Method and composition for reducing weight

A method for reducing weight by the administration of L-Dopa or a stabilized form thereof with or without a decarboxylase inhibitor and Molindone wherein Molindone acts as a potentiator to enhance the weight reducing potency of L-Dopa in warm-blooded animals. The synergistic effect of the combination of L-Dopa and Molindone reduces the required dosage of the two drugs to levels which can be tolerated by higher forms of mammals, whereas individually the dosages required to reduce weight in higher mammals is not easily tolerated and may be toxic or lead to undesirable side effects.

The present invention relates generally to the treatment of obesity by 
means of the internal administration of pharmaceuticals. More 
particularly, the invention pertains to the improved administration of 
L-Dopa with or without a decarboxylase inhibitor plus a potentiator, 
Molindone, to treat obesity. 
BACKGROUND OF THE INVENTION 
The health problems associated with the widespread problem of obesity need 
not be elaborated. A need exists for pharmaceutical treatments which are 
effective for the treatment of obesity in mammals with a minimum of 
undesirable side effects. By "obese warm-blooded animal" is meant a human 
or other mammal which is more than 10 percent overweight as judged by 
contemporary medical standards. Many treatments have been proposed for 
obesity. For example, U.S. Pat. No. 3,867,539 to Henkin describes a 
treatment wherein anorexia is produced by administration of histidine to 
the obese patient. However, no effective pharmaceutical treatment is 
believed in widespread use due to a lack of either lasting effectiveness 
or of undesirable side effects. 
DESCRIPTION OF THE PRIOR ART 
L-Dopa is the trivial name for the naturally occurring compound L-3, 
4-dihydroxyphenylalanine, which is commercially available--its synthesis 
having been reported in the literature (Yamada et al., Chem. Pharm. Bull., 
10:693 (1962)). 
The most widely recognized therapeutic use of L-Dopa is in the treatment of 
Parkinson's disease. The mechanism of L-Dopa in the treatment of this 
disease is attributed to its presumed role in the correction of an 
imbalance of dopamine and acetylcholine in the basal ganglia, a 
biochemical defect associated with Parkinsonism. 
L-Dopa has also been used as a treatment of ethanol withdrawal symptoms, as 
reported in the U.S. Pat. No. 3,995,058 to Hammond et al. The treatment of 
paralysis agintans with L-Dopa and with mixtures of L-Dopa and 
benzodiazepines is reported in U.S. Pat. No. 3,984,545 to Frills, Jr. et 
al. Therapeutic use of L-Dopa in the treatment of depression, sleep 
production in mice, supranuclear palsy and hepatic coma has also been 
reported. 
It has been reported by Leonor Rivera-Calimlim, et al. in The Journal of 
Pharmacology and Experimental Therapeutics, 184:2 Sept. 18, 1972 that 
daily administration of L-Dopa causes weight reduction in rats. Weight 
loss in Parkinson patients treated long term with L-Dopa has also been 
reported, T Vardi etc. L-Dopa induced weight reduction is believed to be 
the result of several factors including altered absorptive capacity of the 
gut, loss of appetite, enhanced lipid metabolism and/or basal metabolism. 
(There have also been reports showing that L-Dopa induces weight gain). 
Molindone hydrochloride is the trivial name of 3-ethyl-6,7 dihydro-2-methyl 
5 morpholinomethyl indol-4(5H) one hydrochloride, which is described in 
U.S. Pat. No. 3,491,093 and is commercially available from Endo 
Laboratories under the trademark "Moban" and from Abbott Laboratories 
under the trademark "Lindone". 
Molindone has an action which resembles that of major tranquilizers causing 
reduction of spontaneous locomotion aggressiveness, suppression of a 
conditional response and antagonism of the bizarre stereotyped behavior 
and hyperactivity induced by amphetamines. Heretofore, Molindone was 
prescribed primarily for the treatment of schizophrenia. Recommended human 
dosages generally range from 15 to 225 mg. per day, although 800 mg. has 
been administered in one case. 
It has been reported by George Gardos and Jonathan Cole in The American 
Journal of Psychiatry 134:3, March 1977, that Molindone has caused weight 
loss in schizophrenics. A usual clinical course in schizophrenics is for 
improvement of patient's clinical condition to be accompanied by weight 
gain and deterioration to be accompanied by a corresponding weight loss. 
Gardos and Cole reported that when schizophrenic patients were 
administered Molindone, improvements of their clinical conditions were 
achieved without accompanying weight gain and in most cases by significant 
weight loss. There are also reports showing weight gain and improved 
appetite in Molindone treated patients, e.g., Sugarmann & Herrmann, Chem. 
Pharm. Ther. 8:261-65, 1967. 
SUMMARY OF THE INVENTION 
It has been found that simultaneous administration of L-Dopa, with or 
without a decarboxylase inhibitor, plus Molindone hydrochloride results in 
weight loss substantially in excess of that which would be expected by the 
additive effects of the drugs individually and that the combination of 
L-Dopa and Molindone is a unique combination demonstrably superior as an 
anti-obesity composition to doses of either drug alone. The effective 
dosage of the two drugs in combination is reduced to levels that can be 
tolerated without the undesirable side effects of the higher dosage 
required if the drugs were administered singly. 
DETAILED DESCRIPTION OF THE INVENTION 
Molindone and L-Dopa, each of which have previously been known to cause 
weight reduction in warm-blooded animals, have been found to have a 
synergistic effect when used in combination with each other. It has been 
found that Molindone functions as a potentiator to significantly increase 
the weight reducing functions of L-Dopa or L-Dopa compositions. Although 
the term "L-Dopa" is used throughout the application, it should be 
construed to include other known compounds in chemically equivalent 
amounts which are converted in the body to L-Dopa, such as known 
precursors, i.e., pro-L-Dopa. 
Dopamine, which is formed by the decarboxylation of L-Dopa, is the chemical 
which actually associates with the brain receptors to produce the 
pharmaceutical effects associated with L-Dopa. The amount of dopamine 
available to the brain is generally provided by the L-Dopa which 
decarboxylizes within the brain. The action of the Molindone potentiates 
the effect of the dopamine in the brain or peripherally. 
Accordingly, the L-Dopa is preferably used in combination with a 
stabilizer, such as an L-Dopa decarboxylase inhibitor, to prevent 
premature metabolism and breakdown of the L-Dopa which may occur in the 
gut mucosa or elsewhere before reaching the brain. The level of L-Dopa 
required is reduced if the L-Dopa is administered in stabilized form, and 
it is known to stabilize L-Dopa with an L-Dopa decarboxylase inhibitor. 
Stabilized compositions of L-Dopa may contain an L-Dopa decarboxylase 
inhibitor in amounts of from about 6% to about 100% and preferably between 
10% and 20% by weight of the L-Dopa. Stabilized compositions of L-Dopa may 
be from about 4 to about 10 times as effective as L-Dopa in providing the 
precursor L-Dopa which metabolizes dopamine in the brain. 
Examples of suitable L-Dopa decarboxylase inhibitors include 
N'-(D,L-seryl)-N"-3,3,5-(trihydroxybenzyl)-hydrazine (benzerside), the 
hydrochloride or maleate salt thereof and .alpha.-methyl-dopahydrazine 
(carbidopa). Commercially available stabilized L-Dopa products include an 
L-Dopa composition sold under the trademark "Sinemet", available from 
Merck, Sharpe and Dome, Inc., which contains ten parts L-Dopa to one or 
two parts carbidopa by weight. A similar product is available under the 
trademark "Madopar" from Hoffman Laroche, Inc., which contains four parts 
of L-Dopa to one part of benzerside. 
The daily dosage of L-Dopa, decarboxylase and Molindone (stabilized form) 
which is effective may be varied within a relatively wide range and, to 
some extent, is dependent upon the requirements of the individual subject 
or species. In general, in animals, the daily administration of from about 
0.005 milligrams of L-Dopa per gram of body weight to about 1 milligram 
per gram of body weight plus between 0.5% to 50% Molindone to L-Dopa by 
weight is effective, dependent always on the species and the individual. 
If administered on a dosage per weight of food basis, L-Dopa is 
administered at between 2 mgs and 400 mgs per gram of food along with the 
Molindone and preferably the decarboxylase. The dosage of a simple L-Dopa 
composition and Molindone without a decarboxylase inhibitor (unstabilized 
form) will be administered in amounts to generally provide about 4 times 
as much as the L-Dopa in a stabilized L-Dopa composition with up to 50% 
Molindone by weight. 
While it is useful to define dosages in terms of milligrams of drug per 
gram of body weight for lower animals, for the treatment of obesity in 
humans, it is more useful to speak of a particular dosage administered per 
day. For an adult human, the effective daily dosage of non-stabilized 
L-Dopa to effect weight loss is between about 0.5 to about 20 grams per 
day, plus a proportionate amount of Molindone between 0.5 and 50% of the 
L-Dopa. For a stabilized form of L-Dopa the dosage is between about 0.25 
to about 4 grams per day. The percentage of Molindone is between 1.0 and 
50% of the L-Dopa. 
It has been found that when Molindone in a proportion of 0.5 to 50% of the 
L-Dopa is administered with L-Dopa or an L-Dopa composition, warm-blooded 
animals experience a weight loss significantly greater than would be 
expected from the weight reducing effects of either drug or drug form 
alone. While there are some reports in the literature which show that when 
used alone, Molindone and L-Dopa are each known to cause weight reductions 
in warm-blooded animals, there are also reports to the contrary. However, 
the synergistic effect of the two compounds is unexpected. 
To potentiate the weight reducing properties of L-Dopa, an effective amount 
of Molindone is administered daily along with, perferably simultaneously 
with, an effective daily dosage of L-Dopa or an L-Dopa composition. 
The amount of L-Dopa in stabilized or unstabilized form plus the percentage 
by weight of Molindone is determined according to the amounts that reach 
the brain. It has been found that using the stabilized form plus the 
Molindone is advantageous since it permits the use of less L-Dopa and 
Molindone to achieve the desired weight loss. The large doses of these 
drugs used singly needed to effect weight reduction in higher mammals lead 
to the creation of undesirable side effects while the smaller doses of the 
two drugs in combination causes less undesirable side effects.

EXAMPLE 1 
In order to demonstrate the efficacy of Molindone as a potentiator of the 
weight reducing properties of Sinemet, genetically obese Zucker rats are 
provided with ad lib access to food (as much food as they choose to eat) 
which is admixed with various proportions of Sinemet (1 part Carbidopa to 
10 parts by weight of L-Dopa) and/or Molindone. The rats are allowed ad 
lib access to food in order to best measure the combined appetite and 
metabolic weight reducing effects. The subjects for this invention are 
Zucker rats which are homozygous for a form of obesity which is carried as 
a recessive gene. When allowed ad lib access to normal rat feed, the 
Zucker rats become hyperphagic and invariably gain weight. Excessive 
weight is added to the Zucker rat by the preferential utilization of 
dietary amino acids for fat synthesis and is a constant characteristic of 
the genotype. With advancing age, the Zucker rat becomes sedentary and 
grossly obese. 
Male obese Zucker rats are weight matched into groups of four or five 
animals each. The rats are individually caged, and all animals are allowed 
ad lib access to a powdered rat feed and water. Throughout the experiment 
the proportions of Molindone and/or Sinemet admixed with each rat's food 
is kept constant. 
A conrol group (Group 1) is allowed ad lib access to unadulterated powdered 
rat feed to measure the normal food intake and weight gain to be expected 
from Zucker rats which are not administered weight reducing drugs. 
Groups 2 and 7 are included to demonstrate the efficacy of L-Dopa as a 
weight reducing compound. Group 2 receives 8.8 mgs. of Sinement (8 mgs. 
L-Dopa and 0.8 mg. carbidopa) per gram of feed. Group 7 receives more than 
triple the proportion of Sinemet per gram of food as Group 2, i.e., 27.5 
mg Sinemet per gram of food, to demonstrate the effects of exaggerated 
amounts of Sinemet. 
Groups 8 and 9 are included to illustrate the efficacy of Molindone as a 
weight reducing compound. Group 8 receives 0.55 mg Molindone per gm. of 
food. Group 9 receives 1.1 mg Molindone per gm. of food to demonstrate the 
effects of exaggerated amounts of Molindone. 
In Groups 3-6, Molindone and L-Dopa are simultaneously administered to the 
rats. All groups received 8.8 mg of Sinemet per gm. of food intake (as 
does Group 2). Groups 3, 4, 5 and 6, respectively, receive Molindone at 
Sinemet to Molindone ratios of 48:1, 32:1, 24:1 and 16:1 by weight. Group 
6 which receives Molindone at a Sinemet to Molindone ratio of 16:1 
receives an amount of Molindone per gram of food identical to that of 
Group 8. 
The food intake of each animal is measured on a daily basis. The animals 
are weighed every 4 days. 
The experiment is carried out over a period of 60 days. At the end of 60 
days the results are achieved as set forth in Table 1 below. 
TABLE 1 
__________________________________________________________________________ 
Comparison of Sinemet, Molindone and food intake with weight change 
Mg Sinemet 
Sinemet Wt. Change as 
(10 parts L-Dopa 
mg. Approx. Mg Food gm. 
% of Orig. Wt. 
to 1 part 
(Average 
Molindone 
Molindone 
(Average 
(Collective Wt. 
Carbidopa) per 
per rat 
(mg/gm 
per gram 
per rat 
change of group at 
Group 
gm of Food 
per day) 
of Food 
of food 
per day) 
end of 60 days) 
__________________________________________________________________________ 
1 0 0 0 0 27.6 +12% 
2 8.8 195 0 0 22.1 -25% 
3 8.8 184 0.18 3.9 20.9 -32% 
4 8.8 173 0.27 5.5 19.6 -38% 
5 8.8 125 0.37 5.3 14.2 -49% 
6 8.8 109 0.55 6.9 12.3 -54% 
7 27.5 371 0 0 13.5 -46% 
8 0 0 0.55 13.4 24.3 -15% 
9 0 0 1.10 23.2 21.1 -24% 
__________________________________________________________________________ 
The rats of Group 1, as is expected of genetically obese Zucker rats, gain 
weight steadily. Groups 2 and 7 confirm the weight reducing properties of 
L-Dopa. Increased dosage of L-Dopa (Group 7) causes corresponding 
increased weight loss. 
Groups 8 and 9 confirm the weight reducing properties of Molindone. 
Increased dosage of Molindone (Group 9) causes increased weight loss. 
It may be seen, when comparing Groups 3 through 6 with Group 2, all of 
which are administered Sinemet in identical proportions per gram of food, 
that simultaneous administration of Molindone potentiates the weight 
reducing properties of a stabilized L-Dopa composition. Within the range 
used herein, the potentiating effect of Molindone on the weight reducing 
properties of a stabilized L-Dopa composition increases with increased 
Molindone concentrations as demonstrated by the progression of increased 
weight loss of Groups 3 through 6. 
Particularly significant is the fact that when rats are concurrently fed 
Molindone and a stabilized L-Dopa composition, the weight loss is greater 
than that which would be expected from the additive effects of L-Dopa and 
Molindone. On a weight per gram of food basis, Group 6 is administered a 
dosage of Sinemet equal to that of Group 2 (no Molindone) and a dosage of 
Molindone equal to that of Group 8 (no Sinemet). The combined weight loss 
of Group 2 (25%) and Group 8 (15%) is (40%) which is significantly less 
than the weight loss (54%) achieved by Group 6. The synergistic effect of 
the Molindone-stabilized L-Dopa composition is even more dramatically 
illustrated by comparing the weight loss of Group 6 with the combined 
weight losses of Groups 2 and 8 in view of the average daily doses of 
Sinemet and Molindone actually ingested. Due to decreased daily intake of 
food by Group 6, Group 6 actually intakes about one half the Sinemet of 
Group 2 and about one half the Molindone of Group 8, and yet Group 6 loses 
more combined weight than Groups 2 and 8 together. It is therefore 
demonstrated that the combination of L-Dopa, i.e., Sinemet, and Molindone, 
has a synergistic effect. The drugs used in combination result in a weight 
loss significantly greater than that which would be calculated by adding 
the weight losses which are expected from comparable doses of the 
individual drugs. 
A comparison of either Group 5 or Group 6 with Group 7 demonstrates that 
adding Molindone to a stabilized L-Dopa composition in ratios of 1:24 and 
1:16, respectively, is at least as effective in reducing weight as is 
tripling the dosage of the L-Dopa composition on a weight per gram of food 
basis. Approximately the same results may be observed by comparing the 
average daily intake of Sinemet of Groups 5 or 6 with Group 7. 
EXAMPLE 2 
To further illustrate the synergistic effect that Molindone has on L-Dopa, 
another experiment was performed. Lean Zucker rats were given 3.3 
milligrams of Sinemet per 1000 grams of food. This low dose did not reduce 
body weight. At the end of 36 days, the rats on this dosage had gained 
1.2% of their original body weight. Another comparable group of lean 
Zucker rats was placed on the same dosage of Sinemet, but 0.45 millgram or 
less than half a milligram of Molindone was added to the food. At the end 
of 36 days, this group had lost 15.8% of their original body weight. The 
importance of this potentiating effect is that it permits L-Dopa dosages 
in the range already approved for Parkinson patients whereas, used alone, 
L-Dopa would greatly exceed the permitted human dosage in order to be 
effective. 
Molindone and stabilized L-Dopa is thereby shown to potentiate the weight 
reducing properties of L-Dopa in mammals. 
EXAMPLE 3 
A further demonstration of the potentiating effect of Molindone is proven 
in an experiment with Zucker lean rats whereby a composition of 2 mg. of 
L-Dopa, 0.2 mg. of carbidopa and 0.675 mg. of Molindone per gram of food 
is added to the powdered chow. Since a dosage of 3 mg. of L-Dopa, 0.3 mg. 
of carbidopa per gram of food does not cause weight loss, clearly a 2 
mg./0.2 mg. L-Dopa/carbidopa dosage will not. However, when the 0.675 mg. 
of Molindone per gram of food is added, after only eight days the weight 
change is -16.18%. Thus a high weight percent of Molindone to a small 
dosage of L-Dopa/carbidopa is clearly shown to have a very strong 
potentiating effect. 
EXAMPLE 4 
To further test the efficacy of the two drug combination in higher mammals, 
an experiment was performed on Bonnet Macaque monkeys. For a period of 76 
days, the monkeys were fed a diet of bread and peanut butter. The groups 
which received the drug had it mashed in the peanut butter. The control 
group received plain peanut butter sandwiches. Four groups were 
established: 4 Obese Males, 4 Obese Females, 4 Lean Males/Females and 5 
Lean Male/Female controls. The results are summarized in the tabulation 
below: 
__________________________________________________________________________ 
Average Drug Intake 
Decarb- Weight (Lbs.) 
Weight 
No. L-Dopa 
oxylase 
Molindone 
Day 1 Day 76 
% Change 
__________________________________________________________________________ 
Obese 
4 628 126 94 29.81 26.89 
-9.8% 
Males 
Obese 
4 550 110 83 21.5 19.52 
-9.2% 
Females 
Lean 4 462 92 69 12.99 12.27 
-5.5% 
Males/ 
Females 
Lean 5 NO DRUG 17.9 17.56 
-1.9% 
controls 
Males/ 
Females 
__________________________________________________________________________ 
The results clearly demonstrate the efficacy of the two-drug combination on 
higher mammals. The median amount of ingested drug in the animals 
receiving the drug was about 550 mg. of Sinemet plus about 82.5 mg. of 
Molindone. This amount translated to human dosages is within the safe 
effective range. 
L-Dopa, Molindone compositions according to the present invention are 
generally administered orally, subcutaneously, intramuscularly, nasally, 
interperitoneally, intravenously, via any mucus membrane or by any other 
method commonly used to administer pharmaceutical compositions. 
While the whole invention has been described by specific examples, 
modifications obvious to one skilled in the art may be made without 
departing from the teaching of the instant invention which is limited only 
by the following claims.