Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2002-06-26
2004-08-17
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S094500, C424S581000, C128S898000, C222S327000, C604S232000, C604S204000, C604S890100, C604S019000, C604S507000, C604S511000
Reexamination Certificate
active
06776991
ABSTRACT:
BACKGROUND
The present invention relates to methods treating priapism. In particular the present invention relates to methods for treating priapism with a neurotoxin.
Priapism
Priapism is a prolonged, persistent (usually for four hours or longer) and often painful penile erection which is not associated with a sexual stimulus. Typically, only the corpora cavernosa of the penis is affected, the corpora spongiosum of the glans penis remaining flaccid. Both low blood flow and high blood flow forms of priapism have been described. Priapism derives its name from Priapus, the son of Aphrodite the ancient Greek goddess of love. Priapus was the Greek god of fertility and is shown in statutes, mosaics and pottery from the period with enormous genitalia and an apparently perpetual erection.
The most common cause of priapism is as a side effect of certain pharmacologicals, such as neuroleptic (i.e. thorazine and chlorpromazine), and high-blood pressure (i.e. prazosin) drugs. Notably, about 42 percent of all sickle-cell adults and 64 percent of all sickle-cell children develop priapism. Priapism also has been observed in association with: use of intracavernosal injections of medications to treat impotence (i.e. papaverine, phentolamine, and prostaglandin E1); leukemia; multiple myeloma; Fabry disease; mycoplasma pneumonia; amyloidosis; carbon monoxide poisoning; malaria; spider bites; citalopram use (a selective serotonin reuptake inhibitor); hydralazine; metoclopramide; omeprazole; hydroxyzine; prazosin (especially when used in patients with renal failure); tamoxifen; testosterone; calcium channel blockers; anticoagulants (both warfarin-induced and during heparin infusions); cocaine; the drug ecstasy; ethanol abuse; androstenedione (for athletic related purposes); marijuana, and; certain cancers which infiltrate the penis and prevent the outflow of blood.
Childhood priapism is known to occur in association with leukemia (white blood cells occluding outflow of blood from the penis), sickle-cell disease, trauma to the penis or to the perineum, and spinal cord injury. Priapism of the clitoris (female priapism) has been rarely described. See e.g. Brodie-Meijer C. C. et al.,
Nefazodone
-
induced clitoral priapism
, Int Clin Psychopharmacol 1999 July;14(4):257-8.
Priapism can occur as a result of a disturbance to the normal regulatory mechanisms that initiate and maintain penile flaccidity. Thus, it is believed that activation of post ganglionic (cholinergic) parasympathetic autonomic nerves can induce erection of the penis, while sympathetic (adrenergic) innervation of the penis induces penile detumescence and terminate erection.
Thus, parasympathetic relaxation of penile smooth muscle (possibly mediated by nitric oxide induced drop in cytosolic calcium) causes an erection by permitting blood to flow into penile structures and increase penile cavernosal pressure. Contraction of sympathetic (adrenergic) innervated, penile smooth muscle results in detumescence (a flaccid penis) due to increased drainage from the penis via venous outflow channels, thereby decreasing intracavernosal pressure. Compton M. T. et al.,
Priapism associated with conventional and atypical medications: a review
, J Clin Psychiatry 2001;62:362-366; Rochat M. C.,
Priapism: a review
. Theriogenology 2001;56:713-722; Wagner G. et al.,
Pathophysiology and diagnosis of male erectile dysfunction
, BJU International (2001), 88 (Suppl. 3), 3-10; Lue T F. Erectile Dysfunction. New Engl J Med 2001;342:1802-1813.
Priapism with an onset within 4-6 hours can sometimes be treated successfully with a decongestant (i.e. pseudoephedrine or terbutaline) which acts to decrease blood flow to the penis. If the erection is non-responsive, aspiration can be used to remove about 50 to 150 cc of blood out of the penis through a small needle placed directly in the corporal body, thereby allowing detumesce.
If the erection reoccurs, certain vaso-active type drugs including epinephrine may be instilled into the penis, causing the blood vessels to constrict and prevent the priapism. If this is unsuccessful an alpha-adrenergic agonist (e.g. metaraminol bitartrate, phenylephrine, metaraminol) can be tried, Alpha agonists counteract penile smooth muscle relaxation which causes an erection. However, it is known that an alpha-agonist can cause significant systemic hypertension as well as ventricular tachycardia. Another treatment option is a shunting procedure to permit blood to drain from the engorged penis.
Unfortunately, current therapies for priapism, including drugs, aspiration and shunting, have significant drawbacks and disadvantages, including recurrence of the priapism; bleeding from the holes placed in the penis as a part of a shunt procedure; post-surgical infections including infection of the corporal body and infection of the skin around the corporal body; necrosis of the penis; damage to the urethra; holes between the urethra and the skin; loss of the penis, and death.
Loss of the penis can occur due to post surgical infection or because of penile necrosis due to the duration of the priapism before an effective treatment was initiated. Priapism has resulted in death from suicide as well as from a blood clot formed in the penis after a shunting procedure breaking off and causing pulmonary embolism.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. Clostridium botulinum and its spores are commonly found in soil and the bacterium can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and poison peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a botulinum toxin (purified neurotoxin complex) type A from the Hall strain of a Clostridium botulinum is a LD
50
in mice. Interestingly, on a molar basis, botulinum toxin type A is 1.8 billion times more lethal than diphtheria, 600 million times more lethal than sodium cyanide, 30 million times more lethal than cobrotoxin and 12 million times more lethal than cholera. Singh,
Critical Aspects of Bacterial Protein Toxins
, pages 63-84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1976) (where the stated LD
50
of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinum toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each.
In other words, one unit of botulinum toxin is the amount of botulinum toxin that kills 50% of a group of female Swiss Webster mice. Seven generally immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C
1
, D, E, F, and G, each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD
50
for botulinum toxin type A. The botulinum toxins apparently bind with high affinity to cholinergic motor neurons, are translocated into the neuro
Allergan Inc.
Donovan Stephen
Portner Ginny Allen
Smith Lynette R. F.
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