Am Acad Dermatol, 48 (6): 836-845), while no statistically significant difference with respect to the median inflammatory lesion counts or the median percentage change in inflammatory lesion counts was observed at any evaluation time during the study (P>0.29) of topical treatment of moderate to severe PPR using once-daily 0.75% or 1.0% metronidazole (Dahl et al., 2001, J. Am Acad Dermatol, 45 (5): 723-730).
 This early onset of significant effectiveness is also unexpected and surprising in view of the prior teaching, that topical treatment with ivermectin would be anticipated to require once- or twice-daily applications for as long as four weeks to achieve sufficient follicle penetration and effective miticidal activity; and that after ivermectin carries out its miticidal activity on skin Demodex folliculorum organisms, remnants of the dead mites still elicit some flushing and lesion formation until the cleanup processes of the body remove them, a process that requires six to eight weeks; and that conventional anti-rosacea medications, such as oral tetracycline and topical metronidazole, are suggested to be employed to suppress early flareups and to give early clinical response during the initial phase of ivermectin administration (see, e.g., U.S. Pat. No. 5,952,372).
 Side-by-side clinical studies in the present invention also showed that methods according to embodiments of the present invention result in more effective treatment of PPR as well as longer time for the relapse of PPR to occur than the conventional topical treatment, such as that with metronidazole. In addition, methods according to embodiments of the present invention also result in less frequent adverse skin reactions than the conventional topical treatments.
 While not wishing to be bound by the theory, it is believed that the mechanism of action of ivermectin in treating papulopustular rosacea may be linked to anti-inflammatory effects of ivermectin as well as the death of Demodex mites that have been reported to be a factor in inflammation of the skin. Because ivermectin has both anti-inflammatory and anti-parasitic activities, treatment of PPR with ivermectin represents an innovative therapy addressing these relevant pathogenic factors in PPR, thus a novel addition to the current treatment armamentarium.
 According to an embodiment of the present invention, a method of treating papulopustular rosacea in a subject in need thereof, comprises topically administering to a skin area affected by the papulopustular rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier.
 As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable vehicle or diluent comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.
 The pharmaceutical compositions according to the invention are suited for treating the skin. They can be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks, pomades, powders, impregnated pads, syndets, towelettes, solutions, gels, sprays, foams, suspensions, lotions, sticks, shampoos or washing bases. They can also be in the form of suspensions of microspheres or nanospheres or of lipid or polymeric vesicles or of polymeric patches and of hydrogels for controlled release. These compositions for topical application can be in anhydrous form, in aqueous form, or in the form of an emulsion.
 In one embodiment of the present invention, the pharmaceutical composition being formulated as an emulsion, the topical pharmaceutical emulsion comprises ivermectin, and one or more other ingredients selected from the group consisting of: an oily phase comprising dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the oily phase further comprising fatty substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; at least one surfactant-emulsifier selected from the group consisting of glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a mixture of solvents and/or propenetrating agents selected from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; one or more gelling agents selected from the group consisting of carbomers, cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and modified starches; and water.
 In a preferred embodiment of the present invention, the pharmaceutical composition comprises 0.5-1.5% (w/w) ivermectin, more preferably, about 1% (w/w) ivermectin, and a pharmaceutically acceptable carrier.
 In another preferred embodiment of the present invention, the pharmaceutical composition comprises about 1% (w/w) ivermectin, and one or more inactive ingredients selected from the group consisting of carbomer, such as carbomer copolymer type B; cetyl alcohol; citric acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin; isopropyl palmitate; methyl paraben; oleyl alcohol; phenoxyethanol; polyoxyl 20 cetostearyl ether; propylene glycol; propyl paraben; purified water; sodium hydroxide; sorbitan monostearate and stearyl alcohol.
 As used herein, the term “subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been administered compounds or topical formulations according to embodiments of the invention. Preferably, a subject is in need of, or has been the object of observation or experiment of, treatment or prevention of papulopustular rosacea.
 As known to those skilled in the art, an “intent-to-treat population” or “ITT population” refers to all subjects who are randomized in a clinical study and to whom the study drug is administered. “ITT-LOCF” refers to the ITT population using the Last Observation Carried Forward (LOCF) method, a standard method of handling missing data, which imputes or fills in values based on existing data. “ITT-MI” refers to the ITT population using the multiple imputations (MI) method based on all the data available in the model, another method for processing data known to those skilled in the art. A “per protocol population” or “PP population” refers to subjects of the ITT population in a clinical study who have no major deviations from the protocol of study.
 In one embodiment, “treatment” or “treating” refers to an amelioration, prophylaxis, or reversal of a disease or disorder, or of at least one discernible symptom thereof. In another embodiment, “treatment” or “treating” refers to an amelioration, prophylaxis, or reversal of at least one measurable physical parameter related to the disease or disorder being treated, not necessarily discernible in or by the mammal. In yet another embodiment, “treatment” or “treating” refers to inhibiting or slowing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, “treatment” or “treating” refers to delaying the onset of a disease or disorder.
 Success of treating PPR can be measured using methods known in the art, such as by the reduction of inflammatory lesion count from the baseline before treatment, by an improvement from the baseline in an investigator's global assessment (IGA) score, or by both the reduction of inflammatory lesion count and the IGA score.
 The IGA score is determined by a trained medical professional evaluating the skin condition of a patient utilizing an investigative global assessment of the skin condition. Typically, such global assessments assign a value to the degree of rosacea exhibited by the skin. In addition to the assessment made by the medical professional, the patient's input and observations of their skin condition and responses to various inquiries (e.g., stinging or burning sensations) also play a role in determining the IGA score that is assigned. For example, the IGA score for rosacea (Table 1) can range, for example, from 0 (clear) to 1 (almost clear) to 2 (mild) to 3 (moderate) to 4 (Severe), including values between these numeric gradings, such as 1.5, 2.6, 3.4 etc. (e.g., intervals of 0.1).
 In view of the present disclosure, a skin area that is affected by papulopustular rosacea can be identified using any diagnostic signs or means known in the art, and can be treated by methods according to embodiments of the present invention. Patients can have papulopustular rosacea at different stages, from mild to severe.
 In a preferred embodiment, the patient has moderate to severe papulopustular rosacea. As used herein, a patient having “moderate to severe papulopustular rosacea” has at least moderate facial erythema and at least 10 papulopustular lesions before treatment. For example, the patient can have an IGA of rosacea of 3 or 4, and at least 10, 15, 20, 25 or more papulopustular lesions before treatment.
 According to embodiments of the present invention, the papulopustular rosacea is treated by topically applying to a skin area affected by the papulopustular rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier, and the treatment results in a reduction in the inflammatory lesion count from the baseline number of PPR lesions (before treatment) by at least 1 to 100 lesions or more, such as at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 50, 60, 70, 80, 90 or 100 lesions or more. According to embodiments of the present invention, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% reduction in inflammatory lesion count is observed after the treatment. Depending on the number of inflammatory lesions, and other factors, such as the conditions of the patient, the treatment can last as long as it is needed, such as 4 to 12 weeks.
 According to other embodiments of the present invention, the treatment reduces the IGA score in the treated subject. As used herein, the “success rate” in a clinical study refers to the percentage of subjects in the study having an IGA of 0 (“clear”) or 1 (“almost clear”) after the treatment.
 According to embodiments of the present invention, the pharmaceutical composition can be topically administered once or twice daily, preferably once daily.
 According to embodiments of the present invention, after the initial successful treatment with ivermectin, i.e., to an IGA of 0 or 1, it takes a longer time to relapse, i.e., to an IGA of 2 or above, as compared to the conventional treatments, such as topical treatment with 0.75% by weight metronidazole. For example, treatment with ivermectin (1%) once daily (QD) resulted in a statistically significant extended remission (e.g., delayed time to first relapse, and increase in the number of treatment free days) of rosacea when compared to metronidazole 0.75% BID in subjects who were successfully treated (IGA 0 or 1) for 16 weeks. There was also a numerical trend in favor of ivermectin 1% QD for the relapse rates.
 As used herein, “time to first relapse” is defined as the time elapsed between initial successful treatment to an IGA of rosacea of 0 or 1 to the first reoccurrence of the IGA to 2 or more in a subject. According to embodiments of the present invention, the median time to first relapse is about 110, 115, 120, 125, 130, 135, 140, 145 or 150 days or more in subjects treated with ivermectin, with a p value of 0.05 or less.
 Another aspect of the present invention relates to a method of treating inflammatory lesions of papulopustular rosacea in a subject in need thereof, comprising topically administering to a skin area affected by the inflammatory lesions of papulopustular rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier.
 Preferably the subject has moderate to severe PPR before the treatment. More preferably, the subject has at least 15 inflammatory lesions of PPR before the treatment.
 In another preferred embodiment, at two weeks after the initial treatment, about 27% or more median reduction of the inflammatory lesion counts is observed from subjects treated with ivermectin, with a p value of 0.01 or less.
 Preferably, the pharmaceutical composition comprises 0.5% to 1.5% by weight ivermectin, more preferably about 1% by weight ivermectin.
 In an embodiment of the present invention, as early as 2 weeks after the initial administration of the pharmaceutical composition to the subject, significant reduction in the inflammatory lesion count in the subject is observed. In other embodiments of the present invention, the method results in more reduction of the inflammatory lesion count and longer relapse-free time of the inflammatory lesions of rosacea in the subject in comparison to that achieved by topically administering to the subject a second pharmaceutical composition comprising 0.75% by weight metronidazole.
 This invention will be better understood by reference to the non-limiting examples that follow, but those skilled in the art will readily appreciate that the examples are only illustrative of the invention and the claims which follow thereafter.
 Unless otherwise indicated, all percentages of the ingredients in the present application are percentages by weight (w/w).
 A phase II, randomized, investigator-blinded, parallel-group, active- and vehicle-controlled study was conducted to determine the optimal concentration and dose regimen of topical ivermectin cream for the treatment of inflammatory lesions of rosacea, and evaluate efficacy and safety.
 The subjects were randomized to receive one of the following six (6) regimens for 12 weeks: ivermectin 0.1% (w/w) once-daily (QD), ivermectin 0.3% (w/w) QD, ivermectin 1% (w/w) QD, ivermectin 1% (w/w) twice-daily (BID), metronidazole gel 0.75% (w/w) BID, or vehicle QD. The 6 groups were comparable in terms of demographic and baseline disease characteristics (Table 2): majority were female, Caucasian, with a skin phototype II and a mean age of 51.9±14.2 years. On average, the subjects had 35.4±23.8 inflammatory lesions, and the majority (51.0%) had an IGA of 3 (moderate).
 Inflammatory lesion (sum of papules and pustules) counts, rate of success [% subjects “clear” or “almost clear” based on Investigator's Global Assessment (IGA), a scale from 0 (clear) to 4 (severe)], erythema [from 0 (none) to 3 (severe)], telangiectasia [from 0 (none) to 3 (severe)], adverse events, and satisfaction questionnaire (at the end of the study) were determined during the study.
 FIG. 1 shows the median percentage change from baseline in lesion counts (ITT-LOCF population).
 At week 12, both ivermectin 1% (w/w) QD and BID were significantly more effective than vehicle QD in the ITT-LOCF analysis based on the percentage change from baseline in inflammatory lesion counts (median: −78.3% and −78.9% vs. −60.6%; both p<0.05) (FIG. 1); this was also confirmed in the PP analysis. Although ivermectin 1% (w/w) BID was significantly more efficacious than vehicle, its magnitude of effect was not greater than ivermectin 1% (w/w) QD. A numeric trend favoring ivermectin 1% QD compared with metronidazole 0.75% BID was also observed in terms of median % change from baseline in inflammatory lesion counts [−78.3% vs. −69.2% at Week 12 (ITT-LOCF)]; the sample size was not large enough to detect differences between these groups.
 All ivermectin dose regimens led to a significantly greater success rate than vehicle (70.8%, 65.4%, 63.8% and 62.7% for ivermectin 1% BID, 1% QD, 0.3% QD and 0.1% QD, respectively, vs. 42.0% for vehicle at Week 12; all p<0.05). Furthermore, the success rate for Metronidazole was 62.5%. No difference was observed in the change in erythema or telangiectasia between the active and control groups.
 All regimens were safe and well-tolerated, with similarly low incidence of adverse events. There were no serious related AEs. The majority of related AEs were mild, transient and dermatologic in nature, the most frequent for the ivermectin groups being skin discomfort (4 subjects), skin burning sensation (4 subjects), and worsening of rosacea (3 subjects).
 FIG. 2 illustrates subjects' response to the statement “the product improves my rosacea” (ITT Observed). With increasing dosage of ivermectin, more subjects agreed with the statement “the product improves my rosacea” (FIG. 2) and were satisfied with the product (data not shown). The result was superior in ivermectin 1% QD and BID groups compared to the metronidazole 0.75% BID group. The majority of subjects in all Ivermectin groups considered that the product was easy to use (at least 95.5%), pleasant to use (at least 77.3%), and did not irritate the skin (at least 70.2%).
 Topical administration of all tested ivermectin dose regimens (1% BID, 1% QD, 0.3% QD and 0.1% QD) led to a significantly greater success rate in treating PPR than vehicle; the result was superior in ivermectin 1% QD and BID groups compared to the metronidazole 0.75% BID group; and once daily topical administration of 1% (w/w) ivermectin was considered the optimal dose regimen, because it was safe, well tolerated, and provided significantly greater efficacy than vehicle for the treatment of PPR. Once daily topical administration is further preferred because it promotes better patient compliance.
 To demonstrate the efficacy and safety of once-daily ivermectin 1% (w/w) cream in subjects with PPR, two identically designed randomized, double-blind, controlled studies were conducted (hereafter designated Study 1 and Study 2). Both studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practices, and in compliance with local regulatory requirements.
 Each study had three parts. In the first part of the study, subjects with PPR were treated with ivermectin 1% cream (IVM 1%) or vehicle once daily at bedtime for 12 weeks. In the second part of the study, subjects initially treated with IVM 1% once daily at bedtime continued the same treatment, while subjects treated with the vehicle once daily switched to topical treatment with azelaic acid 15% gel twice daily, in the morning and evening. The third part of the study consisted of 4 weeks safety follow-up, without treatment.
 Eligible subjects were 18 years or older, with moderate or severe papulopustular rosacea as noted by an IGA of 3 (“several small or large papules/pustules, moderate erythema”) or 4 (“numerous small and/or large papules/pustules, severe erythema”), and presenting with 15-70 facial inflammatory lesions (papules and pustules). A total of 683 subjects with moderate to severe PPR were randomized in Study 1 (IVM 1%: 451, vehicle: 232), and 688 subjects in Study 2 (IVM 1%: 459, vehicle: 229) (FIG. 3).
 Eligible subjects received either ivermectin cream 1% cream (once daily every day at bedtime) or vehicle cream (once daily every day at bedtime) on the entire face for 12 weeks. They were instructed to apply a thin film of cream on the entire face (right and left cheeks, forehead, chin and nose), e.g., in a pea-size amount of the cream, avoiding the upper and lower eyelids, lips, eyes and mouth. Subjects were also instructed to avoid rosacea triggers, such as sudden exposure to heat, certain foods, and excessive sun exposure. Study visits during the first study were as follows: screening visits, baseline, weeks 2, 4, 8, and 12 after the initial administration.
 Efficacy assessments at each visit were the IGA of disease severity, and inflammatory lesion counts (papules and pustules) on each of the five facial regions (forehead, chin, nose, right cheek, left cheek). Safety assessments included adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each study visit evaluated on a 4-point scale [from 0 (none) to 3 (severe)], and laboratory parameters (hematology and biochemistry) measured before and after treatment. Other assessments included the subject's evaluation of their rosacea improvement at the end of the study (week 12) compared to their condition at baseline, and two quality of life (QoL) questionnaires [a dermatology-specific instrument, the Dermatology Life Quality Index (DLQI)],17 and a rosacea-specific instrument, the RosaQoL™18 completed at baseline and week 12.
 The co-primary efficacy endpoints in both studies were the success rate based on the IGA outcome and absolute change from baseline in inflammatory lesion counts at the end of week 12 of the studies. The success rate based on IGA score [% of subjects who achieved “clear” or “almost clear” ratings on the IGA scale at week 12 (ITT-LOCF)] was analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by analysis site, using the general association statistic. The absolute change in inflammatory lesion counts from baseline to week 12 (ITT-LOCF) was analyzed by analysis of covariance (ANCOVA). Missing data at week 12 in the ITT population were imputed by the LOCF approach. Also, sensitivity analyses were conducted to impute missing data in order to assess the robustness of the primary efficacy results. The secondary efficacy endpoint was percent change in inflammatory lesion counts from baseline at week 12 (ITT-LOCF). The QoL questionnaires were analyzed using the Wilcoxon rank sum test, and other variables were descriptively analyzed. High mean scores from the QoL questionnaires indicated a low quality of life.
 In Studies 1 and 2, the vast majority of subjects completed the study (91.4% and 92.6%, respectively). The treatment groups were similar at baseline in terms of demographics and baseline disease characteristics, with about 31-33 inflammatory lesions on average and the majority having moderate rosacea (Table 3). Most subjects were female (68.2% and 66.7% in Studies 1 and 2, respectively) and Caucasian/white (96.2% and 95.3%), with a mean age of 50.4 and 50.2 years, respectively. Additionally, treatment groups were comparable regarding rates/reasons for early study discontinuation (FIG. 3).
 The proportion of subjects achieving IGA success (“clear” or “almost clear”) at week 12 for Studies 1 and 2 were 38.4% and 40.1%, respectively for IVM 1% compared to 11.6% and 18.8% for vehicle (both p<0.001; FIG. 4A). A significant difference between treatment arms in both studies was observed based on IGA since week 4 (10.9% and 11.8% versus 5.6% and 5.7%, respectively; both p<0.05), and was sustained until Week 12 (FIGS. 4B and 4C).
 For inflammatory lesion counts, the mean difference between IVM 1% and vehicle from baseline to week 12 was −8.13 lesions for Study 1 and −8.22 for Study 2 (both p<0.001 versus vehicle), with a 95% CI of [−10.12, −6.13] and [−10.18, −6.25], respectively (FIGS. 5A and 5B). A mean reduction of 9 lesion counts was observed at week 2 in both studies when treated with IVM 1% (FIGS. 5A and 5B). Median reduction from baseline in inflammatory lesion counts for both studies was 76.0% and 75.0%, respectively, versus 50.0% for both vehicle groups at week 12 (p<0.001), with significant difference observed by week 2 at a median reduction of 30% and 27.3% (FIGS. 5C and 5D). This significant reduction in inflammatory lesion counts as early as week 2 was exceptional when compared with similar data from treatment with metronidazole or azelaic acid.
 The incidence of AEs was comparable between Studies 1 and 2 (40.5% and 36.5% for IVM 1% versus 39.4% and 36.5% for vehicle, respectively). Fewer subjects in IVM 1% groups tended to report related AEs than in vehicle groups (4.2% and 2.6% versus 7.8% and 6.5%, respectively), as well as for related dermatologic AEs (3.5% and 1.5% versus 6.9% and 5.7%) and related AEs leading to discontinuation (1.3% and 0.2%, versus 1.7% for both vehicle groups). A similarly low proportion of subjects reported serious AEs for IVM 1% and vehicle groups (0.7% and 1.5% versus 0.4% and 1.7%). There were no related serious AEs. The most common related AE in Study 1 was sensation of skin burning: 8 (1.8%) in IVM 1% subjects versus 6 (2.6%) for vehicle. For Study 2, the most common related AEs for IVM 1% were pruritis and dry skin (3 subjects each (0.7%)) compared to 0 and 2 subjects (0.9%) for vehicle, respectively. In addition, laboratory tests did not demonstrate clinically significant abnormalities.
 At baseline before treatment application, a large proportion of subjects presented with local cutaneous symptoms consistent with rosacea, especially mild or moderate dry skin (for Studies 1 and 2, 63.0% and 57.0% for IVM 1%, and 59.3% and 60.0% for vehicle, respectively) and mild or moderate itching (57.3% and 49.4% for IVM 1%, and 45.4% and 49.1% for vehicle). At week 12 (last available data observed), the majority of subjects had none of the 2 cutaneous symptoms. A trend was observed in terms of absence of dryness in 83-86% of IVM 1% subjects versus 72-76% for vehicle, as well as for absence of itching in 82-85% for IVM 1% versus 70-78% for vehicle.
 Improvement after treatment was rated by subjects as “excellent” or “good” by 69% and 66.2% for IVM 1% compared to 38.6% and 34.4% for vehicle (p<0.001), respectively (FIG. 6). “Excellent” improvement was reported by 34.3% and 32.0% for IVM 1% versus 9.5% and 7.3% for vehicle.
 After 12 weeks of treatment, improved QoL scores were observed for subjects in the IVM 1% compared to vehicle groups. For the DLQI, it is of note that no difference between treatment groups was observed at baseline. At the end of each study, more subjects in the IVM 1% group (about 53%) than vehicle (about 35%) considered that their disease had no effect on their overall QoL (p<0.001). For RosaQoL™, improvement in QoL from baseline was higher in both studies for IVM 1% (−0.64±0.7 and −0.60±0.6 versus −0.35+0.5 for both vehicle groups (p<0.001 and p=0.001 for Studies 1 and 2, respectively). This result indicates that a higher proportion of subjects felt that their quality of life was not negatively impacted by rosacea in the group treated with IVM, compared to the control group treated with vehicle.
 IGA was assessed during the second part of the studies (40 weeks). The percentages of subjects treated with IVM 1% achieving an IGA score of 0 or 1 continued to increase up to week 52, the end of the second part of the studies. The success rate (IGA=0 or 1) at week 52 was 71.1% and 76% in studies 1 and 2 respectively. In both studies, the incidences were comparable in the 2 groups of subjects treated by IVM 1% cream QD and azelaic acid 15% gel BID across the categories of related AEs, dermatologic AEs, serious AEs, related AEs leading to discontinuation, and AEs of special interests. There was no serious related AEs.
 In the follow up third part of the studies, subjects treated with IVM 1% cream QD and azelaic acid 15% gel BID during the second part of the studies were comparable in reporting AEs. No subjects reported related serious AEs, related AEs leading to discontinuation.
 The most frequent (>0.5% in any arm) AEs were skin disorders, and were less frequent with IVM 1% cream QD than azelaic acid 15% gel BID in both studies.
 These two pivotal studies demonstrated the efficacy and safety of topical ivermectin 1% cream in the treatment of inflammatory lesions of rosacea with reproducibility. The effect was robust and highly significant (p, 0.001) in all primary and secondary endpoints at week 12 (ITT-LOCF). Onset of treatment effect was observed at week 4 in each study based on both IGA and lesion counts. Onset of treatment effect was observed at week 2 in each study based on lesion counts. The ivermectin 1% cream was well tolerated and safe in both studies. No notable difference was observed between the ivermectin 1% cream QD and corresponding vehicle and azelaic acid 15% gel BID. The most frequent (>0.5% in any arm) AEs were skin disorders, and were less frequent with IVM 1% cream QD than with the respective comparator. In addition, the continued daily application of the Ivermectin 1% Cream QD up to 1 year is well tolerated, with no unexpected safety findings associated with chronic use.
 In conclusion, ivermectin, such as 1% ivermectin cream, was effective and safe in treating papulopustular rosacea.
 This was an investigator-blinded, randomized, parallel group study comparing the efficacy and safety of ivermectin (hereafter designated IVM) 1% (w/w) cream vs. metronidazole 0.75% (w/w) cream with a 16-week period A and a 36-week period B to study recurrence. Study visits during Period A were as follows: a screening visit, and at baseline, weeks 3, 6, 9, 12 and 16.
 Eligible subjects were 18 years or older, with moderate or severe papulopustular rosacea as noted by an IGA of 3 (“several small or large papules/pustules, moderate erythema”) or 4 (“numerous small and/or large papules/pustules, severe erythema”), and presenting with 15-70 facial inflammatory lesions (papules and pustules).
 Subjects were randomized in a 1:1 ratio to receive either IVM 1% cream (once daily, QD, at bedtime) or metronidazole 0.75% cream (twice daily, BID, as per labelling at morning and bedtime) for 16 weeks. Study drugs were applied in a thin film on the entire face (right and left cheeks, forehead, chin and nose), avoiding the upper and lower eyelids, lips, eyes and mouth. The subjects were instructed to maintain a consistent lifestyle throughout the study regarding rosacea triggers (i.e. avoiding environmental factors, certain foods, and excessive sun exposure).
 Efficacy assessments at each visit were inflammatory lesion counts (papules and pustules) counted on five facial regions (forehead, chin, nose, right cheek, left cheek), and the Investigator's Global Assessment (IGA) of disease severity. Safety assessments included adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each visit evaluated on a 4-point scale (from 0 (none) to 3 (severe)), and laboratory parameters measured at baseline, weeks 9 and 16. Other assessments included the subject's evaluation of rosacea improvement compared to their condition at baseline, and subject's appreciation questionnaire at the end of the study (regarding satisfaction with the study drug). Lastly, a quality of life questionnaire (Dermatology Life Quality Index (DLQI)) was completed at baseline and at the end of the study (week 16).
 The ITT population included all subjects who were randomized and to whom the study drug was administered. The safety population included all subjects who received the study medication. The primary efficacy endpoint, percent change in inflammatory lesion counts from baseline to week 16, was analyzed using the CMH test stratified on center, with ridit transformation and row mean score difference statistic. Secondary efficacy endpoints included success rate (percent of subjects with IGA rated 0 (“clear”) or 1 (“almost clear”) (analyzed by CMH test stratified on center using general association statistic), IGA and absolute change in lesion counts (analyzed using ANCOVA, including treatments and analysis center as factors, and baseline as covariate). LOCF was the primary method for imputation of missing data, and multiple imputations (MI) method was used for sensitivity. Other variables were descriptively analyzed.
 A total of 1,034 subjects were screened and 962 randomized to receive IVM 1% cream (n=478) or metronidazole 0.75% cream (n=484); 902 (93.8%) completed the study (FIG. 8). Treatment groups were comparable at baseline in terms of demographics and baseline disease characteristics, with about 32 inflammatory lesions on average and the majority having moderate rosacea (83.3% with an IGA of 3) (Table 5). As expected, the quantity of product applied in the metronidazole group (BID applications) was nearly twice as much as the product applied in the IVM 1% group (QD), with a mean of 1.31 g vs. 0.72 g, respectively.
 Regarding the primary endpoint, at week 16 (ITT-LOCF), IVM 1% cream was significantly superior to metronidazole 0.75% cream in terms of percent reduction from baseline in inflammatory lesion counts (83.0% vs. 73.7%; p<0.001; FIG. 9). This difference was observed as early as week 3 (ITT-LOCF) (as soon as week 6 with ITT-MI), and this continued through week 16 (all p-values <0.04). It should be noted that in this study, there was no study visit or assessment prior to Week 3, thus the differences in treatment could have been observed earlier than week 3 if the first study visit was conducted earlier. Similar results were found for the IGA success rate (subjects rated “clear” or “almost clear”): 84.9% for IVM 1% cream vs. 75.4% for metronidazole 0.75% cream at week 16 (ITT-LOCF) (p<0.001). As illustrated in FIG. 10, the difference in IGA was the highest at week 12 (14.9% superior for ivermectin).
 About 13% more subjects were rated as “clear” in terms of IGA for IVM 1% than metronidazole 0.75% (34.9% vs. 21.7%, respectively). Furthermore, in a subgroup analysis of success rate according to IGA severity, about 20% more subjects with severe rosacea at baseline in the IVM 1% group achieved success (82.5% vs. 63.0%).
 The incidence of adverse events (AEs) was similar between groups (32.4% vs. 33.1% of subjects in the IVM 1% and metronidazole 0.75% groups, respectively), as well as for related AEs (2.3% vs. 3.7%). Furthermore, a comparably low number of subjects experienced a related dermatologic AE (9 subjects (1.9%) in the IVM 1% group and 12 (2.5%) in the metronidazole 0.75% group). The most common related AE was skin irritation (3 subjects (0.6%) vs. 4 subjects (0.8%) for IVM 1% and metronidazole 0.75%, respectively). Thirteen subjects reported serious but unrelated AEs. A total of 3 subjects (0.6%) in the IVM 1% group experienced related adverse events leading to discontinuation (due to skin irritation and hypersensitivity), compared to 10 (2.1%) subjects in the metronidazole 0.75% group (due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritis, and general disorders (hot feeling)).
 In terms of local tolerance, the incidence of worsening from baseline was higher in the metronidazole 0.75% group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10.0%), and itching (11.4% vs. 8.8%). Laboratory tests did not demonstrate clinically significant abnormalities.
 At the end of period A of this study, the majority (85.5%) of subjects in the IVM 1% group rated their global improvement as “excellent” or “good” compared to 74.8% in the metronidazole 0.75% group. Furthermore, more subjects receiving IVM 1% reported an “excellent” improvement of their rosacea (52.3% vs. 37.0%, respectively; FIG. 11). Regarding the subject's appreciation questionnaire, more subjects in the IVM 1% group were satisfied with the study drug (76.0% vs. 61.3% in the metronidazole 0.75% group). In addition, more subjects treated by IVM 1% tended to consider the product easy to use and that the time needed for application was satisfactory, whereas more subjects found metronidazole 0.75% to be irritating (data not shown).
 At baseline, the mean DLQI scores were similar between groups (6.95 for IVM 1% and 6.05 for metronidazole 0.75%, respectively). Patients treated with IVM 1% showed a higher numerical decrease in their DLQI score than patients treated with metronidazole 0.75% (−5.18 vs. −3.92; p<0.01), indicating a higher improvement in quality of life. At the end of the study, 71% of patients treated with IVM 1% reported no effect at all on their quality of life (vs. 64% for metronidazole 0.75%), which means that a higher proportion of subjects felt that their quality of life was not negatively impacted by rosacea in the group treated with IVM, compared to the group treated with metronidazole. The study drugs diverged in favor of IVM 1% in the symptoms and feelings sub-scale (level of itching, soreness, pain or stinging: “not at all” for 78.7% vs. 63.0% in the metronidazole 0.75% group; level of embarrassment or self-consciousness: “not at all” for 70.3% vs. 60.1%, respectively).
 Topical metronidazole 0.75% (w/w) has been one of the most frequently used therapies in the treatment of papulopustular rosacea. In this study, IVM 1% cream was significantly superior to metronidazole 0.75% cream in terms of percent reduction from baseline in inflammatory lesion counts, with an onset of efficacy (first difference vs. metronidazole 0.75%) as early as 3 weeks (or even earlier) that continued through 16 weeks. The findings show that ivermectin is more efficacious than metronidazole, with a tendency even in patients with higher lesion counts.
 An overall good safety profile was observed for IVM, and it was well-tolerated in comparison with metronidazole. It is not surprising that for both products, patients experienced a similarly low number of related adverse events, particularly since the tolerability of metronidazole is known to be satisfactory. Metronidazole's higher incidence of worsening from baseline concerning stinging/burning, dryness, and itching may be attributed to the usual signs and symptoms of rosacea. Nevertheless, this affected the level of quality of life as measured by the DLQI, as more patients in the metronidazole group reported itching, soreness, pain or stinging.
 Patient-reported outcomes for IVM 1% cream were consistent with its superior efficacy results. More patients using IVM indicated that the product was easy to use and that the time needed for application was satisfactory, implying that the daily application is more convenient than metronidazole's twice-daily regimen. Related to quality of life measures, fewer patients using IVM considered themselves to be embarrassed or self-conscious. Thus, ivermectin appears to be adapted to the complex etiology of rosacea, and in the study IVM 1% cream demonstrated superiority to metronidazole 0.75% cream in terms of inflammatory lesion reduction. As noted in the afore-mentioned Cochrane review, few robust studies have compared topical metronidazole with another rosacea treatment and in three identified studies, topical metronidazole was either non-significantly different or less effective than azelaic acid.8 While metronidazole has been used in the past as a reasonable treatment for the papulo-pustular lesions of rosacea, its efficacy is surpassed by that of ivermectin along with the advantage of once-daily dosing.
 The relapse among subjects successfully treated at the end of the Period A was studied during the treatment free Period B (36 weeks). At the end of Period A, only subjects with an IGA of “0” or “1” (clear or almost clear) were eligible for entering Period B. Then, their study treatment was discontinued and the subjects were followed for up to 8 months (36 weeks). In case of reoccurrence of an IGA of at least “2” (mild) at any time during Period B, the subjects were retreated with the same treatment received during the Period A. The re-treatment was stopped as soon as the IGA was back to “0” or “1” (clear or almost clear). The maximum duration of re-treatment was 16 consecutive weeks to mimic the Period A treatment duration. In order to characterize the relapses, the following parameters were assessed: (1) time of first relapse (time elapsed between Week 16 and first reoccurrence of IGA at “2”, “3” or “4” inducing a retreatment course), (2) relapse rate (percentage of subjects with reoccurrence of IGA at “2”, “3” or “4” after a period free of study treatment) and (3) number of days free of treatment.
 At the start of Period B, treatment groups were comparable with respect to the demographic. Of the total 757 subjects included in Period B (399 in Ivermectin 1% and 358 in Metronidazole 0.75% groups, respectively), 504 (66.6%) were female, 754 (99.6%) were Caucasian and the mean age was 51.9 years. In terms of disease characteristics, the means inflammatory lesion counts were similar in both groups (median 2.0). But, the proportion of subjects with an IGA of 0 was higher in Ivermectin group than in Metronidazole group (41.6% versus 29.1%) due to the higher efficacy of Ivermectin treatment from Period A.
 The time to first relapse, defined as time elapsed between Week 16 and first reoccurrence of IGA at “2”, “3” or“4” was analyzed following 2 definitions: (1) the first one was based on IGA only; and (2) the second one took also into account any major deviations by imputing relapse the day of first major deviation. For each definition, a sensitivity analysis was performed by imputing relapse 4 weeks after discontinuation for all subjects who discontinued early from Period B without relapse. Relapse rates followed the same convention analyses as the time to relapse.
 The median times to first relapse were 115 days for ivermectin 1% QD and 85 days for Metronidazole 0.75% BID (p=0.0365), the relapse rates were 62.7% and 68.4% respectively (Table 7). See also FIG. 12. When conducting the sensitivity analysis by imputing relapse 4 weeks later to subjects who discontinued early without relapse, the medians were 114 days and 85 days (p=0.0594) and the relapse rates were 66.2% and 70.4%, respectively. Similar results were obtained when taking also into account the day of first major deviation.
 Number of days free of treatment was defined for each subject enrolled in period B as the time interval between a visit where IGA is assessed as 0 or 1 and the next visit. The number of treatment-free days is the summation over all visits of period B meeting this criterion. An additional analysis was also performed by subtracting from the days free of treatment any time interval between visits when the subject while being IGA 0 or 1 had a major protocol deviation.
 Based on IGA score showed a mean days free of treatment of 183 days for ivermectin 1% QD versus 170 days for metronidazole (p=0.026). When taking into account the protocol deviations the mean days free of treatment remained nearly the same 181 days versus 168 days (p=0.021) in favor of ivermectin 1% QD.
 Ivermectin 1% cream QD treatment resulted in a statistically significant extended remission (i.e. delayed time to first relapse, and increase in the number of treatment free days) of rosacea when compared to Metronidazole 0.75% BID in subjects who were successfully treated (IGA 0 (clear) or 1 (almost clear)) for 16 weeks. There was also a numerical trend in favor of Ivermectin 1% cream QD for the relapse rates (62.7% and 68.4% in the Ivermectin 1% group and Metronidazole 0.75% group, respectively). It should be noted that the differences observed in favor of Ivermectin 1% in Period B are presumably the consequence of the higher efficacy of Ivermectin compared to Metronidazole observed at the end of Period A, with a higher proportion of subjects with an IGA=0 in the Ivermectin group (41.6% and 29.1% in Ivermectin and Metronidazole, respectively).
 The overall pharmacoeconomic benefit of Ivermectin 1% cream QD versus Metronidazole 0.75% cream BID over the one year duration of the study (Period A & B), is considerable when viewed as the sum of the following elements: benefit of Ivermectin over Metronidazole observed at the end of Period A (84.9% of success in Ivermectin group Vs. 75.4% in Metronidazole group), time to first relapse (115 Vs. 85 days), relapse rate (62.7% Vs. 68.4%) and number of days free of treatment (183.4 Vs. 170.4).
 1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 2002; 46:584-587.
 2. Gupta M A, Gupta A K, Chen S J, Johnson A M. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey-Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol 2005; 153(6):1176-81.
 3. Del Rosso J Q, Gallo R L, Tanghetti E, Webster G, Thiboutot D. An evaluation of potential correlations between pathophysiologic mechanisms, clinical manifestations, and management of rosacea. Cutis 2013; 91(3 Suppl):1-8.
 4. Del Rosso J Q, Gallo R L, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol 2012; 11:694-700.
 5. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc 2011; 15:2-11.
 6. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. Br J Dermatol 1993; 128(6):650-9.
 7. Karincaoglu Y, Bayram N, Aycan O, Esrefoglu M. The clinical importance of demodex folliculorum presenting with nonspecific facial signs and symptoms. J Dermatol 2004; 31(8):618-26.
 8. van Zuuren E J, Kramer S F, Carter B R, Graber M A, Fedorowicz Z. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol 2011; 165(4):760-81.
 9. Elewski B E. Results of a national rosacea patient survey: common issues that concern rosacea sufferers. J Drugs Dermatol 2009; 8(2):120-3.
 10. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol 2009; 23(4):449-55.
 11. Yanagihara K, Kadoto J, Kohno S. Diffuse panbronchiolitis-pathophysiology and treatment mechanisms. Int J Antimicrob Agents 2001; 18 Suppl 1:S83-7.
 12. Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombola L, Carnuccio R, et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292(1):156-63.
 13. Campbell W C. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol 2012; 13(6):853-65.
 14. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol 1999; 41: 775-7.
 15. Trendelenburg M, Büchner S, Passweg J, Rätz Bravo A R, Gratwohl A. Disseminated scabies evolving in a patient undergoing induction chemotherapy for acute myeloblastic leukaemia. Ann Hematol 2001; 80(2):116-8.
 16. Pariser D M, Meinking T L, Bell M, Ryan W G. Topical 0.5% ivermectin lotion for treatment of head lice. N Engl J Med 2012; 367(18):1687-93.
 17. Finlay A Y, Khan G K. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19(3): 210-6.
 18. Nicholson K, Abramova L, Chren M M, Yeung J, Chon S Y, Chen S C. A pilot quality-of-life instrument for acne rosacea. J Am Acad Dermatol 2007; 57(2):213-21.
 19. Zhang X, Song Y, Ci X et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 2008; 57:524-9.
 20. Gerber P A, Buhren B A, Steinhoff M, Homey B. Rosacea: The cytokine and chemokine network. J Investig Dermatol Symp Proc 2011; 15(1):40-7.
 21. Wolstenholme A J, Rogers A T. Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology 2005; 131 Suppl:S85-95.
 22. Damian D. Demodex infestation in a child with leukemia: treatment with ivermectin and permethrin. Int J Dermatol 2003; 42:724-6.
 23. Filho P A, Hazarbassanov R M, Grisolia A B et al. The efficacy of oral ivermectin for the treatment of chronic blepharitis in patients tested positive for Demodex spp. Br J Ophthalmol 2011; 95: 893-5.
 24. Powell F C. Rosacea and the pilosebaceous follicle. Cutis 2004; 74 (3 Suppl): 9-12.
 25. Marks R. The enigma of rosacea. J Dermatol Treat 2007; 18:326-8.
 26. Forton F M N. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol 2012; 26:19-28.
 27. Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: An antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol 2012; 24(2):126-135.
 28. Millikan L. Rosacea as an inflammatory disorder: a unifying theory? Cutis 2004; 73(suppl 1): 5-8.
1. A method of treating papulopustular rosacea in a subject in need thereof, comprising topically administering to a skin area affected by the papulopustular rosacea a therapeutically effective amount of a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier to thereby obtain a significant reduction in inflammatory lesion count in the subject.
4. The method of claim 1, wherein as early as 2 weeks after the initial administration of the pharmaceutical composition, the significant reduction in inflammatory lesion count is observed.
5. The method of claim 1, wherein the pharmaceutical composition is administered once daily to the skin area.
6. The method of claim 5, wherein the pharmaceutical composition comprises about 0.5% to 1.5% by weight ivermectin.
7. The method of claim 6, wherein the pharmaceutical composition comprises about 1% by weight ivermectin.
8. The method of claim 6, wherein the pharmaceutical composition further comprises one or more ingredients selected from the group consisting of: an oily phase comprising dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the oily phase further comprising fatty substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; at least one surfactant-emulsifier selected from the group consisting of glyceryl/PEG 100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a mixture of solvents and/or propenetrating agents selected from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; one or more gelling agents selected from the group consisting of carbomers, cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and modified starches; and water.
9. The method of claim 5, wherein the once daily topical administration to the subject the pharmaceutical composition results in more reduction in inflammatory lesion count in the subject in comparison to that achieved by topically administering to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight metronidazole.
10. The method of claim 5, wherein the once daily topical administration to the subject the pharmaceutical composition results in longer relapse-free time of the papulopustular rosacea in the subject in comparison to that achieved by topically administering to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight metronidazole.
11. A method of treating inflammatory lesions of rosacea in a subject in need thereof, comprising topically administering, once daily, to a skin area affected by the inflammatory lesions of papulopustular rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier to thereby obtain a significant reduction in inflammatory lesion count in the subject.
14. The method of claim 11, wherein as early as 2 weeks after the initial administration of the pharmaceutical composition, the significant reduction in inflammatory lesion count is observed.
15. The method of claim 11, wherein the pharmaceutical composition is administered once daily to the skin area.
16. The method of claim 15, wherein the pharmaceutical composition comprises about 0.5% to 1.5% by weight ivermectin.
17. The method of claim 16, wherein the pharmaceutical composition comprises about 1% by weight ivermectin.
18. The method of claim 16, wherein the pharmaceutical composition further comprises one or more ingredients selected from the group consisting of: an oily phase comprising dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the oily phase further comprising fatty substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; at least one surfactant-emulsifier selected from the group consisting of glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a mixture of solvents and/or propenetrating agents selected from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; one or more gelling agents selected from the group consisting of carbomers, cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and modified starches; and water.
19. The method of claim 15, wherein the once daily topical administration to the subject the pharmaceutical composition results in more reduction in inflammatory lesion count in the subject in comparison to that achieved by topically administering to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight metronidazole.
20. The method of claim 15, wherein the once daily topical administration to the subject the pharmaceutical composition results in longer relapse-free time of the inflammatory lesions in the subject in comparison to that achieved by topically administering to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight metronidazole.
21. The method of claim 1, wherein the pharmaceutical composition comprises about 0.1% to 1.5% by weight ivermectin.
22. The method of claim 11, wherein the pharmaceutical composition comprises about 0.1% to 1.5% by weight ivermectin.

matches:
application No. 61
application No. 61
application No. 61
§119
Application No. 61
Application No. 61
Application No. 61


§ 1.1 All services are subject to the following agreement in their entirety, provided that they have not been supplemented or modified by other individual agreements.
§ 2.1 MihaPower Training Systems offers the client an optimally oriented and tailor-made training concept. This program may include various training content, sportswear selection and nutritional training, with personal and individual attention from MihaPower Training Systems.
§ 2.2 MihaPower Training Systems undertakes to provide individual advice and support to clients in the context of the agreed training and health advice.
§ 2.3 The concept tailored to the client is based on the information was given by the client in the medical history form to be completed and signed by him. Incorrect or missing information will not be charged to MihaPower Training Systems.
§ 2.4 MihaPower Training Systems carries out the activity as a self-employed activity. A business registration exists.
§ 2.5 The terms and conditions also apply to the users of training vouchers. The latest version of the General Terms and Conditions applies.
§ 3.1 Prior to the start of the training, the content and objectives of the training are agreed with the client in a counselling session. In addition, the type, extent and location of the training sessions are discussed with the client.
§ 3.2 The duration of a personal training session is 60 minutes or longer. Shorter training sessions must be expressly agreed. A cancellation of the training session by the client, before the end of the agreed training period, does not entitle to reimbursements or time credits.
§ 3.3 MihaPower Training Systems is also available outside of training times by telephone and by e-mail as part of the agreed advisory and support measures. A claim to constant accessibility cannot be derived from this.
§ 4.1 The client receives a written invoice from Miha Power Training Systems, which must be paid within 14 days without any deductions.
§ 4.2 The billing of the training sessions is completely in advance. In the case of an agreement between MihaPower Training Systems and the customer, full payment may be made in instalments.
§ 4.3 The price of the respective training session results from the respective current price list.
§ 4.4 Travel costs will be charged separately if the training takes place outside of Munich.
§ 4.5 For appointments that are agreed during the weekend, MihaPower Training Systems charges a surcharge of 25 EUR per training session.
§ 5.1 Services that are provided by cooperation partners or other service providers (eg physicians, physiotherapists, performance diagnosticians, etc.) are not included in the remuneration for personal training. The resulting costs are borne by the client himself and must either be paid directly to the respective service provider or charged to the client by Miha Power Training Systems.
§ 5.2 If, due to the desired sports, additional costs (eg for sports halls, fitness centres, indoor swimming pools, sports facilities, etc.) are borne in full by the client.
§ 6.1 The medical history form must be completed in full before the start of the first training session. In order not to endanger your health this is obligatory. MihaPower Training Systems assumes the duty of secrecy.
§ 6.2 MihaPower Training Systems excludes any liability for material damage and/or personal injury to the client, which was not caused by a grossly negligent or intentional breach of duty by any vicarious agents. Both contractual and non-contractual claims are affected by the aforementioned limitation of liability.
§ 6.3 MihaPower Training Systems shall not be liable beyond the provision of its service for a possible failure to achieve the purpose pursued by the client when entering into the contract.
§ 6.4 If the client uses the services of cooperation partners or other companies or persons mediated by MihaPower Training Systems, he does so on his own responsibility. Miha Power Training Systems assumes no responsibility or warranty for goods or services received from the client.
§ 6.5 The client is responsible for his own insurance against accidents and injuries that may occur as part of personal training. The same applies to the direct route to and from the training location.
§ 6.6 MihaPower Training Systems cannot be held liable for general risks (such as sprains, colds, soiled or damaged clothing, etc.) associated with the pursuit of the desired sport or training. The resulting damage to property and personal injury must always be borne by the client.
§ 6.7 In order to satisfy any legal liability of the client MihaPower Training Systems owns it’s own liability insurance.
§ 7.1 To enable effective training, punctuality to the agreed time is expected. Any delaying at the start of the training session caused by the client’s delaying will automatically shorten the training session and no prolonged session can be provided.
§ 7.2 In case of inability to attend, the client has to cancel as soon as possible, but no later than 24 hours before the beginning of the training. Otherwise, the agreed fee for the booked training session will be charged in full. MihaPower Training Systems is not obliged to make up for the late start of a training session that is not its own fault.
§ 7.3 Should the execution of a training session be too dangerous or impossible due to unforeseeable circumstances (such as weather conditions, accident, etc.), the training session may take place indoors or be postponed after consultation. The decision on the implementation is made by mutual agreement with the client.
§ 8.1 In the case of a short-term training cancellation by Miha Power Training Systems no compensation claims can be asserted. Already paid training sessions will be credited or refunded upon request.
§ 9.1 The personal data of the clients are stored by Miha Power Training Systems and used exclusively for the fulfilment of the aforementioned subject matter.
§ 9.2 The stored data will be deleted on request, but no later than 24 months after the last booked training session.
§ 10.1 The client undertakes to maintain confidentiality with regard to any trade and business secrets of Miha Power Training Systems, even beyond the termination of the framework agreement.
§ 10.2 Miha Power Training Systems is required to maintain secrecy about all information disclosed in connection with the fulfilment of the training and support measures, even beyond the termination of the framework agreement.
§ 11.1 By signing the anamnesis form and the disclaimer, the contract between the client and Miha Power Training Systems is deemed to be final.
§ 11.2 If the customer fails to pay on a payment by more than 14 days, Miha Power Training Systems may terminate the contract extraordinarily. Further claims remain reserved.
§ 11.3 Miha Power Training Systems generally concludes fixed-term contracts. The client has the right to withdraw from the contract within the first 7 days from the date of conclusion of the contract. The termination of a temporary contract by the client is excluded unless there is a permanent medical indication that makes a continuation of the contract impossible. This indication must be proven by a current medical certificate.
§ 11.4 The right to termination for an important reason remains unaffected.
§ 11.5 Miha Power Training Systems is entitled to terminate any contract at any time without giving reasons. Prepayments for 1: 1 Personal Training will be reimbursed to the client pro rata and promptly in this case. This does not apply to online training.
§ 12.1 Both parties accept agreements and arrangements for the booking of training sessions as binding, provided they have been mutually confirmed. This applies to all means of communication used, such as telephone, fax or e-mail.
§ 12.2 Should one of the contracting parties be unavailable in the event of short-term changes (for example, a delay, location, etc.), the last reconfirmed agreement shall apply.
§ 12.3 Both parties commit themselves to mutual loyalty and will in no case negatively express themselves over the person or products or services of the other or impair its reputation and prestige.
§ 13.1 Miha Power Training Systems points out that risk-free body fat measurement and electronic pulse control can only be performed if there are no implants with electronic components (such as cardiac pacemakers) in the body.
§ 14.1 The customer assures to be fit for sport. Regardless of the Health Check to be performed by Miha Power Training Systems at the beginning, the client is required to have his health checked, if necessary and if advised by Miha Power Training Systems, to a physician of his choice and personally assess the outcome with Miha Power Training Systems. openly and truthful to discuss. If there are any health problems, a possible training session/schedule is discussed in cooperation with the respective specialist.
§ 14.2 The client will inform Miha Power Training Systems immediately about sudden dysfunctions (such as dizziness, nausea, pain, etc.) before, during or after training.
§ 14.3 If necessary, the customer must ensure that he obtains a medical license for the sporting activities.
§ 15.1 Amendments, additions and additional agreements require the written form to be effective unless otherwise stated in these Terms and Conditions.
§ 15.2 Should one of the preceding provisions be ineffective or unenforceable, the validity of the remaining provisions shall remain unaffected. In place of the invalid or unenforceable provisions, both parties mutually agree upon a suitable, legally effective replacement provision as closely as possible to economic success.
Do you want to be my next challenge?
Book your first free session now!


§ 62-2 Commission created; authority; membership.
§ 62-3 Commissioners appointed; terms; alternate members.
§ 62-6 Powers of Commission.
§ 62-7 Required permits for non-utility operations.
§ 62-8 Required permits for utility operations; exceptions for emergencies.
§ 62-9 Issuance of permits.
§ 62-10 Public improvements affecting trees; consent of Commission, county park commissions unaffected.
§ 62-11 Annual appropriation; estimated amount.
§ 62-12 Penalty, jurisdiction of courts; copy of ordinance as evidence.
§ 62-13 Disposition of penalties.
§ 62-14 Regulations by Commission.
§ 62-15 Public notice of regulations.
§ 62-17 Effect on other ordinances.
Streets and sidewalks — See. Ch. 168, Art. I.
PERSON — Every person, firm, association, partnership and corporation.
As applied to public utility companies shall mean poles, wires, cables, subsurface conduits, pipes, manholes and appurtenant facilities of such companies installed in a street.
A public utility as defined in the Revised Statutes of the State of New Jersey (N.J.S.A. 48:2-13).
The Shade Tree Commission of the City of Hoboken.
Any public street, designated by the Governing Body, to be within the jurisdiction of the Shade Tree Commission.
The regulation, planting, care and control of shade and ornamental trees and shrubbery upon and in the streets, public places, parks and parkways of the City of Hoboken, except state highways, unless the Department of Transportation shall assent thereto, and except county highways, parks and parkways, if a county shade tree commission is operative and gives assent to, shall be exercised by and be under the authority of the City of Hoboken Shade Tree Commission, which is hereby created. The Commission shall consist of five members, and shall include the Director of the Department of Environmental Services or his/her designee and two alternate members. The members and alternate members shall be appointed by the Mayor, shall be residents of this municipality and shall serve without compensation except as hereinafter provided. At least one member should have specific expertise in urban forestry, landscape architecture, horticulture or arboriculture.
The first Commissioners shall be appointed within 60 days after the effective date of this chapter, and their terms of office shall commence upon the date of their appointment and be for the respective periods: five members — one, two, three, four, and five years. The terms of each appointee shall be designated in his appointment. All subsequent appointments, except to fill vacancies, shall be for the full term of five years, to take effect on January 1, next succeeding such appointment. In event that the membership of any Commission is increased, the new members shall be appointed in such manner that their terms shall expire in accordance with the foregoing.
The term of each alternate member shall be five years commencing on January 1 of the year of appointment, provided, however, that in the event two alternate members are appointed, the initial term of Alternate No. 1 shall be five years, and the initial term of Alternate No. 2 shall be four years.
The Commission shall organize within 30 days after the appointment of its total membership for the remainder of the then calendar year, and thereafter annually by the election of one of its members as Chairman, and the appointment of a Secretary, who need not be a member. The salary of the Secretary, who may be compensated even if a member of the Commission, shall be fixed by the Governing Body of the municipality; the salary of all other employees shall be fixed by the Commission. All salaries shall be fixed as nearly as practicable in accordance with the salary schedule, if any, of the municipality for corresponding positions.
Any vacancy occurring by reason of the death, resignation or removal of any Commissioner shall be filled for the unexpired term by the Mayor or other chief executive of this municipality.
Cut, prune, climb with spikes, break, damage, remove or kill.
Maintain a stationary fire or device, which vaporizes noxious fumes deleterious to tree health.
Plant any tree or shrub within the designated area under the control of the Commission.
The Shade Tree Commission may grant to public utility companies a blanket permit for (i) tree pruning for line clearance and (ii) for the installation and maintenance of subsurface and aboveground plant construction if there is interference with or endangerment to street trees.
Public utility companies may, during periods of emergency, without specific prior permit (i) install temporary attachments to trees and (ii) make emergency subsurface repairs.
Each public utility company shall exercise reasonable diligence in the maintenance of its plant construction so as to avoid damage to trees under the jurisdiction of the Hoboken Shade Tree Commission.
Requests for permits required by the provisions of this chapter for the performance of work should be directed to the Shade Tree Commission, City of Hoboken, Hoboken, New Jersey.
No statute giving any person or state, county or municipal board, body or official power or authority to lay any sidewalk along, or to open, construct, curb or pave any street, or to do any similar act, shall be construed to permit or authorize any interference with or injury to a highway shade tree without the consent of the Shade Tree Commission within whose jurisdiction such tree shall be located. In all cases such Commission shall reasonably cooperate with such person, board, body or official for the general public good. Nothing contained in this chapter shall be held to take away or diminish any of the powers or authority of the Hudson County Park Commission over the trees or shrubbery in any Hudson County Park within its jurisdiction, or to give any other commission or board any power or authority with respect to such trees or shrubbery.
Purchase of necessary equipment and materials and the cost of services for the prudent promotion of the work. The Governing Body of this municipality shall annually appropriate such sum, as it may deem necessary for said purposes.
The Commission may prescribe a fine for violation of its ordinances in an amount not exceeding $1,500 for each violation, and the Municipal Court of Hoboken shall have jurisdiction over actions for the violation of such ordinances, and its ordinances shall be enforced by like proceedings and process as that provided by law for the enforcement of ordinances of this municipality. The officers authorized by law to serve and execute process for the Municipal Court of this municipality shall be the officers to serve and execute any process issued out of the Municipal Court for violations of the ordinances of the Commission.
A copy of any ordinance of the Commission, certified to under the hand of its Secretary, or Chairman shall be received in any court of this state as full and legal proof of the existence of the ordinance, and that all requirements of law in relation to the ordaining, publishing and making of the same, so as to make it legal and binding, have been complied with, unless the contrary be shown.
In addition to the penalties authorized by subsection A. of this section, the Commission may require a person who removes or otherwise destroys a tree in violation of a municipal ordinance to pay a replacement assessment to the municipality. The replacement assessment shall be the value of the tree as determined by the appraisal of a trained forester or certified tree expert retained by the Commission for that purpose. In lieu of an appraisal, the Commission may adopt a formula and schedule based upon the number of square inches contained in a cross section of the trunk of the tree multiplied by a predetermined value per square inch, not to exceed $27 per square inch. The square inch cross section shall be calculated from the diameter at breast height and, if there is a multiple stem tree, then each trunk shall be measured and an average shall be determined for the tree. For the purpose of this section, "diameter at breast height" shall mean the diameter of the tree taken at a point 4.5 feet above ground level. The Commission shall modify the value of the tree upon its species variety, location and its condition at the time of removal or destruction.
Any public utility or cable television company that clears, moves, cuts or destroys any trees, shrubs or plants for the purpose of erecting, installing, moving, removing, altering or maintaining any structures or fixture, necessary for the supply of electric light, heat or power, communication, or cable television services upon any lands in which it has acquired an easement or right-of-way, shall not be subject to any penalty imposed by a Commission pursuant to subsections A. or B. of this section. This subsection shall not exempt any public utility or cable television company from any penalty or replacement assessment imposed for negligent actions.
All moneys collected, either as fines or penalties, for any violation of a rule or regulation of a Shade Tree Commission enacted by ordinance, or as a charge against real estate, under any provision of this chapter shall be forthwith paid over to the custodian of the municipal funds.
The Shade Tree Commission is hereby authorized and empowered to promulgate such regulations as may be necessary, pursuant to statute, and for the proper interpretation, administration and enforcement of this basic chapter, provided that such ordinances do not conflict with this chapter and conform to the general standards prescribed by this chapter.
All regulations adopted by the Shade Tree Commission shall be filed with the Municipal Clerk for inspection by the public during regular business hours.
If any section, subsection, paragraph, sentence, clause, phrase or word contained in this code shall be declared invalid for any reason whatsoever, such decision shall not affect the remaining portions of this Code which shall remain in full force and effect, and to this end the provisions of this ordinance are hereby declared to be severable.
Nothing in this chapter shall prevent the appropriate Municipal Body from enforcing any other ordinance of the Code of the City of Hoboken dealing with property maintenance, which may include maintenance of trees on private property or public sidewalks adjacent to private property.


text:
Asa and his army were now returning in triumph from the battle, laden with spoils and adorned with the trophies of victory, the pious prince, we may now suppose, studying what he should render to God for this great favour. He knew that the work of reformation, which he had begun in his kingdom, was not perfected; his enemies abroad were subdued, but there were more dangerous enemies at home that were yet unconquered梚dols in Judah and Benjamin: his victory over the former emboldened him vigorously to renew his attack upon the latter. Now here we have, I. The message which God sent to him, by a prophet, to engage him to, and encourage him in, the prosecution of his reformation (v. 1-7). II. The life which this message put into that good cause, and their proceedings in pursuance of it. Idols removed (v. 8). The spoil dedicated to God (v. 9�). A covenant made with God, and a law for the punishing of idolaters (v. 12�). A reformation at court (v. 16). Dedicated things brought into the house of God (v. 18). All well, but that the high places were permitted (v. 17). And the effect of this was great peace (v. 19).
It was a great happiness to Israel that they had prophets among them; yet, while they were thus blessed, they were strangely addicted to idolatry, whereas, when the spirit of prophecy had ceased under the second temple, and the canon of the Old Temple was completed (which was constantly read in their synagogues), they were pure from idolatry; for the scriptures are of all other the most sure word of prophecy, and most effectual, and the church could not be so easily imposed upon by a counterfeit Bible as by a counterfeit prophet. Here was a prophet sent to Asa and his army, when they returned victorious from the war with the Ethiopians, not to compliment them and congratulate them on their success, but to quicken them to their duty; this is the proper business of God's ministers, even with princes and the greatest men. The Spirit of God came upon the prophet (v. 1), both to instruct him what he should say and to enable him to say it with clearness and boldness.
II. He set before them the dangerous consequence of forsaking God and his ordinances, and that there was no way of having grievances redressed, but by repenting, and returning unto God. When Israel forsook their duty they were over-run with a deluge of atheism, impiety, irreligion, and all irregularity (v. 3), and were continually embarrassed with vexatious and destroying wars, foreign and domestic, v. 5, 6. But when their troubles drove them to God they found it not in vain to seek him, v. 4. But the question is, What time does this refer to? 1. Some think it looks as far back as the days of the Judges. A long season ago Israel was without the true God, for they worshipped false gods; it was a time of ignorance, for, though they had priests, they had no teaching priests, though they had elders, yet no law to any purpose, v. 3. These were sad times, when they were frequently oppressed by one enemy or other and grievously harassed by Moabites, Midianites, Ammonites, and other nations. They were vexed with all adversity (v. 6), yet when, in their perplexity, they turned to God by repentance, prayer, and reformation, he raised up deliverers for them. Then was that maxim often verified, that God is with us while we are with him. Whatsoever things of this kind were written aforetime were written for our admonition. 2. Others think it describes the state of the ten tribes (who were now properly called Israel) in the days of Asa. "Now, since Jeroboam set up the calves, though he pretended to honour the God that brought them out of Egypt, yet his idolatry has brought them to downright infidelity; they are without the true God,'' and no marvel when they were without teaching priests. Jeroboam's priests were not teachers, and thus they came to be without law. It is next to impossible that any thing of religion should be kept up without a preaching ministry. In those times there was no peace, v. 5. Their war with Judah gave them frequent alarms; so did the late insurrection of Baasha and other occasions not mentioned. They provoked God with all iniquity, and then he vexed them with all adversity; yet, when they turned to God, he was entreated for them. Let Judah take notice of this; let their neighbours' harms be their warnings. Give no countenance to graven images for you see what mischiefs they produce. 3. Others think the whole passage may be read in the future tense, and that it looks forward: Hereafter Israel will be without the true God and a teaching priest, and they will be destroyed by one judgment after another till they return to God and seek him. See Hos. 3:4.
III. Upon this he grounded his exhortation to prosecute the work of reformation with vigour (v. 7): Be strong, for your work shall be rewarded. Note, 1. God's work should be done with diligence and cheerfulness, but will not be done without resolution. 2. This should quicken us to the work of religion, that we shall be sure not to lose by it ultimately. It will not go unrewarded. How should it, when the work is its own reward?
We are here told what good effect the foregoing sermon had upon Asa.
I. He grew more bold for God than he had been. His victory would inspire him with some new degrees of resolution, but this message from God with much more. Now he took courage. he saw how necessary a further reformation was, and what assurance he had of God's presence with him in it; and this made him daring, and helped him over the difficulties which had before deterred him and driven him off from the undertaking. Now he ventured to destroy all the abominable idols (and all idolatries are abominable, 1 Pt. 4:3) as far as ever his power went. Away with them all. He also renewed the altar of the Lord, which, it seems, had gone out of repair, though it was not above thirty-five years since Solomon's head was laid, who erected it. So soon did these ceremonial institutions begin to wax old, as things which, in the fulness of time, must vanish away, Heb. 8:13.
II. He extended his influence further than before, v. 9. He summoned a solemn assembly, and particularly brought the strangers to it, who had come over to him from the ten tribes. 1. Their coming was a great encouragement to him; for the reason of their coming was because they saw that the Lord his God was with him. It is good to be with those that have God with them, to come into relation to, and contract acquaintance and friendship with, those that live in the fear and favour of God. We will go with you, for we have heard that God is with you, Zec. 8:23. 2. The cognizance he took of them, and the invitation he gave them to the general assembly, were a great encouragement to them. All strangers are to be helped, but those that cast themselves upon God's good providence, purely to keep a good conscience, are worthy of double honour. Asa gave orders for the gathering of them together (v. 9), yet it is said (v. 10) that they gathered themselves together, made it their own act, so forward were they to obey the king's orders. This meeting was held in the third month, probably at the feast of Pentecost, which was in that month.
III. He and his people offered sacrifices to God, as his share of the spoil they had got, v. 11. Their offering here was nothing to Solomon's (ch. 7:5), which was owing to the diminution either of their zeal or of their wealth, or of both. These sacrifices were intended by way of thanksgiving for the favours they had received, and supplication for further favours. Prayers and praises are now our spiritual sacrifices. And, as he took care that the altar should have its gift, so he took care that the temple should have its gold: He brought into the house of God all the dedicated things, v. 18. It is honesty to render to God the things that are his. What has been long designed for him, and long laid by for him, as it should seem these dedicated things had been, should at length be laid out for him. Will a man rob God, or make slow payment to him, who is always ready to do us good?
1. What was the matter of this covenant. Nothing but what they were before obliged to; and, though no vow or promise of theirs could lay any higher obligation upon them than they were already under from the divine precept, yet it would help to increase their sense of the obligation, to arm them against temptations, and would be a testimony to the equity and goodness of the precept. And, by joining all together in this covenant, they strengthened the hands one of another. Two things they engaged themselves to:�(1.) That they would diligently seek God themselves, seek his precepts, seek his favour. What is religion but seeking God, enquiring after him, applying to him, upon all occasions? We shall not enjoy him till we come to heaven; while we are here we must continue seeking. They would seek God as the God of their fathers, in the way that their fathers sought him and in dependence upon the promise made to their fathers; and they would do it with all their heart and with all their soul, for those only seek God acceptably and successfully that are inward with him, intent upon him, and entire for him, in their seeking him. We make nothing of our religion if we do not make heart-work of it. God will have all the heart or none; and, when a jewel of such inestimable value as the divine favour is to be found, it is worth while to seek it with all our soul. (2.) That they would, to the utmost of their power, oblige others to seek him, v. 13. They agreed that whosoever would not seek the Lord God of Israel (that is, would either worship other gods or refuse to join with them in the worship of the true God, that was either an obstinate idolater or an obstinate atheist) he should be put to death. This was no new law of their own making, but an order to put in execution that law of God to this purport, Deu. 17:2, etc. If this law had been duly executed, there would not have been so many abominable idols found in Judah and Benjamin, v. 8. Whether men may now, under the gospel, be compelled by such methods as these to seek the Lord is justly questioned; for the weapons of our warfare are not carnal, and yet mighty.
2. In what manner they made this covenant. (1.) With great cheerfulness, and all possible expressions of joy: The swore unto the Lord; not secretly, as if they were either ashamed of what they did or afraid of binding themselves too fast to him, but with a loud voice, to express their own zeal and to animate one another; and they all rejoiced at the oath, v. 14, 15. They did not swear to God with reluctancy (as the poor debtor confesses a judgment to his creditor), but with all the pleasure and satisfaction imaginable, as the bridegroom plights his troth to the bride in the marriage covenant. Every honest Israelite was pleased with his own engagements to God, and they were all pleased with one another's. They rejoiced in it as a hopeful expedient to prevent their apostasy from God and a happy indication of God's presence with them. Note, The times of renewing our covenant with God should be times of rejoicing, and national reformation cannot but give general satisfaction to all that are good. It is an honour and happiness to be in bonds to God. (2.) They did it with great sincerity, zeal and resolution: They swore to God with all their hearts, and sought him with their whole desire. The Israelites were now in an extraordinarily good frame. O that there had always been such a heart in them! This comes in as the reason why they rejoiced so much in what they did: it was because they were hearty in it. Note, Those only experience the pleasure and comfort of religion that are sincere and upright in it. What is done in hypocrisy is a mere drudgery. But, if God has the heart, we have the joy.
V. We are told what was the effect of this their solemn covenanting with God. 1. God did well for them: He was found of them, and gave them rest round about (v. 15), so that there was no war for a long time after (v. 19), no open general war, though there were constant bickerings between Judah and Israel upon the frontiers, 1 Ki. 15:16. National piety procures national blessings. 2. They did, on the whole, well for him. They carried on the reformation so far that Maachah the queen-mother was deposed for idolatry and her idol destroyed, v. 16. This was bravely done of Asa, that he would not connive at idolatry in those that were nearest to him, like Levi, that said to his father and mother, I have not seen him, Deu. 33:9. Asa knows he must honour God more than his grandmother, and dares not leave an idol in an apartment of his palace while he is destroying idols in the cities of his kingdom. We may suppose this Maachah was so far convinced of her sin that she was willing to subscribe the association mentioned (v. 12, 13), binding herself to seek the Lord, and therefore was not put to death as those were that refused to sign it, great as well as small, women as well as men: probably it was with an eye to her that women were specified. But because she had been an idolater Asa thought fit to divest her of the dignity and authority she had, and probably he banished her the court and confined her to privacy, lest she should influence and infect others. But the reformation was not complete; the high places were not all taken away, though many of them were, ch. 14:3, 5. Those in the cities were removed, but not those in the cities of Judah, but not those in the cities of Israel which were reduced to the house of David; or those that were used in the service of false gods, but not those that were used in the service of the God of Israel. These he connived at, and yet his heart was perfect. There may be defects in some particular duties where yet the heart, in the man, is upright with God. Sincerity is something less than sinless perfection.

matches: v. v. v. v. v. v. v. v. v. v. V. v.