Zonagen due diligence part 1. Using Medline I have found that workers at Zonagen have published two articles (both unrelated to phentolamine) and the abstracts are given below. There are hundreds of articles on the role of phentolamine on male erectile dysfunction (and yes there is female clitorial erectile dysfunction as well) and the abstracts of some of these are listed below and the first few are of review articles. Also given is the abstract of Pfizer's only article on their drug.
There are only two publications from Zonagen:
J Reprod Fertil Suppl 1996;50:35-41
The expression and localization of zona pellucida glycoproteins and mRNA
in cynomolgus monkeys (Macaca fascicularis).
Martinez ML, Fontenot GK, Harris JD
Zonagen, Inc., Woodlands, TX 77380, USA.
The zona pellucida (ZP) is an extracellular matrix composed of multiple
glycoproteins that surrounds all mammalian oocytes. Analysis of the
genes encoding the ZP proteins indicates that there are three classes
ZPA (largest), ZPB (intermediate) and ZPC (smallest). Polyclonal
antibodies developed against recombinant proteins of human and pig ZP
have been used to identify immunohistochemically the components of the
ZP of cynomolgus monkeys during the course of follicular development.
Digoxigenin-labelled cDNA probes specific for the mRNA encoding ZPA, ZPB
or ZPC were used to probe sections of cynomolgus monkey ovaries by in
situ hybridization. mRNA encoding ZPA was identified in growing
follicles at all stages and was seen in the granulosa cells of mature
preovulatory follicles. ZPB protein and mRNA encoding ZPB were present
in oocytes in secondary follicles and to a lesser extent in tertiary
follicles, but were not found in primordial, primary or antral follicles
or granulosa cells. ZPC protein and mRNA encoding ZPC were present in
oocytes at all stages of folliculogenesis. These results suggest that
each component of the ZP is produced and secreted at specific stages of
folliculogenesis and that granulosa cells may be contributing to the
synthesis of ZPA and ZPC.
DNA Seq 1994;4(6):361-393
Cloning and characterization of zona pellucida genes and cDNAs from a
variety of mammalian species: the ZPA, ZPB and ZPC gene families.
Harris JD, Hibler DW, Fontenot GK, Hsu KT, Yurewicz EC, Sacco AG
Zonagen, Inc., Woodlands, TX.
Full length zona pellucida cDNAs from cat, dog and pig that are
homologous to the ZP2/rc75 genes from mouse, human and rabbit, a full
length zona pellucida cDNA from cat and a gene and full length cDNA from
human that are homologous to the rc55/ZP3 alpha genes from rabbit and
pig, and full length zona pellucida cDNAs from cat, cow, dog, pig and
rabbit that are homologous to the ZP3 genes from mouse, hamster, human
and marmoset have been cloned and characterized. The members of these
gene families are herein referred to as ZPA, ZPB and ZPC genes to avoid
the confusion that currently exists in the zona pellucida of
nomenclature. This report is the first to describe the presence all
three major zona pellucida genes within individual mammalian species.
Within the ZPA, ZPB and ZPC gene families, the DNA and deduced amino
acid sequences are highly homologous to each other, and are most
homologous between members of the same order within the class mammalia.
These results imply that all or most mammalian species express the ZPA,
ZPB and ZPC proteins, which form the zona pellucida layer surrounding
the oocyte.
Phentolamine & erectile failure
J Urol 1996 Mar;155(3):802-815
The rationale for prostaglandin E1 in erectile failure: a survey of
worldwide experience.
Porst H
Urological Office, Hamburg, Germany.
PURPOSE: Prostaglandin E1 (PGE1, alprostadil) is used worldwide for
self-injection therapy in erectile failure and was recently officially
approved for this purpose in the United States and most European
countries. Therefore a comprehensive overview on biochemistry,
pharmacology and therapeutic results of PGE1 is provided. MATERIALS AND
METHODS: The relevant literature on PGE1 was reviewed along with
personal experience with 4,577 patients during a 7-year period. PGE1 was
compared to other vasoactive drugs, such as papaverine, the mixture of
papaverine and phentolamine or linsidomine alone. RESULTS: In Europe
PGE1 was officially approved for the therapy of peripheral arterial
occlusive disease of the lower limbs in 1984. The drug has direct
relaxing effects on smooth muscle cells of vessels and cavernous bodies,
shows inhibitory effects on platelet aggregation, on low-density
lipoprotein entry into the vascular wall and on presynaptic
noradrenaline release and, therefore, it prevents the progress of
atherosclerosis. In erectile failure PGE1 shows a response rate of more
than 70% and, compared to papaverine with phentolamine, a considerably
lower risk of priapism (0.35% versus 6%, respectively) as well as of
local fibrotic complications. Except for rare cases of blood pressure
decrease, no systemic side effects were observed after intracavernous
injection of PGE1. CONCLUSIONS: For self-injection therapy, PGE1
presently represents the most efficacious and safest drug. Ongoing
trials with topical and especially intraurethral PGE1 are promising and
may offer less invasive therapies in the near future.
J Urol 1997 Jun;157(6):2132-2134
Comparative study of papaverine plus phentolamine versus prostaglandin
E1 in erectile dysfunction.
Bechara A, Casabe A, Cheliz G, Romano S, Rey H, Fredotovich N
Urology Division, Hospital Durand, Buenos Aires, Argentina.
PURPOSE: We compared the efficacy and short-term adverse effects of 1
ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine versus 1 ml. 30
micrograms./ml. prostaglandin E1 in patients undergoing pharmacological
erection testing. MATERIALS AND METHODS: A total of 60 patients (mean
age 58 years) with a history of sexual erectile dysfunction longer than
6 months was randomly classified into 6 groups to be tested 1 week apart
with the 2 solutions and with placebo to evaluate erection response and
short-term adverse effects. RESULTS: Of the patients tested with
papaverine plus phentolamine 54% responded with erections adequate for
penetration, compared to 50% of those tested with prostaglandin E1 (p >
0.05). Prolonged erection occurred in 18% of patients tested with
papaverine plus phentolamine and 15% of those tested with prostaglandin
E1 (p > 0.05). Pain was reported by 15 and 35% of patients, respectively
(p < 0.05). CONCLUSIONS: One ml. 30 mg./ml. papaverine plus 0.5 mg./ml.
phentolamine has the same efficacy and equal prolonged erection rate as
1 ml. 30 micrograms./ml. prostaglandin E1 but the latter agent induces
significantly more pain.
J Urol 1996 Mar;155(3):913-914
Prostaglandin E1 versus mixture of prostaglandin E1, papaverine and
phentolamine in nonresponders to high papaverine plus phentolamine
doses.
Bechara A, Casabe A, Cheliz G, Romano S, Fredotovich N
Division Urologia, Hospital Durand, Buenos Aires, Argentina.
PURPOSE: We evaluated the efficacy of 40 micrograms/ml, prostaglandin E1
versus a combination of 17.64 mg./ml. papaverine hydrochloride, 0.58
mg./ml. phentolamine mesylate and 5.8 micrograms/ml. prostaglandin E1
(3-drug mixture). MATERIALS AND METHODS: A total of 32 patients randomly
received 1 ml. of either medication by the intracavernous route. All
patients had presented with erectile dysfunction longer than 6 months in
duration and had failed to respond to high doses of papaverine (60 mg.)
plus phentolamine (1 mg). RESULTS: Of 32 patients 7 (22%) responded to
prostaglandin E1 and 16 (50%) to the 3-drug mixture, achieving erections
allowing penetration (grade E4 or E5, p < 0.05). Pain was reported by
41% of the patients receiving prostaglandin E1 and 12.5% administered
the 3-drug mixture. CONCLUSIONS: The 3-drug mixture may be regarded as
more effective than prostaglandin E1 alone in inducing an erectile
response with a decreased incidence of pain.
Int J Impot Res 1996 Dec;8(4):233-236
A pilot study of the role of intracavernous injection of vasoactive
intestinal peptide (VIP) and phentolamine mesylate in the treatment of
erectile dysfunction.
McMahon CG
St Lukes Hospital Complex, Sydney, Australia.
Twenty men with chronic impotence with a mean age of 46 years (range
26-63 y) were treated with self administration of 0.35 ml of Vasopotin 1
and 2, a combination of 30 mg Vasoactive Intestinal Peptide (VIP) and
either 1.0 or 2.0 mg Phentolamine Mesylate. All patient were assessed
using a standard protocol which included history and examination,
vibratory penile biothesiometry, colour flow duplex Doppler
ultrasonography and where indicated, Rigiscan nocturnal penile
tumescence testing, dynamic infusion cavernosometry and cavernosography
(DICC) and angiography. Impotence was classified as psychogenic in six
patients, arteriogenic in nine patients, neurogenic in two patients and
cavernosal venous leakage in three patients. A total of 60 injections
was given. After sexual stimulation, an erection of sufficient rigidity
for intercourse occurred in six patients with psychogenic impotence,
seven of the nine patients with arteriogenic impotence, two patients
with neurogenic impotence and one of three patients with cavernosal
venous leakage. No patients experienced priapism, two patients
complained of postinjection penile pain and three patients experienced
transient facial flushing. Intracavernous self injection of Vasopotin
appears to be a useful treatment for erectile dysfunction.
Br J Urol 1996 Oct;78(4):628-631
Long-term follow-up of patients with erectile dysfunction commenced on
self injection with intracavernosal papaverine with or without
phentolamine.
Flynn RJ, Williams G
Department of Surgery, Hammersmith Hospital, Royal Postgraduate Medical
School, London, UK.
OBJECTIVES: To determine the usage, complications and satisfaction with
intracavernosal agents in patients with erectile dysfunction commenced
on self-injection treatment at home. PATIENTS AND METHODS: A total of
344 patients who had commenced intracavernosal treatment before December
1992 and had requested a repeat prescription were sent a questionnaire
to determine the usage, complications, satisfaction and reasons for
discontinuing treatment. RESULTS: Replies were received from 216
patients; of those who replied, only 126 were still using the treatment.
The mean duration of treatment was 3.9 years in those continuing
treatment. Whilst satisfaction ratings were high in those continuing
therapy, most patients had experienced some side-effects. CONCLUSION:
The long-term follow-up revealed a high attrition rate and a significant
number of complications. Patients receiving auto-injection therapy
should be offered regular long-term follow-up.
Pfizer's drug
Int J Impot Res 1996 Jun;8(2):47-52
Sildenafil: an orally active type 5 cyclic GMP-specific
phosphodiesterase inhibitor for the treatment of penile erectile
dysfunction.
Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM,
Osterloh IH, Gingell C
Pfizer Central Research, Sandwich, Kent, UK.
Sildenafil (Viagra, UK-92,480) is a novel oral agent under development
for the treatment of penile erectile dysfunction. Erection is dependent
on nitric oxide and its second messenger, cyclic guanosine monophosphate
(cGMP). However, the relative importance of phosphodiesterase (PDE)
isozymes is not clear. We have identified both cGMP- and cyclic
adenosine monophosphate-specific phosphodiesterases (PDEs) in human
corpora cavernosa in vitro. The main PDE activity in this tissue was due
to PDE5, with PDE2 and 3 also identified. Sildenafil is a selective
inhibitor of PDE5 with a mean IC50 of 0.0039 microM. In human
volunteers, we have shown sildenafil to have suitable pharmacokinetic
and pharmacodynamic properties (rapid absorption, relatively short
half-life, no significant effect on heart rate and blood pressure) for
an oral agent to be taken, as required, prior to sexual activity.
Moreover, in a clinical study of 12 patients with erectile dysfunction
without an established organic cause, we have shown sildenafil to
enhance the erectile response (duration and rigidity of erection) to
visual sexual stimulation, thus highlighting the important role of PDE5
in human penile erection. Sildenafil holds promise as a new effective
oral treatment for penile erectile dysfunction.
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