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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism

Definitions

• This invention relates generally to weight promotion.
• Weight promotion is desirable in treating many medical and physiological conditions as well as for sports training and other activities.
• other means of treatment are used to limit the clinical effects of compromised weight.
• Weight promotion can include increasing weight, maintaining weight, or slowing weight loss.
• weight loss can lead to severe illness.
• frail elderly often suffer loss of appetite due to multiple factors such as anosmia, lack of exercise and depression. Wasting in the elderly constitutes a serious challenge in gerontology.
• the depressive component of anorexia nervosa and elderly wasting can be treated, in some cases successfully, with counseling and anti depressant drugs.
• lack of appetite with resulting body emaciation often persists.
• Modification of body form perception in anorexia nervosa, and engaging activities for the elderly often assists in reversing these conditions.
• Forced feeding is resorted to in serious cases. While these and other clinical approaches are successful in some cases, disability and even death may occur in others.
• systemic steroids has been previously employed to increase muscle mass.
• Systemically administered steroids while highly effective in promoting body mass, have numerous side effects, including toxicity and aggressive behavior. Because of these attendant problems, systemic steroid use has been banned from most sporting events. These drugs are now strictly controlled or illegal in most jurisdictions.
• VNO vomeronasal organ
• vomeropherins a class of pharmaceuticals which directly stimulate the vomeronasal organ
• vomeropherins a class of pharmaceuticals which act through the vomeronasal system
• vomeropherins are administered directly to the VNO, vomeropherins do not need to enter the systemic circulation in order to exert their therapeutic effects. Instead, when administered to the VNO, such as by a nasal spray, vomeropherins stimulate the VNO directly, triggering a response in the brain, such as in the hypothalamic regions.
• vomeropherins do not need to cross the biological barriers that are associated with systemic drug abso ⁇ tion and distribution in order to produce the desired therapeutic effect. Consequently, this class of pharmaceuticals enjoys a rapid onset of action. In addition, because typically only minute quantities of vomeropherins are required to induce a biological response, both production costs and the potential for adverse side effects are minimized.
• vomeropherins One characteristic of vomeropherins is that they are typically associated with reproductive factors. In certain treatment schemes, this aspect of vomeropherins is very useful. However, this gender specificity can prove a disadvantage for general applications (Monti-Bloch et al, J. Steroid Biochem. Molec. Biol. 39, 573-582 (1991)). Additionally, many of the reproductive effects in female patients are limited to pre-menopausal women.
• the present inventive weight promoting composition is an important advancement in the field of weight promotion.
• the inventors have unexpectedly discovered a VNO administered pharmaceutical composition which promotes weight gain in all ages and both genders, while avoiding problems of systemic administration.
• the special qualities of VNO drug administration provide the weight promoting composition of the present invention with unique advantages over currently available pharmaceuticals and feeding regimens.
• the inventive composition acts synergistically with these prior art approaches.
• the activity of the inventive composition is not limited to one gender, or pre- menopausal women, and thus enjoys broad applicability.
• the present inventive composition, method, and product allow, for the first time, weight promotion without the disadvantages of systemic exposure to a drug.
• This special advantage is accomplished by administration of the pregnane vomeropherin of formula I, or a pharmaceutical composition containing it, to the VNO.
• the present invention was made when the inventors unexpectedly discovered that these compounds, when administered to the VNO, promotes weight gain.
• the compounds of the present invention are effective in all ages and genders.
• vomeropherins which can be appropriately used in the present invention are pregnanes of the formula:
• R ⁇ H, C ⁇ -4 alkyl, C ⁇ - 4 alkanoyl, S0 3 H, or a salt thereof,
• R 2 C alkyl
• R 3 H or methyl, and one or two non-adjacent members of a, b, c, and d are optional double bonds.
• VNO drug administration provides the weight promoting composition, method, and product of this invention with unique advantages over currently available pharmaceuticals and feeding regimens.
• activity of the inventive composition, method, and product is not limited by age or gender.
• Anorexia Nervosa One important embodiment of the weight promoting method of the present invention is the treatment of anorexia nervosa.
• anorexia nervosa is a particularly important application. A disease which has long been recognized as prevalent in pubertal girls, anorexia is now identified as affecting at least 1% of American males.
• Anorexia nervosa is a challenging disease of complex etiology, characterized by a distorted perception of body weight, horror of eating, and loss of appetite. It typically has a psychiatric aspect, including depression, beyond a disinterest or actual fear of eating. In some cases, anorexic patents display bulimic behavior, i.e. binge eating followed by resort to self-induced vomiting.
• the subnormal weight of the patients can by itself exacerbate an underlying depression, or even be a primary cause of depression. Listlessness and other effects of starvation mirror and support the clinical depression.
• force-feedings of various types are used in an effort to counter the ill effects of appetite failure.
• This approach has potential problems with injury, and can worsen patient-care taker relations. Additionally, patients will often resort to self-induced vomiting to circumvent forced feedings.
• the elegant approach of the present invention is to induce a desire to eat in the patent using the inventive pharmaceutical composition. This allows appropriate treatment without often self-defeating forced eating. Forced eating can in fact serve to worsen eating disorders.
• the method of the present invention may be sufficient in itself to alleviate or even cure anorexia nervosa.
• systemic or VNO antidepressants and psychological counseling and body image modification can be used as adjunct therapy to the present weight enhancing method.
• Tube feeding requires increased patient care.
• the tube feeding procedure and devices can also cause patient discomfort.
• the lack of roughage available in such feeding approaches may result in poor bowel mobility.
• the loss of patient involvement in the pleasurable activity of natural eating may lower morale.
• HIV/ AIDS HIV patients who have developed serious symptoms often suffer from cachexia.
• the general effects of the present invention to promote weight in these patents will be very useful in the management of AIDS.
• the dosing of AIDS patients with the inventive weight promoting composition can be timed to increase appetite during the times of day most amenable to eating adequate amounts of food.
• AIDS patients can use the present invention to provide increase weight gain prior to a weight challenging treatment, such as chemotherapy.
• Renal Disease Renal disease and attendant dialysis treatment is often associated with wasting. This wasting can complicate the health management of already compromised individuals.
• the present weight promoting invention is an important adjunct therapy for renally compromised individuals. Wasting secondary to renal disease is particularly harmful when it affects growing children, and in such cases can lead to a permanently smaller stature.
• Several different therapies have been used in an effort to circumvent long term side effects of pediatric renal disease. Most recently human growth hormone has been employed to stimulate appropriate growth in these children. However, there are concerns about toxicity and other implications of chronic exogenous HGH exposure.
• the present invention is an important alternative approach to human growth hormone exposure to provide improved or normal adult stature in children with chronic renal disease.
• the inventive composition, method, and product can be administered prophylactically to avert potential wasting.
• the present invention alone is not able to fully compensate for growth failure, it can be used in adjunct therapy with HGH, allowing a lower exposure level of the more toxic pharmaceutical.
• compositions, methods, and product can be used to ameliorate existing cachexia, or can be administered prophylactically to avert this potential wasting.
• Eating disorders can be associated with a psychological state or a physiologically predisposing condition. Depression, as well as anxiety and stress, can have eating disorders as a side effect. In some cases, these disorders are self-correcting, such as when stressful situations are resolved. However, eating disorders can progress to unhealthy levels when the underlying condition persists. As with anorexia, a particularly dramatic form of eating disorder, the sequelae can be serious.
• the frail elderly are often predisposed to physiological challenges which exacerbate poor eating. Factors such as anosmia and lack of physical activity serve to further undercut weight maintenance in these individuals. For instance, physical frailty complicated by osteoporosis can lead to isolation from family and friends, and limitation of beloved activities. These factors predispose the frail elderly to depression.
• the present invention can be used to promote weight in these weight challenged individuals. It can be administered prophylactically at the first sign of weight loss to avert potential wasting. Larger dosages can be provided prior to a particular challenge, such as surgery, to increase body mass. Such an effect will improve the likely outcome of the surgery.
• Childhood Eating Disorders Childhood eating disorders pose a serious challenge to the pediatrician. These feeding disturbances are manifested by persistent failure to eat adequately with significant failure to gain weight or significant loss of weight over at least one month. Onset of these disorders occur before age six. The loss of weight from those disorders is not exclusively due to an associated gastrointestinal or other general medication conditions, such as esophageal reflux.
• a variety of combinations of treatments are normally prescribed for such disorders.
• Psychotherapy for the mother is used to increase her emotional availability to her infant.
• Behavioral techniques can be used to diminish maladaptive behaviors in the infant's eating habits.
• the infant is kept upright during and after feedings.
• Surgical repair may be consider if growth retardation is severe.
• These complex approaches require a treatment team.
• the present invention represents an important adjunct to current therapies for childhood eating disorders.
• the inventive pharmaceutical composition provides both motivation to eat and weight gain necessary to sustain appropriate growth in these compromised infants. It may also allow the child to stay with their mother while she is improving her maternal skills, avoiding disruption of the family unit.
• Anosmia is an appetite disorder which occurs when patients have a diminished sense of taste and/or smell. Over time there is typically a degeneration of the olfactory organs. As a result, anosmia can be an important factor in frail elderly wasting. Anosmia can also occur secondary to injury or illness, thus effecting other patient groups as well.
• Morning Sickness The present invention can also be used for direct treatment of weight compromising morning sickness. This condition tends to be at its height in the first trimester of pregnancy, and is often associated with HCG production. However, queasiness and inability to eat can last throughout the pregnancy. Efforts to provide relief from the often serious effects of morning sickness have included thalidomide treatment, predominately in Europe. Unfortunately, the first trimester is a sensitive period in gestation, and many children were born with severe birth defects secondary to this treatment.
• the present weight promoting invention provides this needed therapy.
• the aversion to eating associated typically with the first trimester of pregnancy may be partially or fully offset by this administration.
• a customized dosage scheme can improve the results of the present invention. It is a current standard approach that, during the period of day when nausea abates somewhat, pregnant women are encouraged to eat as much as is possible short of triggering vomiting. This approach would be supported by timing the administration of the present invention to encourage eating during the period where food ingestion is more tolerable.
• Estrogen replacement therapy limits the progression of osteoporosis to varying degrees. Additionally, drugs which limit the effects of osteoclastic activity are used to slow, and sometimes restore, loss of bone calcium. High dietary calcium is also used to promote bone density.
• the present weight promoting invention is useful in promoting optimal body mass where there is a predisposition to osteoporosis; and can be used as adjunct therapy with estrogen replacement and other therapies.
• the invention is particularly useful in treatment of cases where exogenous estrogen treatment is counter- indicated, as in women with a history of breast cancer.
• the present invention will allow the administration of extraneous estrogen at more moderate levels, diminishing attendant risks.
• Prophylactic Weight Gain The present invention can provide an increase in weight prior to weight challenging activities. For instance, severely underweight women can run a severe risk to themselves and their unborn child if challenged by serious morning sickness. Such women will often be admitted to the hospital with this condition, in part due to the potentially serious effects of starvation on both mother and unborn child.
• underweight women often have irregular reproductive cycles and an increase in weight can improve the chance of a desired pregnancy.
• slightly built women contemplating pregnancy can increase their weight prior to conception, both increasing their chances of early conception and circumventing in some cases the potential sequelae to morning sickness mentioned above.
• the administration is non- systemic, there are no attendant risks to a fetus if the women becomes pregnant during the period of treatment.
• Sports Applications There are a wide range of situations in which an increase in body mass is desirable.
• current approaches to building body mass for sports activities are used in wrestling, body building, football, hockey, weight lifting, and other sports calling for an increase of body mass to optimize performance.
• This weight promoting invention can be used to replace a number of these prior art approaches, while avoiding many of their attendant problems.
• the effects of the present invention can be supplemented by concurrent use of prior art methods.
• Self- forced eating by athletes has been a method used for thousands of years to increase body mass, such as with Sumo wrestling. More recently, supercaloric supplements have been used to increase the weight gain effects over those from a standard diet.
• One disadvantage to these approaches is that, through normal metabolic regulation, eating beyond normal hunger prompters satiates the appetite. This natural feedback inhibition discourages further eating.
• Self-forced feeding also results in lower metabolism and sedentary behavior, further off-setting weight promoting effects of this approach.
• eating habits which force eating in the face of satiety may be established during an individual's athletically active years. These habits lead to obesity when an athlete later adopts a more sedentary life style.
• the present weight promoting invention provides the advantage in sports of a large body mass without the attendant disadvantages and side effects of current approaches. Systemic exposure to synthetic steroids is eliminated. Additionally, weight increases can be accomplished before the start of the sports season, with a more normal weight level being maintained during the balance of the year. Avoiding chronic self forced feeding beyond satiety avoids establishment of unhealthy eating habits. Administration
• the activity for the invention in men is similar to that in women.
• men When tested by electrovomerogram, men showed an average reaction of 30 mV and women a reactions of 50 mV (see Example 2 below).
• the comparable response of the VNO in men and women to the inventive weight enhancing composition is a strong predictor that pre-pubertal girls and menopausal women, and well as children, will benefit from the inventive composition.
• the lack of reproductive hormone modification by the present invention suggests its effect will not be limited to pre-menopausal women.
• the invention elicits an unusually strong response in the VNO, as compared to other pharmacologically active vomeropherins. This robust response was the motivation for the initial studies to test for the possibility of gonadotrophic hormone release effects.
• Effective dosage levels of the active ingredient of the invention when applied to the facial skin of the patient can be from about 1-100 ⁇ g, preferably about 10-50 ⁇ g, and most preferably about 20-30 ⁇ g.
• an effective amount of the active ingredient is about 1 pg to about 1 ng, or preferably about 10 pg - 50 pg.
• an effective amount is about 100 pg to about 100 ⁇ g, preferably about 1 ng to about 10 ⁇ g.
• VNO active drugs there are also differences in patient groups for dosages, timing, and other drug administration considerations. However, certain considerations are much less critical with VNO medications. For instance, body size is much less of a factor in determining dosages. Clearance rates are not compromised by renal dysfunction. Thus, the VNO as a drug administration site has advantages in regards to these considerations. In some cases it is still appropriate to provide adjustments to dosage levels for various patent groups. These modifications will be easily ascertained by one of ordinary skill in the art, such as by experimentation with dose and time of dose.
• the weight promoting method of the present invention enjoys the unique advantages of VNO administration.
• a simple nasal spray bottle can provide a dose, similar to those used to administer nasal decongestants, typically calling for a water soluble derivative of the active compound.
• a propellant bottle similar to those used for asthma drug administration can be employed.
• the latter administration method typically uses a hydrophobic derivative of the inventive compound.
• spiked dose administration can be used to coordinate with schedules or natural rhythms to produce an enhanced effect. For instance, pregnant women with all-day "morning sickness” will often have specific periods during the day, typically in late evening, when their nausea is less acute. If the woman administers the active ingredient in anticipation of this time, her increased appetite can be timed to the most useful period.
• high-strung squeamish teenage eaters may have a period during the day in which they are calmer and less prone to eating disorders. This will often occur when they are removed from the stress of school, for instance, or if they have a habit of late evening snacking. Again, the dosage of the active ingredient could be timed to optimize this opportunity of predilection towards food intake. Infants suffering from eating disorders will also have periods of the day more amenable to successful feeding.
• Single dose exposure to the active ingredient can be administered as a dry powder, in much the same way as snuff.
• a preferable means of administration is use of a metered device. Rather than use a pure form, this form of administration would typically have the active ingredient on a carrier. This approach is preferable because the effect of small dosages of the inventions active ingredient is so intense that the carrier may be needed to provide an appropriate dosage and avoid overdosing.
• breakable capsules can be employed. This means of administration proves measured single dose exposure.
• the breakable capsules can be provided on a bubble pack card, with the days or times of the doses stamped next to the appropriately measured dose. For instance, the optimal time lag prior to a scheduled meal can be printed next to the appropriate dose.
• Other approaches of continuous or pulsatile dosing can include providing a gel or pad containing the active ingredient in the nose. These administration approaches provide retention of the active ingredient in the nose for an extended period of time, providing continuous exposure.
• the active ingredient can also be encapsulated in a slow release or timed release form, avoiding the potential problem of fatigue and attendant rebound effects.
• the present invention can be administered in the form of an ointment. This approach to administration will also provide a long term effect. Therefore, the ointment embodiment of the present invention would typically be applied near, but not on, the VNO. Appropriate placement would be on the upper lip. The ointment allows a longer lasting exposure to the active ingredient than certain other approaches.
• Respiratory exposure devices can provide simultaneous administration of the active ingredient with other substances. For instance, chronically ill patients are often provided with supplemental oxygen, either in an oxygen tent, or through nasal tubes. Such patients may be ambulatory, carrying their oxygen units with them. Respirators are often used in very ill, bed ridden patients.
• Respiratory administration units may be supplement with a dose of the active ingredient for ease of administration by introduction into the air stream.
• This airborne administration can provide concurrent single, measured doses, or exposure on a continuous basis. Because of the relatively stable chemical structure of the active ingredient, numerous means of administration are useful. Nebulizers, vaporizers, sonicators and other devices which produce an airborne mist can also be used to administer appropriate doses of the active ingredient, again either in measured doses, or on a continuous bases. A continuous institutional dose in specific rooms in nursing homes can be provided where humidifier or other air circulating mechanisms are currently employed.
• VNO receptor fatigue One potential pitfall to continuous exposure of the VNO to the active ingredient is the potential for VNO receptor fatigue, and a potential rebound effect after cessation of administration.
• Several administration techniques can be used to avoid this potential problem
• a simple and elegant approach to providing a pulsatile exposure is to have the dose flow with normal breathing.
• a suitable carrier e.g. a n alcohol-based solution or gel
• the active ingredient in a suitable carrier can be swabbed on the upper lip.
• a gel or pad containing the active ingredient near, but not directly at, the VNO would also serve to provide intermittent exposure.
• the appropriate treatment protocol will become apparent when using standard optimization criteria.
• a "pregnane” or “pregnane steroid” refers to a polycyclic hydrocarbon with a four-ring steroidal structure with methylation at the 10- and 13-positions and ethylation (including unsaturated groups) at the 17-position.
• the 19-no ⁇ regnanes lack a methyl or other carbon-containing substituent on C-10 where C-19 would normally be found.
• 19- no ⁇ regnenes are a subset of pregnanes and contain at least one double bond.
• the following structure shows the four-ring steroidal structure common to 19- no ⁇ regnanes (which, as already mentioned, include the pregnenes). In describing the location of groups and substituents, the following numbering system is employed:
• the active ingredient of the present invention has the general structure:
• R ⁇ H, C alkyl, C 1- alkanoyl, S0 3 H, or a salt thereof,
• R 2 C alkyl
• R 3 H or methyl, and one or two non-adjacent members of a, b, c, and d are optional double bonds.
• the 13- and 17-positions are chiral centers.
• reference to a compound of formula (I) will be used to mean that the 13-methyl is 13 ⁇ , while the 17-ethyl can be either ⁇ or ⁇ (when one or the other only is being referenced, then it will be specifically identified as the 17 ⁇ or 17 ⁇ diastereomer).
• the compound 19-no ⁇ regna-l,3,5(10)-trien-3-ol has the structure illustrated in formula (I) above in which Rj is H, R 2 is ethyl, and R is H, and none of the optional double bonds are present.
• the name 19-no ⁇ regna- l,3,5(10)-trien-3-ol, without more, requires either 17 ⁇ or 17 ⁇ substitution.
• the compound of formula (la) represents a preferred embodiment of the present invention.
• Other preferred embodiments include 17 ⁇ -methylestra-l,3,5(10)-trien-3-ol, and 21 -methyl- 19-no ⁇ regna- l,3,5(10)-trien-3-ol.
• Crowe et al. teaches that their compounds should be used as an orally administered contraceptive. Crowe et al. also teaches a dosage level many orders of magnitude above those appropriate for the present invention, that is a in daily doses of between 0.01 mg to 5 mg.
• Example 1 The synthesis procedure developed by the inventors to produce the potassium salt of the sulfate compound to the inventive composition is set forth in Example 1, below. This derivative was designed to provide increased water solubility.
• the following synthetic method provides for the potassium salt form of one embodiment of the active ingredient.
• This compound enjoys an increased water solubility, and so is well suited for a water based carrier.
• the mean peak amplitude of the EVG (electrovomerogram) response to intranasal administration of (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol reported as the magnitude of the difference from the response to placebo, was 30 mV in men and 50 mV in women (13.9 mV in women and 5.3 mV in men difference from the response to placebo).
• the peak amplitude of the response to (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol was significantly greater than that to placebo.
• the peak amplitude of the response in women was greater than that in men.
• EVG Electrodermal activity
• RF Respiratory frequency
• CF cardiac frequency
• EVG alpha-cortical activity
• ⁇ -CA alpha-cortical activity
• ⁇ -CA beta-cortical activity
• ⁇ -CA -2.2 ⁇ V /Hz.
• the performance is EVG++, EDA+, ⁇ -CA++, where + indicates a moderate increase in activity and ++ indicates a substantial increase in activity.
• (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol produced a mean EVG response significantly different from placebo (p ⁇ 0.05), but also smaller than that recorded in female volunteers. This was followed by increased EDA (p ⁇ 0.05), but in a lesser amount than the EDA change observed in female subjects. Body temperature and alpha rhythm also decreased in male subjects treated with (17 ⁇ )19- no ⁇ regna-l,3,5(10)-trien-3-ol (p ⁇ 0.05) as compared to placebo. Other biological parameters did not change significantly in males.
• Study CL003 was designed to investigate possible effects of (17 ⁇ )19- no ⁇ regna-l ,3,5(10)-trien-3-ol on gonadotropin secretion in healthy female volunteers. Because gonadotropins typically are secreted in a pulsatile pattern with 4-6 peaks per day, (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol was administered at 10- minute intervals over a 6-hour period. This timing was provided in order to determine whether (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol affected the pattern of pulsatility and/or the magnitude of the gonadotropin release. No consistent changes in gonadotropin secretion were observed, and no changes in menstrual cycle pattern or ovulation were observed.
• the investigators received spontaneous, anecdotal post-study reports from the subjects indicating that they had experienced increased appetite.
• the investigators gave the subjects a questionnaire one month after completing their participation in the study to assess this effect of (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol in a systematic fashion. All subjects indicated they had experienced a large increase in appetite, which was associated with the (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol treatment arm of the study.
• Study CL004 was conducted as a follow-on to the su ⁇ rising appetite results of study CL003, and was designed to provide a more focused investigation of the effects of (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol on appetite. In the interest of providing a comparable investigatory scheme as the initial study, the same dosing regimen (one dose every 10 minutes for 6 hours) was used as had been used for study CL003.
• Study CL004 was conducted after study CL003 had been completed. The interim findings are that all subjects in this study reported an increase in appetite for at least one week after administration of (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol but not after administration of placebo. This increase in appetite was associated with a persistent increase in body weight. Study CL005. Study CL005 was designed to investigate in detail the effects of (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol on food consumption in studies CL003 and CL004. The (17 ⁇ )19-norpregna-l ,3,5(10)-trien-3-ol dosing regimen was the same as had been used for the previous studies. Food intake and appetite were examined in this study in great detail.
• Study CL006 was designed to provide an evaluation of a more clinically meaningful (17 ⁇ )19-no ⁇ regna-l,3,5(10)-trien-3-ol dosing regimen, as well as to provide a more controlled environment in which to evaluate appetite and food intake effects.
• An informal analysis during this study in progress of the blinded data suggests that some participants experienced a treatment-related increase in food intake and body weight.

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• 1999
  • 1999-12-30 US US09/475,328 patent/US6555531B1/en not_active Expired - Fee Related
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