Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics

Definitions

• This invention relates to amelioration of the adverse effects, such as nausea, yawning, vomiting, and cardiovascular effects, caused to human patients when taking apomorphine for Parkinson's disease, psychogenic male erectile dysfunction (MED), and female sexual dysfunction, or the like afflictions.
• adverse effects such as nausea, yawning, vomiting, and cardiovascular effects
• Apomo ⁇ hine has been used to treat Parkinsonian patients. See, for example, Deffond et al., J. Neurology, Neurosurgery, and Psychiatry 56: 101-103 (1993) and Durif et al. , Clinical Neuropharmacology 16(2): 157- 166 (1993). Additionally, apomo ⁇ hine has been considered for the treatment of alcoholism, schizophrenia, dystonia musculorum deformans, hallucinations, migraine headaches, hiccups, Huntington's chorea, tardative dyskinesia, and more recently male erectile dysfunction.
• apomo ⁇ hine administered to mammals such as humans, dogs and the like usually results in nausea and vomiting, and is believed to be due to the action of apomo ⁇ hine on the chemoreceptor trigger zone (CTZ) of the medulla oblongata, a structure of the mammalian central nervous system. It is also believed that additional chemoreceptors triggering emesis are present in the gastro- intestinal tract as well.
• CTZ chemoreceptor trigger zone
• Impotence or male erectile dysfunction is defined as the inability to achieve and sustain an erection sufficient for intercourse. Impotence in any given case can result from psychological disturbances (psychogenic), from physiological abnormalities in general (organic), from neurological disturbances (neurogenic), hormonal deficiencies (endocrine) or from a combination of the foregoing.
• psychogenic impotence is defined as functional impotence with no apparent overwhelming organic basis. It may be characterized by an ability to have an erection in response to some stimuli (e.g. , masturbation, spontaneous nocturnal, spontaneous early morning, video erotica, etc.) but not others (e.g., partner or spousal attention).
• stimuli e.g. , masturbation, spontaneous nocturnal, spontaneous early morning, video erotica, etc.
• others e.g., partner or spousal attention
• apomo ⁇ hine The effect of apomo ⁇ hine on penile tumescence in male patients afflicted with psychogenic impotence has also been studied. These studies show that while apomo ⁇ hine can indeed induce an erection in a psychogenic male patient, the apomo ⁇ hine dose required to achieve a significant erectile response is usually accompanied by nausea or other serious undesirable side effects, including hypertension, flushing and diaphoresis (sweating). The specific mechanisms by which apomo ⁇ hine acts to produce an erectile response in a human patient are not yet completely understood, however.
• apomo ⁇ hine has been shown to have very poor oral bioavailability. See, for example, Baldessarini et al. , in Gessa et al., eds., Apomorphine and Other Dopaminomimetics, Basic Pharmacology, Vol. 1, Raven Press, N.Y. (1981), pp. 219-228. Thus the search is continuing for an effective treatment of psychogenic impotence in male patients as well as for diagnostic methods that can identify such patients.
• Acute and subacute testing of apomo ⁇ hine HCl has been reported in studies with daily doses ranging to over 300 milligrams per kilogram (mg/kg) in lower vertebrates (amphibian and birds), and to 10 mg/kg in higher mammals (primates). In mammals, it appears doses of apomo ⁇ hine HCl are tolerated up to about 13 mg/kg in a single bolus subcutaneous injection. Doses at or above this amount have been reported lethal in mouse, although, the LD50 is considerably higher (> 50 mg/kg) in this species. Continuous infusion of apomo ⁇ hine has been tolerated and reported to doses of 420 ⁇ g/kg/hr for 14 days.
• apomo ⁇ hine dosage forms have been found to be effective in treating Parkinson's disease as well as in male patients suffering from psychogenic erectile dysfunction for the induction and maintenance of an erection sufficient for intercourse (i.e., vaginal penetration). While at relatively lower dosages apomo ⁇ hine can be administered without nausea or other undesirable side effects, such side effects do manifest themselves as the dosages of apomo ⁇ hine are increased.
• apomo ⁇ hine When the plasma concentration of apomo ⁇ hine is maintained at no more than about 5.5 nanograms per milliliter (ng/ml), the incidence of adverse side effects is minimal.
• Such monitoring requires either an invasive procedure, such as blood analysis or urinalysis, to determine proper dosing requirements.
• the present method provides for the amelioration of adverse effects due to apomo ⁇ hine use without the invasiveness of previous methods.
• Summary of the Invention Adverse effects of apomo ⁇ hine, such as nausea, vomiting, yawning, cardiovascular effects, etc. , on a human patient are minimized by administration of an escalating dosage of apomo ⁇ hine over a period of time.
• the method begins with the administering of a threshold or initial dose of apomo ⁇ hine, followed by periodic increasing doses of apomo ⁇ hine until a final dose in excess of a therapeutic dose is administered. A therapeutic dose of apomo ⁇ hine is then administered to the patient for pu ⁇ oses of treatment.
• sublingual doses of apomo ⁇ hine are administered periodically.
• the final dose of apomo ⁇ hine is preferably in excess of that needed to produce a sufficiently rigid erection in the patient.
• the therapeutic sublingual dose is less than the final dose of apomo ⁇ hine but still sufficient to produce an erection with sufficient rigidity for vaginal penetration without the attendant substantial adverse effects.
• the sublingual threshold dose of apomo ⁇ hine for a human patient can be in the range of about 2 to about 8 milligrams (mg), and more preferably about 4 mg.
• the increased dosing occurs preferably at a rate of about 2 mg each day for a period of no less than three days, with the therapeutic dose of apomo ⁇ hine administered after the final dose is given.
• the final dose of apomo ⁇ hine administered to a human patient suffering from psychogenic erectile dysfunction is about 8 to 10 mg.
• the sublingual therapeutic dose of apomo ⁇ hine is preferably 6 mg, and can vary, depending upon the patient in the range of about 35 to about 74 micrograms per kilogram ( ⁇ g/kg) of the patient's body weight, and most preferably within the range of about 50 to about 74 micrograms per kilogram ( ⁇ g/kg) of body weight.
• a subcutaneous therapeutic dose i.e.
• Parkinsonism symptoms sufficient to ameliorate Parkinsonism symptoms, can be as high as about 8 mg, usually about 3-5 mg, per administration.
• a sublingual therapeutic dose for treating Parkinsonism symptoms can be as high as about 60 mg, usually about 20 to about 40 mg.
• Subcutaneous threshold doses can be in the range of about 1.25 mg to about 5 mg, usually about 3 mg.
• Nothwithstanding dosage form, the plasma concentration of apomo ⁇ hine is preferably maintained in the range of about 3 to about 20 nanograms per milliliter for treatment of Parkinsonism symptoms.
• apomo ⁇ hine For patients with female sexual dysfunction, administration of apomo ⁇ hine to females has been shown to increases nerve stimulated clitoral intracavernosal blood flow and vaginal wall blood flow, each of which is associated respectively with enhanced clitoral erection and vaginal engorgement in a female.
• a sublingual apomo ⁇ hine dosage form usually containing about 2 to about 12 mg, preferably about 2 to about 8 mg, of apomo ⁇ hine, is effective for producing sexual readiness in human females without inducing substantial nausea or other undesirable side effects.
• administration is effected preferably about 15 to about 20 minutes prior to sexual activity.
• the plasma concentration of apomo ⁇ hine is maintained at no more than about 5.5 ng/ml, preferably about 0.3 to about 4 ng/ml, and more preferably about 1 to about 2 ng/ml, to maintain a circulating serum level and mid-brain tissue level of apomo ⁇ hine during the period of sexual activity sufficient to maintain vaginal engorgement, its associated lubrication and clitoral erection during coitus.
• a dopaminergic agonist such as apomo ⁇ hine reduces the patient's inability to engage in social interactions that characterizes social phobia.
• Treatment regimens that achieve a target plasma concentration of apomo ⁇ hine in the range of about 0.5 ng/ml to about 10 ng/ml at C ma ⁇ with chronic therapy of 2 or more treatments provide a therapeutically effective dose that produces amelioration of social phobia in a patient.
• FIG. 1 is a plot of duration of nausea/retching and vomiting versus time for dogs at an apomo ⁇ hine acclimatization dose of 0.05 mg/kg
• FIG. 2 is a plot of duration of nausea/retching and vomiting versus time for dogs at an apomo ⁇ hine acclimatization dose of 0.4 mg/kg;
• FIG. 3 is a plot over several days of number of dogs experiencing vomiting in the first five minutes following apomo ⁇ hine administration at three different dosages of apomo ⁇ hine
• FIG. 4 is a plot over several days of number of dogs experiencing vomiting within three time periods following administration of 0.04 mg apomo ⁇ hine per kg dog;
• FIG. 5 is a plot over several days of number of dogs experiencing vomiting within three time periods following administration of 0.1 mg apomo ⁇ hine per kg dog;
• FIG. 6 is a plot over several days of number of dogs experiencing vomiting within three time periods following administration of 0.4 mg apomo ⁇ hine per kg dog;
• FIG. 7 is a plot of mean arterial pressure versus time for dogs receiving three different dosages of apomo ⁇ hine measured after 5 months of daily apomo ⁇ hine administration;
• FIG. 8 is a plot of heart rate versus time for dogs receiving three different apomo ⁇ hine dosages measured after 5 months of daily apomo ⁇ hine administration;
• FIG. 9 is a plot of mean plasma concentrations of apomo ⁇ hine versus time for dogs receiving 0.04 mg apomo ⁇ hine per kilogram;
• FIG. 10 is a plot of mean plasma concentrations of apomo ⁇ hine versus time for dogs receiving 0.1 mg apomo ⁇ hine per kilogram;
• FIG. 11 is a plot of mean plasma concentrations of apomo ⁇ hine versus time for dogs receiving 0.4 mg apomo ⁇ hine per kilogram;
• FIG. 12 is a bar graph which represents the incidence of nausea (an adverse event) in humans at each dosage administered as a percentage of the doses administered;
• FIG. 13 is a bar graph which represents the incidence of vomiting (an adverse event) in humans at each dosage administered as a percentage of the doses administered;
• FIG. 14 is a line graph representing the mean RIGISCANTM score for human participants at each dosing level and for each video type (i.e., erotic and neutral);
• FIG. 15 represents a sample sexual function study home questionnaire for the male participant, which required completion within about 12 to about 24 hours after administering a sublingual dose of apomo ⁇ hine;
• FIG. 16 represents a sample sexual function study home questionnaire for the female partner of the male participant, which required completion within about 12 to about 24 hours after administration of sublingual dose of apomo ⁇ hine;
• FIG. 17 represents a sample Visual Analogue Scale questionnaire used to determine the patient's sense of well being, level of sedation, tranquilization, anxiousness, arousal and any changes in yawning behavior. Description of the Preferred Embodiment
• Apomo ⁇ hine is a dopamine receptor agonist that has a recognized use as an emetic when administered subcutaneously in about a 5-milligram dose.
• apomo ⁇ hine is administered in an amount sufficient to excite cells in the mid-brain region of a patient. This cell excitation is believed to be part of a cascade of stimulation that is likely to include neurotransmission with serotonin and oxytocin.
• Apomo ⁇ hine also known by the chemical name (R) -5, 6,6a, 7- Tetrahydro-6-methyl-4H-dibenzo- tfe,g/ quinoline-10,ll-diol, has the following chemical structure:
• the sublingual administration usually takes place over a time period in the range of about 2 to about 10 minutes, or longer.
• the amount of apomo ⁇ hine administered sublingually over this time period preferably is in the range of about 35 to about 74 micrograms per kilogram ( ⁇ g/kg) of the patient's body weight, and most preferably within the range of about 50 to about 74 ⁇ g/kg of body weight.
• apomo ⁇ hine for acclimatization may take the form of parenteral, oral or sublingual routes of administration.
• the sublingual route is preferred for patients suffering from psychogenic erectile dysfunction.
• a customized, responsive regimen is preferred.
• the therapeutic dose is preferably identified as the smallest dose of apomo ⁇ hine at which the patient experiences related adverse effects.
• the threshold dose is repeated until no unacceptable side effects are found.
• the frequency of repeated apomo ⁇ hine administrations may vary, but is preferably in the range of about 1 day to about 1 week per administration.
• the apomo ⁇ hine dose is increased until adverse effects are again experienced.
• Administration of the increased dosage is now repeated until the patient no longer experiences adverse effects.
• the previously tolerated dose preferably is doubled.
• the dosage escalation is repeated until the dosage level of apomo ⁇ hine exceeds the therapeutic dose for the target medical condition.
• Table la Dose Schedule For Apomorphine Acclimatization
• Plasma Range is the therapeutic target and based on the Therapeutic C max in nanograms of apomorphine per milliliter of plasma.
• the frequencies are average intervals between the given doses. A higher frequency is desirable in routes where the plasma concentration is shorter lived, e.g. subcutaneous or continuous infusion. Hourly doses can be administrated for patients requiring very high plasma concentrations of apomo ⁇ hine, such as in Parkinson's disease.
• a more structured acclimatization regimen is preferred.
• impotence sublingual doses of apomo ⁇ hine are administered according to the acclimatization regimen presented in Table lb.
• the 2-mg tablet called for during week 1 has been found to be a threshold dose for most impotence patients.
• the therapeutic sublingual dose called for in week 4 is less than the final dose of apomo ⁇ hine but still sufficient to produce an erection with sufficient rigidity for vaginal penetration. Without violating this constraint, the therapeutic dose may vary by patient.
• Table Ic represents an acclimatization regimen for treating Parkinsonism symptoms.
• the therapeutic sublingual dose called for in week 4 is less than the final dose of apomo ⁇ hine but still sufficient to substantially reduce Parkinsonism symptoms.
• the structured acclimatization regimens presented in Tables lb and Ic have advantages for patient acceptance and compliance.
• the necessary sublingual tablets can be arranged in a calendar-card tablet dispenser.
• Example 1 Vomiting and Retching in Dog Following Daily Subcutaneous Administration of Apomorphine HCl - Measurement of the Duration of Vomiting and Retching After Dosing.
• subcutaneous apomo ⁇ hine HCl was administered to dogs starting at 0.05 or 0.4 mg/kg. The dosages were eventually escalated. The duration of nausea/retching and vomiting were monitored and are reported in FIGs. 1 and 2. Dogs are known to be 5 to 10 times more sensitive than humans to apomo ⁇ hine induced emesis. At the lower doses, acclimatization of the animals as evidenced by the incidence of retching and vomiting occurred within 3 days of the initial dose.
• the average duration of the retching/ vomiting period following the initial dose was about 30 minutes. This duration was reduced markedly to about 5 minutes following daily administration. Further, once the acclimation had been established, increasing the dose by a 100% of the acclimation dose produced no corresponding increase in the duration of retching and vomiting.
• Example 2 Measurement of the Time to Maximum Number of Animals Acclimatized to the Side Effects of Daily Administration of Subcutaneous Apomorphine.
• the number of animals retching or vomiting during selected time periods after subcutaneous administration of apomo ⁇ hine HCl was recorded. Specifically, the occurrence of retching or vomiting was recorded for the following periods after apomo ⁇ hine administration: 0 to 5 minutes, 5 to 30 minutes, and 30 to 60 minutes.
• This study provides a different view of data recorded in Example 1.
• the data studied in Example 1 revealed the average period of retching and vomiting, while in this Example the number of affected animals was examined in selected periods.
• peripheral vasodilation appears to be compensated by an increase in the cardiac output.
• badycardia was reported in some subjects exposed to apomo ⁇ hine HCl. This effect is lost by acclimation of the vagus nerve dopamine receptor producing a compensated signal invoking an increase heart rate to account for the decreasing blood pressure.
• Example 3 Comparison of Sublingual, Oral and Subcutaneous Administration of Apomorphine HCl in Dog.
• Dogs were exposed to a single dose of Apomo ⁇ hine HCl, first by subcutaneous administration of 0.04 mg/kg, then subsequently at 3 day intervals to
• Example 4 Pharmacokenetic Comparison of a 4-mg and 8-mg Sublingual Tablet to an Intravenous Injection of 1 mg of Apomorphine HCl.
• Vd volume of distribution @ ⁇ stage.
• Vd (SS) volume of distribution steady state
• a drug plasma concentration of about 2.5 nanograms/milliliter is considered the threshold concentration (C, ⁇ ) at which the onset of adverse effects, such as nausea, typically occur in human male subjects.
• C, ⁇ the threshold concentration
• the threshold is readily su ⁇ assed.
• the drug plasma concentration may be more readily maintained at approximately C ⁇ .
• Example 5 Apomorphine HCl Sublingual Tablet Escalating Dose Tolerance
• Example 5-Summary This clinical study was conducted in three phases. In Phase 1 subjects were selected from among patients complaining of impotence by a thorough physiological and psychological assessment. For example, one step in the assessment process required candidates to undergo Rigiscan measurement of penile rigidity and circumference following administration of a placebo tablet in single blind fashion. Phase 2 consisted of a dose escalation (4, 6, and 8 mg tablets) administered on 4 visits. An out-patient phase was conducted as Phase 3. Patients were given apomo ⁇ hine HCL tablets to use at home. Adverse events (side effects) attributable to the apomo ⁇ hine HCL were reported in all three phases of the study.
• Table IV is a summary of the frequency of side effects to the number of patients in Escalation Phase (Phase 2) compared to Out-Patient Phase (Phase 3).
• the frequency of side effects was noted to increase from 61.5% to 105.8% and began to decline for the 8-mg tablet to 94.2%.
• the frequency of side effects at the 4- and 6-mg doses were about one half and one third, respectively, compared to the patients initial exposure to these doses.
• the acclimatization evidence here demonstrates the utility of dose escalation for reduction of overall side effects. Side effects reported in this study were: Nausea, Fatigue, Dizziness, Sweating, Yawning, Hypotension and Vomiting.
• Table IV demonstrates that an escalating weekly exposure to apomo ⁇ hine will be followed initially by an increase in the side effects until acclimation is achieved. The number and severity of the side effects reported by subjects subsequently decreased.
• Example-5 Detailed Description (Clinical Study #94-03-01). The human study was conducted in three separate phases. Phase 1 consisted of selecting appropriate subjects and obtaining baseline information on sexual performance for each subject. Phase 2 consisted of dose escalation where subjects were administered increasing doses of apomo ⁇ hine during a four- week period. Finally, phase 3 consisted of a five-week take-home trial where patients administered to themselves constant doses of apomo ⁇ hine prior to sexual intercourse. Phase 1 : Subject Selection
• Participating patients were selected from among those that initially presented with the complaint of impotence. These patients underwent a thorough urological assessment by a urologist as well as an assessment by a psychiatrist (See “Baseline” column in Table VII, below).
• Subject is presently in a stable, heterosexual relationship; Subject and partner agree to at least one attempt at vaginal intercourse each week during the study;
• Subject is without evidence of male erectile dysfunction due to non-psychogenic causes such as relational discord, physiologic or organic dysfunction;
• Endocrine disease (diabetes mellitus, Addison's disease, etc.); b. Multiple sclerosis; c. Neurologic disease or injury (spinal cord injury or lesion, neuropathy, etc.); d. Vascular disease (Leriche Syndrome, aneurysm, atherosclerosis, cerebrovascular disease, etc.);
• CABG cardiac glycosides
• arrhythmia etc.
• i Pelvic disease, trauma, or injury
• j Psychiatric disorders other than psychogenic impotence (including antisocial disorders, depression, schizophrenia, etc.);
• VAS visual analog scale
• Tables Xa-c The VAS data compiled on the fifty subjects was used in the study for baseline information, as shown in Tables Xa-c, below.
• Table Xa gives the mean, SEM, median and range scores for several demographic categories for all sites combined, as well as each individual site as listed in Table VIII, above.
• Table Xb shows the mean, SEM, median and range scores for all sites combined, and each individual site regarding the subjects' satisfaction with his recent and overall sexual performance and erection.
• Table Xc shows the mean, SEM, median and range scores for all sites combined, and each individual site regarding the subjects' erection results and frequency of sexual intercourse.
• an apomorphine hydrochloride tablet (4, 6, or 8 mg) or placebo was administered to the patient sublingually during each of the four visits. Because of the possibility of nausea and the tolerance to this effect that prior dosing conveys, the patient was given increasing doses of the apomorphine at each testing, with the placebo being randomly assigned at one of the visits. Patients were instructed not to swallow the medication, but to keep it under their tongue and allow it to be absorbed there.
• Symptoms as they were volunteered were recorded by the research clinician. If the patient complained of nausea or felt unwell in any way he was asked if he wanted to abort the trial. If the trial was aborted, the patient was given the choice of having Gravol 50 mg p.o. (an anti-emetic) administered at that time or enduring the adverse events as they arose. In either event, the patient was monitored by the research clinician until all side-effects had subsided. The patient was asked to return the following week for the next scheduled dose. Patients not experiencing nausea or any other significant adverse effects within fifteen minutes post-dosing with APO or placebo viewed segments of standardized erotic videos to provide sexual stimulation.
• FIG. 12 is a bar graph which shows the incidence of nausea as a percentage of doses administered for each level.
• hypotension was reported as an adverse event in some subjects in this study, along with bradycardia, dizziness, syncope, and pallor. Only single cases of hypotension and pallor were judged severe in this study. Increased sweating and fatigue were also reported. One of the cases of increased sweating was considered severe. The other severe adverse events (mouth edema, dysphagia, upper respiratory tract infection) were judged unrelated to treatment.
• the active doses of APO improved significantly the RIGISCANTM scores for penile increases at each of the four sites in both the neutral and erotic sequences—the only exception being a slightly lower erotic #1 RIGISCANTM score at 4 mg for Site #1 (test results for the erotic video sequence at test site #3 are not available because these sequences were not shown to the subjects).
• Placebo #1 11 9 73 2 854 9 73 2 931 6mg vs Placebo #2 0 0166
• Placebo #2 10 9 00 3 300 9 21 2 996 8mg vs Placebo #2 0 0005
• Placebo #1 vs. #2 0.6243 The effects were seen especially in measurements conducted at the base of the penis, although all summed scores showed significant treatment effects at one or more of the three doses of APO.
• the above-referenced Tables and FIG. 14 show the overall RIGISCANTM score results were significant to highly significant for a treatment effect of 4, 6, and 8 mg. compared to the initial placebo. In addition, most of the treatment effects were significant to highly significant compared to the second placebo. While the first and second placebo did not differ statistically, the results in the second were numerically higher.
• Evaluateable subjects first recorded a success rate, then completed VAS for erection results and satisfaction with intercourse following take-home treatment.
• the success rates as shown in Tables XVa-XVb, below, were calculated for milligrams of APO as well as for micrograms per kilogram of the patient's body weight doses (males). There were four criteria for recording a success in the take- home phase.
• the overall success rate for the study was 70% with APO treatment, as shown in the above tables, which is statistically greater than the baseline rate of 28% .
• the success rate showed numerical increases from four milligrams to six milligrams for male and female participants, but a decrease at eight milligrams for each group.
• the highest success rate, as shown by Table IVa was 73% in both males and females at six milligrams.
• a dose range of 50 to 74 ⁇ g/kg gave the highest success rate of 82% in females and 73 % in males, as shown in Table XVb.
• the success rate by testing site is shown in Table XVI, below.
• Tables XVIIa-XVIId show the statistical results of phase III with respect to RigiscanTM results (a and b) and intercourse satisfaction (c and d) based on question 1 and question 3, respectively, from the completed questionnaires (see FIGs. 15 and 16).
• These scores for erection rigidity (question 1) showed numerical improvement from baseline with the best results seen at 4 mg in males and 8 mg in females. The maximum improvement from baseline were 56% in males and 59% in females. The mean improvement were 29% in males and 34% in females.
• the VAS for satisfaction (question 3) showed similar results with a maximum improvement from baseline of 62% in females and 57% in males, both at 8 mg. The mean improvements were 34% in females and 45% in males.
• Table XVIIa shows the statistical results of phase III with respect to RigiscanTM results (a and b) and intercourse satisfaction (c and d) based on question 1 and question 3, respectively, from the completed questionnaires (see FIG

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